Next Article in Journal
Synthesis of Fluorescent, Dumbbell-Shaped Polyurethane Homo- and Heterodendrimers and Their Photophysical Properties
Next Article in Special Issue
Specific Mutations near the Amyloid Precursor Protein Cleavage Site Increase γ-Secretase Sensitivity and Modulate Amyloid-β Production
Previous Article in Journal
Odorant Receptor OR2C1 Is an Essential Modulator of Boar Sperm Capacitation by Binding with Heparin
Previous Article in Special Issue
Microglia and Alzheimer’s Disease
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Rationale for a Multi-Factorial Approach for the Reversal of Cognitive Decline in Alzheimer’s Disease and MCI: A Review

Apollo Health, Burlingame, CA 94011, USA
Department of Psychology, University of California, Davis, CA 95616, USA
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90024, USA
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(2), 1659;
Submission received: 30 November 2022 / Revised: 3 January 2023 / Accepted: 9 January 2023 / Published: 14 January 2023
(This article belongs to the Special Issue Frontier on Alzheimer's Disease)


Alzheimer’s disease (AD) is a multifactorial, progressive, neurodegenerative disease typically characterized by memory loss, personality changes, and a decline in overall cognitive function. Usually manifesting in individuals over the age of 60, this is the most prevalent type of dementia and remains the fifth leading cause of death among Americans aged 65 and older. While the development of effective treatment and prevention for AD is a major healthcare goal, unfortunately, therapeutic approaches to date have yet to find a treatment plan that produces long-term cognitive improvement. Drugs that may be able to slow down the progression rate of AD are being introduced to the market; however, there has been no previous solution for preventing or reversing the disease-associated cognitive decline. Recent studies have identified several factors that contribute to the progression and severity of the disease: diet, lifestyle, stress, sleep, nutrient deficiencies, mental health, socialization, and toxins. Thus, increasing evidence supports dietary and other lifestyle changes as potentially effective ways to prevent, slow, or reverse AD progression. Studies also have demonstrated that a personalized, multi-therapeutic approach is needed to improve metabolic abnormalities and AD-associated cognitive decline. These studies suggest the effects of abnormalities, such as insulin resistance, chronic inflammation, hypovitaminosis D, hormonal deficiencies, and hyperhomocysteinemia, in the AD process. Therefore a personalized, multi-therapeutic program based on an individual’s genetics and biochemistry may be preferable over a single-drug/mono-therapeutic approach. This article reviews these multi-therapeutic strategies that identify and attenuate all the risk factors specific to each affected individual. This article systematically reviews studies that have incorporated multiple strategies that target numerous factors simultaneously to reverse or treat cognitive decline. We included high-quality clinical trials and observational studies that focused on the cognitive effects of programs comprising lifestyle, physical, and mental activity, as well as nutritional aspects. Articles from PubMed Central, Scopus, and Google Scholar databases were collected, and abstracts were reviewed for relevance to the subject matter. Epidemiological, pathological, toxicological, genetic, and biochemical studies have all concluded that AD represents a complex network insufficiency. The research studies explored in this manuscript confirm the need for a multifactorial approach to target the various risk factors of AD. A single-drug approach may delay the progression of memory loss but, to date, has not prevented or reversed it. Diet, physical activity, sleep, stress, and environment all contribute to the progression of the disease, and, therefore, a multi-factorial optimization of network support and function offers a rational therapeutic strategy. Thus, a multi-therapeutic program that simultaneously targets multiple factors underlying the AD network may be more effective than a mono-therapeutic approach.

1. Introduction

Alzheimer’s disease (AD) was officially listed as the sixth-leading cause of death in the United States in 2019 and is the fifth leading cause of death among Americans aged 65 and older [1]. As it has impacted the lives of the elderly around the world, it is now more important than ever to develop an effective treatment not only to slow the progression of this disease but also to create a preventive approach [2,3,4,5,6].
The major genetic risk factor for AD is apolipoprotein E, epsilon 4 allele (ApoE4), and the inheritance of one or two copies of ApoE ε4 increases AD risk approximately 3- or 12-fold, respectively [7]. Based on recent findings, it appears that ApoE4 acts as a transcription factor and binds to the promoters of genes involved in a range of processes linked to AD disease pathogenesis. Interestingly, several of these genes have previously been linked to AD pathogenesis and include genes involved in inflammation, energy metabolism, cardiovascular disease, estrogen regulation, axon guidance, neuronal survival, and cell death [8,9,10,11]. The transcriptional role of ApoE4 needs further investigation since it influences brain health and homeostasis beyond the known β-amyloid or Tau pathways, thus pointing to novel therapeutic strategies for AD [8,12,13,14].
While the development of effective treatment and prevention is a major healthcare goal, unfortunately, therapeutic approaches to AD to date have not led to sustainable improvements. The best results from recent clinical trials have been to delay the progression of cognitive decline rather than improve cognition or halt the decline [15,16]. More than two hundred promising drug candidates have failed clinical trials in the past decade, suggesting that AD and its causes may be complex [15,16]. Some of the potential reasons for failure in effective drug development include the following: (1) AD starts out with a long pre-symptomatic period, but treatment is typically initiated late in the pathophysiological process [17]; (2) it appears that AD is not a single disease as it exhibits several different subtypes [18]; (3) there may be multiple potential contributors to AD, such as inflammation, toxins, infections, trophic withdrawal, insulin resistance, vascular compromise, and trauma [2,18,19,20]; (4) The model of AD on which the drug targets are based (e.g., amyloid-β peptide, tau) is incomplete owing to several potential contributors [15,16].
Based on recent evidence from a number of independent groups, it appears that AD is unique to each individual and, in different individuals, has different genetics, epigenetics, biochemistry, subtypes, and, thus, different responses to treatment. Several of the recent clinical trials and observational studies showed superior outcomes when a multitude of these potential contributors was taken into account and addressed simultaneously. Table 1 shows that, given the complex nature of AD pathophysiology, a “perfect” drug may be required to be highly multi-functional. Thus, identifying and addressing all potential contributors to cognitive decline with a personalized, multi-therapeutic approach may be a more effective disease-modifying strategy [5,18,21,22,23,24,25,26,27,28]. Shown in Figure 1 are the various strategies for the reversal of AD and optimization of brain health.
This article systematically reviews clinical trials and observational studies that have incorporated multiple strategies to target numerous factors simultaneously to reverse, prevent, or treat cognitive decline and dementia.

2. Multiple Strategies to Optimize Brain Health

2.1. Diet & Nutrition

A healthy dietary management strategy including dietary patterns, food, and dietary supplements may be a component of an effective protocol to prevent MCI or AD-associated cognitive impairment. Since gut microbiome and other gastrointestinal (GI) issues, metabolic syndromes, such as diabetes and obesity, gut inflammation, and oxidative stress have long been considered to play major roles in cognitive impairment and AD, not surprisingly, most of the research studies focusing on diet and dietary intervention trials have involved foods or dietary supplements that addressed the above issues [29,30,31,32]. There is sufficient evidence from epidemiological and observational studies and randomized controlled trials (RCTs) that suggest a neuroprotective role of the Mediterranean diet, the Dietary Approaches to Stop Hypertension (DASH) diet, the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, and the KetoFLEX 12/3 diet in reducing cognitive decline [2,19,32,33,34,35,36,37,38,39,40].
The Mediterranean, DASH, and MIND diets encompass a multi-nutrient dietary profile that includes fruits, vegetables, nuts, cereals, legumes, olive oil (as the main source of fat), moderate consumption of fish, and a low to moderate intake of dairy products, red meat, and meat products [40,41,42].
The DASH diet also emphasizes foods that are low in sodium and rich in potassium, calcium, and magnesium [43]. Higher adherence to these diets was associated with better cognitive function, lower rates of cognitive decline, and reduced risk of AD [44,45,46,47]. Furthermore, certain food groups included in these various diet options, such as fruits and vegetables, legumes, whole grains, nuts, and olive oil, are by themselves known to improve cognitive functioning [47,48,49,50,51,52]. Specific nutrients like unsaturated fatty acids, antioxidants, and dietary flavonoids have also been associated with better cognitive functioning and a lower risk of cognitive decline in the follow-up period [53,54,55,56].
The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) program, which was initially developed to improve heart and vascular health, relies on a diet that includes fish, fruits, vegetables, and oils. The intervention also includes physical exercise, cognitive training, social activities, and the management of vascular and metabolic risk factors. This multi-domain lifestyle intervention prevents or slows down cognitive decline. While the participants in the FINGER trial did not exhibit any cognitive issues, they had an increased risk for dementia based on vascular risk factors. While improvement was observed in both the intervention and the placebo groups, the improvement was much greater and better sustained in the intervention group in all cognitive tests administered, namely executive function, information processing, and complex memory tasks. The risk of cognitive decline was 30% higher for the control group compared to the intervention group [4,5,57].
The KetoFLEX 12/3 diet is a part of the ReCODE Program, and unlike other programs (FINGER, DASH, etc.), it is a precision medicine approach that utilizes seven foundational strategies, as well as targeted therapeutics for identified pathogens, toxins, deficiencies, and immune dysfunction, to optimize brain health [2,19]. KetoFLEX 12/3 is a plant-rich ketogenic diet that has proved to be an important component of an effective strategy for the reversal of cognitive decline associated with AD and MCI health [2,19,58]. It is a heavily plant-based, nutrient-dense, whole-food diet that emphasizes local, organic, and seasonal non-starchy vegetables from every color of the rainbow, combined with an adequate amount of protein and generous amounts of healthy fat. KetoFLEX 12/3 also incorporates a long daily fast—a minimum of 12 h, with at least 3 h of fasting before bedtime. This approach utilizes multiple mechanisms to support the brain to prevent and reverse cognitive decline, such as increased energy (via ketosis), insulin sensitivity, reduced inflammation, improved vascular health, and detoxification [2,19,59].
Patients with cognitive impairment and the onset of AD who enrolled in the ReCODE program showed significant improvement in cognitive functioning with outcome measures such as Montreal Cognitive Assessment (MoCA), AQ-21 (a subjective scale completed by the significant other or study partner), and AQ-C change scale (a subjective scale of cognitive improvement or decline completed by the significant other or study partner) [2]. Furthermore, participants in the ReCODE program experienced improved metabolic parameters and cognition, resulting in either arrested cognitive decline or, in most cases, improved cognitive performance [2,19].

2.2. Physical Exercise

Physical exercise (PE) has been proven to help prevent and remediate cognitive decline [60,61,62]. Research studies have shown that a consistent practice of physical activity is associated with a lower risk of cardiovascular disease and physically active individuals are less likely to develop dementia [60,63,64]. Research at the cellular and molecular levels coupled with in silico studies suggested that physical exercise impacts brain health by regulating and enhancing genes, proteins, and other neurotrophic factors that directly affect memory, mood, assimilation, and growth [65,66,67,68,69,70]. Specifically for brain health, three types of exercise are recommended:
Aerobic exercise increases heart rate and oxygen uptake, thereby improving cardiovascular health, which in turn benefits the brain. Studies have shown that aerobic exercise improves blood flow to the brain and stimulates the release of brain-derived neurotrophic factor (BDNF), which promotes neuroplasticity, thereby preserving brain volume. Moderate to vigorous aerobic exercise also activates the glymphatic system that promotes the clearance of β-amyloid and other toxins.
Strength training physical exercises improve muscle strength, muscle mass, and endurance, thereby preventing sarcopenia. Furthermore, strength training exercise improves higher-level cognitive processes and memory, stabilizes brain volume, and decreases white matter lesions.
Mind-body exercise combined with body movement improves balance, coordination, gait, and agility; improves neuronal, synaptic, and vascular systems of the brain; promotes the connectivity of brain regions, thereby improving executive function, memory, and emotional status; and curbs neuronal inflammation, all of which improve brain health [26,27,37,61,62,71,72,73,74,75,76,77,78,79,80,81,82,83].
A multifactorial intervention involving diet, PE, and other lifestyle changes may be more effective for ameliorating cognitive decline and may have a sustained beneficial effect that is more pronounced than a single intervention [21,84,85]. While adherence to a Mediterranean-type diet and higher physical activity was associated with reduced risk for dementia, the FINGER trial and the ReCODE program clearly demonstrated that physical exercise in combination with other interventions, including vascular risk management, diet, and cognitive training, was associated with improved cognitive performance. Among the best improvements were those seen in cognitive functions, cognitive impairment, overall health, and mood status [2,4,19,84].

2.3. Sleep

The core functions of sleep are to repair, reorganize, maintain brain health, and clear waste [86,87,88]. Sleep facilitates memory consolidation and new learning while also laying down new memories as long-term memories [89,90]. Often sleep disturbances will appear in the preclinical phase of AD. Cognitive decline and an increased risk of mild cognitive impairment and dementia are associated with poor sleep quality [91]. Older adults with disturbed sleep experience a faster decline in cognition than those who sleep well. It is now known that people with AD often have sleep difficulties, and the lack of sleep may, in turn, influence Alzheimer’s-related brain changes that can begin several years before memory loss and other AD symptoms appear. Poor sleep or sleep deprivation triggers β-amyloid build-up in brain regions that include the thalamus and hippocampus, which are vulnerable to damage in the early stages of AD. Study participants with elevated levels of β-amyloid reported mood disturbances after sleep deprivation [92,93,94]. Researchers have suggested that a wide variety of cognitive functions, ranging from attention and memory to language and reasoning, are affected by the lack of adequate sleep [95,96,97].
AD may be accompanied by other co-morbid medical conditions or behavioral disorders which can contribute to sleep issues. Conditions including but not limited to restless legs syndrome and mental health disorders, including anxiety and depression, are all associated with sleep difficulties. Certain medications, such as decongestants, steroids, and some medicine for high blood pressure, asthma, and depression, can also trigger sleep disruptions [86,98,99,100,101,102]. Nearly 15% of AD cases may be attributed to sleep problems that can also be due to the long-term use of benzodiazepines [91,103,104]. Further evaluation of the neurophysiological and cellular mechanisms by which poor sleep contributes to AD may help in identifying new molecular targets for intervention [105,106,107,108].
Melatonin is a sleep-influencing, circadian-rhythm-dependent neuroendocrine hormone that has a protective role in the development of AD because of its anti-inflammatory and antioxidative effects [109,110,111]. Studies have shown that healthy subjects have higher levels of melatonin compared to AD patients [112,113,114]. Melatonin acts as an anti-oxidant by blocking free radical production, reduces Aβ- and NFκB-induced inflammation and, thus, serves as an attractive therapeutic candidate for AD [115,116,117,118,119,120]. Thus, combined with a proper diet, PE, and other lifestyle changes, sleep intervention may be more effective in ameliorating cognitive decline and may have a sustained beneficial effect that is more pronounced than a single intervention [2,19].

2.4. Mind and Mental Exercise

Several research studies have now clearly shown the remarkable ability of the brain to reorganize and network in response to various sensory experiences. This neuroplasticity involves adaptive structural and functional changes to the brain [121]. Both healthy and diseased brains have the ability to change their activity in response to intrinsic or extrinsic stimuli by reorganizing their structure, functions, or connections following mental stimulation, brain training, or even traumatic injuries [122,123,124]. AD is characterized by altered hippocampal synaptic efficacy leading to synaptic dysfunction, neuronal degeneration, and cognitive impairment [125,126]. During the pre-AD phase, individuals usually present with mild cognitive impairment [127,128,129]. In the mild to moderate stages of AD, cognitive impairment becomes more profound and widespread, and functional disability becomes increasingly evident—particularly in relation to more complex activities [130,131,132]. In the more advanced stages of AD, most cognitive and functional abilities are profoundly impaired [133].
One of the most important sensory activities is the sense of sound, which has the power to stimulate the brain, which is why hearing loss has a profound impact on brain health. Recent studies suggest that hearing loss causes brain changes that raise the risk for AD. Individuals with moderate to severe hearing loss are up to five times as likely to develop AD-associated dementia, though more research is needed to determine the exact connection between sound, hearing loss, and AD [134,135,136].
AD also features emotional disturbances, including depression, anxiety, irritability, and apathy, that are commonly observed during the mild–moderate stage of AD. Mood disorders in AD patients are also associated with structural changes in the hippocampus, entorhinal cortex, and other regions of the temporal lobe. Researchers believe that mood disorders trigger inflammation and disturb the normal balance of neurotransmission, leading to microglial activation and neurofibrillary tangle formation, which result in neuronal loss, suggesting the need for mental stability and mood stabilizing strategies [137,138,139,140].
Results from several observational studies and randomized clinical trials have indicated that people who engage in cognitively stimulating activities may show improvement in moods, thinking, hearing, problem-solving, reasoning, and memory and have a lower risk of cognitive decline and dementia. Improvement was also seen in activities of daily living (ADLs) [122,141,142,143,144,145].
The ReCODE program clearly demonstrated that cognitive training, together with the other interventions, was associated with improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and AQ-C. The cognitive improvements were sustained, and no serious adverse events were recorded [2,19].

2.5. Stress Management

Research studies have shown that stress is one of the key factors involved in the development of AD [146,147]. In animal models of AD, stress, in large part, activates the hypothalamic-pituitary-adrenal (HPA) axis, which in turn elevates circulating corticosteroid levels [147,148,149,150,151]. The dysregulation of the HPA axis and elevated levels of cortisol are commonly seen in people with AD [148,151,152,153,154]. Stress disrupts the balance between the cortisol receptors (glucocorticoid and mineralocorticoid) that are present in the hippocampal area, leading to atrophy and the degeneration of the hippocampus [155,156,157,158,159]. Stress affects other biological pathways as well, including the brain’s immune system, by producing pro-inflammatory cytokines, thereby promoting inflammation, which underlies AD pathogenesis [160,161,162]. These findings suggest that stress management is critical to maintaining optimal cognitive health.
Stress management techniques for people with AD that are effective in improving the subjective well-being state include breathing exercises, mindfulness techniques, meditation, yoga, tai chi, spiritual practice, socialization, and other activities that focus on the present moment rather than allow distractions of continuous thoughts and mental turbulence [83,163,164,165,166,167,168,169,170,171,172,173].
Other interventions to mitigate lifestyle stressors are dance and music. These interventions have proven to be useful in improving verbal fluency and language ability in patients with AD, specifically those with MCI. There is growing evidence that music and dance reduce stress, increase cognitive acuity, promote a sense of well-being, and improve health span [174,175,176,177]. Dance movements involve a lot of physical activity. Furthermore, dance steps, arm patterns, formations, speed, and various rhythmic movements keep the subjects in a constant mental learning process [178,179,180]. The most challenging aspect of dance training required the subjects to recall the dance steps and routines in a timely manner [181]. While all forms of dance reduce stress, improve cardiovascular health, and stimulate social connectivity, some dance forms that involve split-second changes in steps and complicated moves have an advantage over others when it comes to boosting cognitive acuity [178,179,180,182,183]. Dancing involves continuous learning, which improves the kinesthetic, rational, musical, and emotional aspects of the brain, and ultimately promotes neural connectivity [184,185].
Additionally, music therapy (playing or listening) and art (drawing, painting, and sculpture) improve the quality of life and cognitive and emotional functions. Furthermore, these interventions have also improved stress, mood, well-being, sleep, and the quality of life in adults with subjective cognitive impairment (SCI), MCI, or AD. Significant improvements in anxiety and depression were also observed, and in all these cases, the physical and cognitive benefits were sustained [173,186,187,188,189,190,191,192].
The ReCODE program also reiterates the importance of stress management, which emphasizes regular deep breathing exercises and regular brain training [2,19].

2.6. Toxicity and Detoxification

Toxins are increasingly recognized to raise the risk of developing AD [193,194,195,196,197]. Specific toxins that can lead to dementia are called dementogens and include metals, organic chemicals, and biotoxins [198,199,200,201,202]. Research studies show that most people have varying levels of these toxins within their bodies, which can have a deleterious impact on brain structure and function [197,203,204,205].

2.6.1. Metal Toxicity

Mercury, aluminum, arsenic, lead, and cadmium are associated with numerous health issues, even at low levels of exposure. Although manganese, iron, zinc, and copper are essential metals, toxic levels can be harmful. The neurotoxicity of these metals and their roles in AD pathology have been documented in cell and animal models. Human epidemiologic studies have shown a close relationship between elevated levels of these metals and impaired cognitive function and cognitive decline [193,194,206,207].

2.6.2. Chemical Toxicity

In addition to metal toxicity, chemical toxicity that is a risk for developing AD arises from exposure to inorganic and organic hazards, which include pesticides (e.g., organochlorine and organophosphate insecticides), industrial chemicals (e.g., flame retardants), and air pollutants (e.g., particulate matter). Long-term exposure and the bioaccumulation of these environmental chemicals trigger neuroinflammation and neuropathology, paving the way for developing AD [208,209]. Chronic exposure to chemical toxins triggers the reduction in volumes of the hippocampus and total gray matter. Brain imaging studies have also found that the areas of the brain most vulnerable to the toxic effects of chemicals and other environmental toxins are the pre- and post-central gyri, temporal transverse gyrus, and the calcarine regions. While epidemiologic associations between environmental chemical exposure and AD are still limited, the risk of developing AD in older adults due to neurologic impairments caused by environmental toxins is well established [199,210,211,212,213].
Studies in cell and animal models have revealed alterations in neural pathways and metabolism associated with AD. Neuro-imaging studies have reported associations between exposure to toxic chemicals and white matter volume reduction [213,214,215]. Other reported effects include reduced gray matter, larger ventricular volume, and smaller corpus callosum. In addition, studies have also reported associations between a range of chemical pollutants and effects on cognitive function in older people, including the acceleration of cognitive decline and the induction of dementia [216,217,218,219,220,221].

2.6.3. Infections and Biotoxins

Recent studies have provided overwhelming evidence about the possibility of an infectious etiology for AD. The infiltration of the brain by pathogens, including but not limited to B. fragilis, HSV-type 1, Chlamydia pneumoniae, and P. gingivalis, is most frequently implicated in AD pathogenesis [204,222,223,224,225,226,227]. These pathogens may directly cross a weakened blood–brain barrier and trigger neurological damage by eliciting neuroinflammation. Alternatively, increased gut permeability induced by gut microbiota may promote AD. Inflammatory microorganisms in gut microbiota are associated with peripheral inflammation in subjects with cognitive impairment [222,225,226,228,229,230]. Chlamydia pneumoniae can infect the central nervous system via the olfactory and trigeminal nerves resulting in the dysregulation of key pathways involved in AD pathogenesis. Similarly, bacteria can travel from infections in the mouth through the bloodstream to the brain, and this is one mechanism influencing the cascade of events that leads to dementia. Older adults with signs of gum disease and mouth infections were more likely to develop antibodies against the oral bacterium P. gingivalis, which could cluster with other bacteria, such as C. rectus and P. melaninogenica, to further increase the risk of developing AD [205,224,231,232,233].
Similarly, viruses including Herpes simplex 1 (HSV-1) and Varicella zoster virus (VZV) activate the NF-kB-pro-inflammatory signaling system and have been associated with an increased risk of AD. This suggests that AD can be mitigated using appropriate antivirals for treatment or just possibly for prevention [234,235]. Given the pro-inflammatory nature of the type 4 allele of the apolipoprotein E gene (APOE-ε4), this population may especially benefit from an antiviral regimen [223,227,236,237,238,239,240].
Additionally, while mold exposure has historically been connected with asthma and lung disease, mold-exposed people have reported impaired memory and concentration [197,241,242,243]. Mold toxins, including trichothecenes from Stachybotrys, aflatoxin from Aspergillus, and ochratoxin A from Aspergillus and Penicillium, are risk factors for the progression of AD because of their neurotoxic effects and ability to impair cognitive functioning [197,230,241,242,243,244]. Researchers are beginning to outline the specific inflammatory pathways by which mold affects the brain, particularly in relation to type 3 (toxic) AD [197]. Mold spores trigger the body to mount an immune response, and people who develop chronic inflammation (including brain inflammation) following mold exposure are most likely to experience cognitive decline [197,230,241,245].
Thus, preventing and treating dementogen exposure and limiting ongoing exposure are paramount to optimizing brain health. Detoxification needs to be an integral part of any personalized, multi-therapeutic program to address overall health optimization and improve cognition [2,19,197].

2.7. Supplements & Neuroprotective Herbs

Neuroprotective herbs and supplements have great potential as part of an overall program for preventing and treating cognitive decline associated with MCI and AD. Numerous medicinal plants and their constituents are recommended to enhance cognitive function and alleviate other symptoms of AD, including poor cognition, memory loss, and depression [246,247]. A single herb or a mixture of herbs is normally recommended, depending on the severity of the condition. The rationale is that the bioactive principles present in the medicinal plant act synergistically and modulate the activity of other constituents from the same plant or other plant species [248,249]. Numerous plants and their constituents are reputed in traditional practices of medicine to enhance cognitive function [246,247,250,251]. This approach has been used in Ayurveda, traditional Chinese medicine (TCM), and the Native American system of medicine, where a single herb or a combination of two or more herbs is commonly prescribed [249,252,253,254,255].
Various herbs that inhibit acetylcholinesterase activity, improve cholinergic function, possess anti-inflammatory and antioxidant activities, contain natural COX-2 inhibitors, protect against brain cell degeneration, help in the reduction of amyloid, improve focus and alertness, improve the levels of NGF, stimulate neuronal branching, aid in detoxification, and boost the immune system are recommended for the prevention or treatment of AD [246,248,249,256,257].
Supplements are also a very important contributor to healing for those suffering from specific deficiencies that affect cognitive health. Long-term supplementation with anti-oxidant vitamins and mineral supplements is the most promising area for future research. Supplements including but not limited to ß-carotene, vitamin B12, folate (vitamin B9), vitamin B6, vitamin C, vitamin E, selenium, zinc, omega 3-fatty acids, glutathione, coenzyme Q10, alpha lipoic acid, choline, phosphatidylserine, and acetyl-L-carnitine may (a) improve short term memory in aging patients who have difficulty with recall, (b) improve the memory of patients with SCI or MCI, (c) help reverse some of the degenerative changes in brain function, and (d) prevent age-related mental decline and slow the progression of AD [258,259,260,261,262,263,264,265,266,267,268,269,270].
Thus, as one part of a comprehensive protocol, high-quality herbs and supplements tailored to the specific, evolving needs of each individual with SCI, MCI, or AD have proven to be important in treating or reversing AD [2,18,19,22].

3. Conclusions

Alzheimer’s disease is now the fifth leading cause of death for adults aged 65 and older and the most common cause of dementia among older adults [1]. Research studies have indicated one of the major risk factors for late-onset AD is gender, with postmenopausal women contributing to over 60% of all those affected. Based on the fact that women comprise approximately two-thirds of all AD patients, researchers have put forward the “estrogen hypothesis,” which explains how 17β-estradiol exerts a neuroprotective effect by protecting the female’s brain from AD development. This hypothesis is supported by recent findings showing estradiol’s role in signaling and transcriptional pathways involving cognition and memory. While more work is needed to understand the mechanism of estradiol’s neuroprotective action in AD, recent data lend support to the use of hormone replacement therapy (HRT) as a successful intervention for women at risk for AD [271,272,273,274].
Furthermore, ethnicity also has a role in AD, with African Americans and Hispanics at greater risk than whites to have AD. While African Americans are about two times more likely than whites to have AD, Hispanics are about one and one-half times more likely than whites to have AD and other dementias. While more studies are needed to understand the mechanisms responsible for these differences, better management of these risk factors may help reduce the risk of AD among women, African Americans, and Hispanics [275,276,277].
While the development of effective AD treatment and prevention is a major healthcare goal for all people at risk for AD, thus far, billions have been spent on research and clinical trials, and there is still no mono-therapeutic drug(s) to delay or reverse AD [15,16,278]. The recently approved FDA drugs have failed to show any significant slowing down of the actual symptoms of AD [279]. The drugs for Alzheimer’s that have failed are based on the concept that removing the amyloid would ameliorate AD symptoms. The various amyloid-removing drugs may have reduced the amyloid levels but failed to improve cognition. There may be several reasons for such repeated failure: (1) Treatment for AD is typically initiated late in the pathophysiological process; (2) Alzheimer’s disease is not a single disease but rather exhibits several different subtypes; and (3) AD is a complex chronic condition, and there are several potential contributors to AD, such as inflammation, various chronic pathogens, trophic withdrawal, insulin resistance, vascular defects, trauma, and exposure to specific toxins [2,15,16,18,19,22].
Table 1 illustrates the criteria for a perfect treatment for AD and suggests that a mono-therapeutic approach is likely to be suboptimal; instead, a personalized, multifactorial program based on each individual’s genetics and biochemistry may be preferable, as shown in Figure 1 and Table 2 [2,18,19,22]. Research studies from several independent groups have now revealed an extensive network of molecular interactions involved in AD pathogenesis, suggesting that a network-based therapeutic approach that addresses all the potential contributors to cognitive decline simultaneously, rather than a single target-based approach, may be more effective for the treatment of dementia or MCI due to AD [2,19,23,280,281].
In all these cases, the root cause(s) of the degenerative process is/are being targeted. Thus the AD pathogenesis itself is impacted, resulting in a sustained improvement that represents a major advantage over mono-therapeutics [5,18,21,22,23,24,25,26,27].
The management strategies to treat/reverse cognitive decline include but are not limited to diet, physical exercise, sleep, stress management, brain exercise, detoxification, herbs, and supplements, as shown in Table 1 and Table 2 and Figure 1. A balanced dietary approach utilizes multiple mechanisms to support the brain optimally to prevent and reverse cognitive decline by mechanisms such as increased energy, insulin sensitivity, reduced inflammation, improved vascular health, and detoxification [2,19,32,33,34,35,36,37,38,39,40]. Physical exercise is one of the best ways to reverse cognitive decline. It improves oxygenation, insulin sensitivity, and sleep; reduces overall stress; optimizes BMI (body mass index); and improves overall brain and body physiology [60,63,64]. Obstructive sleep apnea and other causes of poor oxygenation are risk factors for poor cognitive health. Sleep is vital for memory consolidation and promotes metabolic health, reduces inflammation, and upregulates the immune system [95,96,97]. In addition, people who engage in cognitively stimulating activities have a lower risk of cognitive decline and dementia. Mental stimulating tasks improve thinking, problem-solving, reasoning, and memory. Improvement is also seen in activities of daily living [122,142,144]. Stress, especially chronic, unresolved, or severe stress, is another key contributor to AD [160,161,162]. Stress management practices are required to reverse stress-associated cognitive decline [83,164,169,170,171,172]. The detoxification of toxins and avoiding exposure to bacteria, viruses, or mold, which are turning out to be major contributors to cognitive decline, especially in genetically susceptible individuals, is a vital part of optimizing brain health [193,194,195,196,197]. Herbs and supplements are needed to address any specific nutritional deficiency that affects cognitive health and, thus, can be a very important contributor to reversing cognitive decline [248,249].
Thus, results to date suggest that to successfully treat SCI, MCI, or AD, a mono-therapeutic drug strategy may not be optimal; instead, the most pragmatic approach involves addressing the above-mentioned targets underlying AD pathophysiology simultaneously. In other words, a network-based, multi-therapeutic approach may be feasible and potentially more effective (Table 2). While each of these strategies has been shown to reverse cognitive decline and promote neuroplasticity, when practiced together, their combined effect may be additive or even synergistic, and the benefits may be sustained, leading to overall health optimization and improved cognition.

Author Contributions

Conceptualization, D.E.B. and R.V.R.; Methodology, K.G.S., D.E.B. and R.V.R.; Data curation, K.G.S., D.E.B. and R.V.R.; original draft preparation and writing, K.G.S., J.G., A.L.B., and R.V.R.; reviewing and editing, J.G., A.L.B., C.C., S.O., L.K., D.E.B. and R.V.R. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

Not Applicable.

Informed Consent Statement

Not Applicable.

Data Availability Statement

Not Applicable.


The authors thank Laura Lazzarini for assistance with manuscript preparation and editing and all the health coaches for providing support to the individuals that enroll in the ReCODE program.

Conflicts of Interest

This manuscript is not under consideration by another journal, nor has it been published. None of the authors have any competing financial interest.


  1. 2022 Alzheimer’s disease facts and figures. Alzheimers Dement 2022, 18, 700–789. [CrossRef] [PubMed]
  2. Toups, K.; Hathaway, A.; Gordon, D.; Chung, H.; Raji, C.; Boyd, A.; Hill, B.D.; Hausman-Cohen, S.; Attarha, M.; Chwa, W.J.; et al. Precision Medicine Approach to Alzheimer’s Disease: Successful Pilot Project. J. Alzheimers Dis. 2022, 88, 1411–1421. [Google Scholar] [CrossRef] [PubMed]
  3. James, B.D.; Leurgans, S.E.; Hebert, L.E.; Scherr, P.A.; Yaffe, K.; Bennett, D.A. Contribution of Alzheimer disease to mortality in the United States. Neurology 2014, 82, 1045–1050. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Ngandu, T.; Lehtisalo, J.; Solomon, A.; Levalahti, E.; Ahtiluoto, S.; Antikainen, R.; Backman, L.; Hanninen, T.; Jula, A.; Laatikainen, T.; et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): A randomised controlled trial. Lancet 2015, 385, 2255–2263. [Google Scholar] [CrossRef] [PubMed]
  5. Kivipelto, M.; Solomon, A.; Ahtiluoto, S.; Ngandu, T.; Lehtisalo, J.; Antikainen, R.; Backman, L.; Hanninen, T.; Jula, A.; Laatikainen, T.; et al. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER): Study design and progress. Alzheimers Dement 2013, 9, 657–665. [Google Scholar] [CrossRef] [PubMed]
  6. Isaacson, R.S.; Hristov, H.; Saif, N.; Hackett, K.; Hendrix, S.; Melendez, J.; Safdieh, J.; Fink, M.; Thambisetty, M.; Sadek, G.; et al. Individualized clinical management of patients at risk for Alzheimer’s dementia. Alzheimers Dement 2019, 15, 1588–1602. [Google Scholar] [CrossRef]
  7. Raulin, A.C.; Doss, S.V.; Trottier, Z.A.; Ikezu, T.C.; Bu, G.; Liu, C.C. ApoE in Alzheimer’s disease: Pathophysiology and therapeutic strategies. Mol. Neurodegener. 2022, 17, 72. [Google Scholar] [CrossRef]
  8. Theendakara, V.; Peters-Libeu, C.A.; Spilman, P.; Poksay, K.S.; Bredesen, D.E.; Rao, R.V. Direct Transcriptional Effects of Apolipoprotein E. J. Neurosci. 2016, 36, 685–700. [Google Scholar] [CrossRef] [Green Version]
  9. Diaz, J.R.; Marta-Ariza, M.; Khodadadi-Jamayran, A.; Heguy, A.; Tsirigos, A.; Pankiewicz, J.E.; Sullivan, P.M.; Sadowski, M.J. Apolipoprotein E4 Effects a Distinct Transcriptomic Profile and Dendritic Arbor Characteristics in Hippocampal Neurons Cultured in vitro. Front. Aging Neurosci. 2022, 14, 845291. [Google Scholar] [CrossRef]
  10. Huang, Y.A.; Zhou, B.; Nabet, A.M.; Wernig, M.; Sudhof, T.C. Differential Signaling Mediated by ApoE2, ApoE3, and ApoE4 in Human Neurons Parallels Alzheimer’s Disease Risk. J. Neurosci. 2019, 39, 7408–7427. [Google Scholar] [CrossRef]
  11. Blanchard, J.W.; Akay, L.A.; Davila-Velderrain, J.; von Maydell, D.; Mathys, H.; Davidson, S.M.; Effenberger, A.; Chen, C.Y.; Maner-Smith, K.; Hajjar, I.; et al. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature 2022, 611, 769–779. [Google Scholar] [CrossRef] [PubMed]
  12. Theendakara, V.; Peters-Libeu, C.A.; Bredesen, D.E.; Rao, R.V. Transcriptional Effects of ApoE4: Relevance to Alzheimer’s Disease. Mol. Neurobiol. 2018, 55, 5243–5254. [Google Scholar] [CrossRef] [PubMed]
  13. Levros, L.C., Jr.; Labrie, M.; Charfi, C.; Rassart, E. Binding and repressive activities of apolipoprotein E3 and E4 isoforms on the human ApoD promoter. Mol. Neurobiol. 2013, 48, 669–680. [Google Scholar] [CrossRef]
  14. Urfer-Buchwalder, A.; Urfer, R. Identification of a Nuclear Respiratory Factor 1 Recognition Motif in the Apolipoprotein E Variant APOE4 linked to Alzheimer’s Disease. Sci. Rep. 2017, 7, 40668. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Yiannopoulou, K.G.; Anastasiou, A.I.; Zachariou, V.; Pelidou, S.H. Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research. Biomedicines 2019, 7, 97. [Google Scholar] [CrossRef] [Green Version]
  16. Mehta, D.; Jackson, R.; Paul, G.; Shi, J.; Sabbagh, M. Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010–2015. Expert Opin. Investig. Drugs 2017, 26, 735–739. [Google Scholar] [CrossRef]
  17. Dubois, B.; Hampel, H.; Feldman, H.H.; Scheltens, P.; Aisen, P.; Andrieu, S.; Bakardjian, H.; Benali, H.; Bertram, L.; Blennow, K.; et al. Proceedings of the Meeting of the International Working, G.; the American Alzheimer’s Association on “The Preclinical State of, A.D.; July; Washington Dc, U.S.A. Preclinical Alzheimer’s disease: Definition, natural history, and diagnostic criteria. Alzheimers Dement 2016, 12, 292–323. [Google Scholar] [CrossRef]
  18. Bredesen, D.E.; Amos, E.C.; Canick, J.; Ackerley, M.; Raji, C.; Fiala, M.; Ahdidan, J. Reversal of cognitive decline in Alzheimer’s disease. Aging 2016, 8, 1250–1258. [Google Scholar] [CrossRef] [Green Version]
  19. Rao, R.V.; Kumar, S.; Gregory, J.; Coward, C.; Okada, S.; Lipa, W.; Kelly, L.; Bredesen, D.E. ReCODE: A Personalized, Targeted, Multi-Factorial Therapeutic Program for Reversal of Cognitive Decline. Biomedicines 2021, 9, 1348. [Google Scholar] [CrossRef]
  20. Seto, M.; Weiner, R.L.; Dumitrescu, L.; Hohman, T.J. Protective genes and pathways in Alzheimer’s disease: Moving towards precision interventions. Mol. Neurodegener. 2021, 16, 29. [Google Scholar] [CrossRef]
  21. Schneider, N.; Yvon, C. A review of multidomain interventions to support healthy cognitive ageing. J. Nutr. Health Aging 2013, 17, 252–257. [Google Scholar] [CrossRef] [PubMed]
  22. Bredesen, D.E.; Sharlin, K.; Jenkins, D.; Okuno, M.; Youngberg, W.; Cohen, S.H.; Stefani, A.; Brown, R.L.; Conger, S.; Tanio, C.; et al. Reversal of Cognitive Decline: 100 Patients. J. Alzheimer’s Dis. Park. 2018, 8, 450. [Google Scholar] [CrossRef]
  23. Schechter, G.; Azad, G.K.; Rao, R.; McKeany, A.; Matulaitis, M.; Kalos, D.M.; Kennedy, B.K. A Comprehensive, Multi-Modal Strategy to Mitigate Alzheimer’s Disease Risk Factors Improves Aspects of Metabolism and Offsets Cognitive Decline in Individuals with Cognitive Impairment. J. Alzheimer’s Dis. Rep. 2020, 4, 223–230. [Google Scholar] [CrossRef] [PubMed]
  24. Lista, S.; Dubois, B.; Hampel, H. Paths to Alzheimer’s disease prevention: From modifiable risk factors to biomarker enrichment strategies. J. Nutr. Health Aging 2015, 19, 154–163. [Google Scholar] [CrossRef]
  25. Ross, M.K.; Raji, C.; Lokken, K.L.; Bredesen, D.E.; Roach, J.C.; Funk, C.C.; Price, N.; Rappaport, N.; Hood, L.; Heath, J.R. Case Study: A Precision Medicine Approach to Multifactorial Dementia and Alzheimer’s Disease. J. Alzheimer’s Dis. Parkinsonism 2021, 11 (Suppl. 5), 18. [Google Scholar]
  26. Fotuhi, M.; Lubinski, B.; Trullinger, M.; Hausterman, N.; Riloff, T.; Hadadi, M.; Raji, C.A. A Personalized 12-week “Brain Fitness Program” for Improving Cognitive Function and Increasing the Volume of Hippocampus in Elderly with Mild Cognitive Impairment. J. Prev. Alzheimer’s Dis. 2016, 3, 133–137. [Google Scholar] [CrossRef]
  27. Nguyen, S.A.; Oughli, H.A.; Lavretsky, H. Complementary and Integrative Medicine for Neurocognitive Disorders and Caregiver Health. Curr. Psychiatry Rep. 2022, 24, 469–480. [Google Scholar] [CrossRef]
  28. Roach, J.C.; Hara, J.; Fridman, D.; Lovejoy, J.C.; Jade, K.; Heim, L.; Romansik, R.; Swietlikowski, A.; Phillips, S.; Rapozo, M.K.; et al. The Coaching for Cognition in Alzheimer’s (COCOA) trial: Study design. Alzheimer’s Dement. 2022, 8, e12318. [Google Scholar] [CrossRef]
  29. Talbot, K.; Wang, H.Y.; Kazi, H.; Han, L.Y.; Bakshi, K.P.; Stucky, A.; Fuino, R.L.; Kawaguchi, K.R.; Samoyedny, A.J.; Wilson, R.S.; et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J. Clin. Investig. 2012, 122, 1316–1338. [Google Scholar] [CrossRef] [Green Version]
  30. Darweesh, S.K.L.; Wolters, F.J.; Ikram, M.A.; de Wolf, F.; Bos, D.; Hofman, A. Inflammatory markers and the risk of dementia and Alzheimer’s disease: A meta-analysis. Alzheimers Dement 2018, 14, 1450–1459. [Google Scholar] [CrossRef]
  31. Pugazhenthi, S.; Qin, L.; Reddy, P.H. Common neurodegenerative pathways in obesity, diabetes, and Alzheimer’s disease. Biochim. Et Biophys. Acta Mol. Basis Dis. 2017, 1863, 1037–1045. [Google Scholar] [CrossRef] [PubMed]
  32. Gutierrez, L.; Folch, A.; Rojas, M.; Cantero, J.L.; Atienza, M.; Folch, J.; Camins, A.; Ruiz, A.; Papandreou, C.; Bullo, M. Effects of Nutrition on Cognitive Function in Adults with or without Cognitive Impairment: A Systematic Review of Randomized Controlled Clinical Trials. Nutrients 2021, 13, 3728. [Google Scholar] [CrossRef] [PubMed]
  33. Feart, C.; Samieri, C.; Rondeau, V.; Amieva, H.; Portet, F.; Dartigues, J.F.; Scarmeas, N.; Barberger-Gateau, P. Adherence to a Mediterranean diet, cognitive decline, and risk of dementia. JAMA 2009, 302, 638–648. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Morris, M.C.; Tangney, C.C.; Wang, Y.; Sacks, F.M.; Barnes, L.L.; Bennett, D.A.; Aggarwal, N.T. MIND diet slows cognitive decline with aging. Alzheimers Dement 2015, 11, 1015–1022. [Google Scholar] [CrossRef] [Green Version]
  35. Chen, X.; Maguire, B.; Brodaty, H.; O’Leary, F. Dietary Patterns and Cognitive Health in Older Adults: A Systematic Review. J. Alzheimers Dis. 2019, 67, 583–619. [Google Scholar] [CrossRef]
  36. Vinciguerra, F.; Graziano, M.; Hagnas, M.; Frittitta, L.; Tumminia, A. Influence of the Mediterranean and Ketogenic Diets on Cognitive Status and Decline: A Narrative Review. Nutrients 2020, 12, 1019. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Blumenthal, J.A.; Smith, P.J.; Mabe, S.; Hinderliter, A.; Lin, P.H.; Liao, L.; Welsh-Bohmer, K.A.; Browndyke, J.N.; Kraus, W.E.; Doraiswamy, P.M.; et al. Lifestyle and neurocognition in older adults with cognitive impairments: A randomized trial. Neurology 2019, 92, e212–e223. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Blumenthal, J.A.; Smith, P.J.; Mabe, S.; Hinderliter, A.; Welsh-Bohmer, K.; Browndyke, J.N.; Doraiswamy, P.M.; Lin, P.H.; Kraus, W.E.; Burke, J.R.; et al. Longer Term Effects of Diet and Exercise on Neurocognition: 1-Year Follow-up of the ENLIGHTEN Trial. J. Am. Geriatr. Soc. 2020, 68, 559–568. [Google Scholar] [CrossRef] [Green Version]
  39. Smith, P.J.; Mabe, S.; Sherwood, A.; Babyak, M.A.; Doraiswamy, P.M.; Welsh-Bohmer, K.A.; Kraus, W.; Burke, J.; Hinderliter, A.; Blumenthal, J.A. Association Between Insulin Resistance, Plasma Leptin, and Neurocognition in Vascular Cognitive Impairment. J. Alzheimers Dis. 2019, 71, 921–929. [Google Scholar] [CrossRef]
  40. Liu, X.; Morris, M.C.; Dhana, K.; Ventrelle, J.; Johnson, K.; Bishop, L.; Hollings, C.S.; Boulin, A.; Laranjo, N.; Stubbs, B.J.; et al. Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) study: Rationale, design and baseline characteristics of a randomized control trial of the MIND diet on cognitive decline. Contemp. Clin. Trials 2021, 102, 106270. [Google Scholar] [CrossRef]
  41. Lourida, I.; Soni, M.; Thompson-Coon, J.; Purandare, N.; Lang, I.A.; Ukoumunne, O.C.; Llewellyn, D.J. Mediterranean diet, cognitive function, and dementia: A systematic review. Epidemiology 2013, 24, 479–489. [Google Scholar] [CrossRef] [PubMed]
  42. Rosenberg, A.; Ngandu, T.; Rusanen, M.; Antikainen, R.; Backman, L.; Havulinna, S.; Hanninen, T.; Laatikainen, T.; Lehtisalo, J.; Levalahti, E.; et al. Multidomain lifestyle intervention benefits a large elderly population at risk for cognitive decline and dementia regardless of baseline characteristics: The FINGER trial. Alzheimers Dement 2018, 14, 263–270. [Google Scholar] [CrossRef] [PubMed]
  43. Morris, M.C.; Tangney, C.C.; Wang, Y.; Sacks, F.M.; Bennett, D.A.; Aggarwal, N.T. MIND diet associated with reduced incidence of Alzheimer’s disease. Alzheimers Dement 2015, 11, 1007–1014. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Feart, C.; Samieri, C.; Barberger-Gateau, P. Mediterranean diet and cognitive function in older adults. Curr. Opin. Clin. Nutr. Metab. Care 2010, 13, 14–18. [Google Scholar] [CrossRef] [Green Version]
  45. Berendsen, A.A.; Kang, J.H.; van de Rest, O.; Jankovic, N.; Kampman, E.; Kiefte-de Jong, J.C.; Franco, O.H.; Ikram, M.A.; Pikhart, H.; Nilsson, L.M.; et al. Association of Adherence to a Healthy Diet with Cognitive Decline in European and American Older Adults: A Meta-Analysis within the CHANCES Consortium. Dement. Geriatr. Cogn. Disord. 2017, 43, 215–227. [Google Scholar] [CrossRef]
  46. Berendsen, A.A.M.; Kang, J.H.; van de Rest, O.; Feskens, E.J.M.; de Groot, L.; Grodstein, F. The Dietary Approaches to Stop Hypertension Diet, Cognitive Function, and Cognitive Decline in American Older Women. J. Am. Med. Dir. Assoc. 2017, 18, 427–432. [Google Scholar] [CrossRef]
  47. Van den Brink, A.C.; Brouwer-Brolsma, E.M.; Berendsen, A.A.M.; van de Rest, O. The Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) Diets Are Associated with Less Cognitive Decline and a Lower Risk of Alzheimer’s Disease-A Review. Adv. Nutr. 2019, 10, 1040–1065. [Google Scholar] [CrossRef] [Green Version]
  48. Duplantier, S.C.; Gardner, C.D. A Critical Review of the Study of Neuroprotective Diets to Reduce Cognitive Decline. Nutrients 2021, 13, 2264. [Google Scholar] [CrossRef]
  49. Mottaghi, T.; Amirabdollahian, F.; Haghighatdoost, F. Fruit and vegetable intake and cognitive impairment: A systematic review and meta-analysis of observational studies. Eur. J. Clin. Nutr. 2018, 72, 1336–1344. [Google Scholar] [CrossRef]
  50. Theodore, L.E.; Kellow, N.J.; McNeil, E.A.; Close, E.O.; Coad, E.G.; Cardoso, B.R. Nut Consumption for Cognitive Performance: A Systematic Review. Adv. Nutr. 2021, 12, 777–792. [Google Scholar] [CrossRef]
  51. Roman, G.C.; Jackson, R.E.; Reis, J.; Roman, A.N.; Toledo, J.B.; Toledo, E. Extra-virgin olive oil for potential prevention of Alzheimer disease. Rev. Neurol. 2019, 175, 705–723. [Google Scholar] [CrossRef] [PubMed]
  52. Omar, S.H. Mediterranean and MIND Diets Containing Olive Biophenols Reduces the Prevalence of Alzheimer’s Disease. Int. J. Mol. Sci. 2019, 20, 2797. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Solfrizzi, V.; Colacicco, A.M.; D’Introno, A.; Capurso, C.; Torres, F.; Rizzo, C.; Capurso, A.; Panza, F. Dietary intake of unsaturated fatty acids and age-related cognitive decline: A 8.5-year follow-up of the Italian Longitudinal Study on Aging. Neurobiol. Aging 2006, 27, 1694–1704. [Google Scholar] [CrossRef]
  54. Letenneur, L.; Proust-Lima, C.; Le Gouge, A.; Dartigues, J.F.; Barberger-Gateau, P. Flavonoid intake and cognitive decline over a 10-year period. Am. J. Epidemiol. 2007, 165, 1364–1371. [Google Scholar] [CrossRef]
  55. Desideri, G.; Kwik-Uribe, C.; Grassi, D.; Necozione, S.; Ghiadoni, L.; Mastroiacovo, D.; Raffaele, A.; Ferri, L.; Bocale, R.; Lechiara, M.C.; et al. Benefits in cognitive function, blood pressure, and insulin resistance through cocoa flavanol consumption in elderly subjects with mild cognitive impairment: The Cocoa, Cognition, and Aging (CoCoA) study. Hypertension 2012, 60, 794–801. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Grassi, D.; Desideri, G.; Necozione, S.; Ruggieri, F.; Blumberg, J.B.; Stornello, M.; Ferri, C. Protective effects of flavanol-rich dark chocolate on endothelial function and wave reflection during acute hyperglycemia. Hypertension 2012, 60, 827–832. [Google Scholar] [CrossRef] [Green Version]
  57. Lehtisalo, J.; Levalahti, E.; Lindstrom, J.; Hanninen, T.; Paajanen, T.; Peltonen, M.; Antikainen, R.; Laatikainen, T.; Strandberg, T.; Soininen, H.; et al. Dietary changes and cognition over 2 years within a multidomain intervention trial-The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). Alzheimers Dement 2019, 15, 410–417. [Google Scholar] [CrossRef] [PubMed]
  58. Cunnane, S.C.; Swerdlow, R.H.; Inzitari, M.; Olaso-Gonzalez, G.; Vina, J. Multimodal strategy to rescue the brain in mild cognitive impairment: Ketogenic oral nutrition supplementation with B vitamins and aerobic exercise. Eur. J. Clin. Investig. 2022, 52, e13806. [Google Scholar] [CrossRef] [PubMed]
  59. Cunnane, S.C.; Sieber, C.C.; Swerdlow, R.H.; Cruz-Jentoft, A.J. Mild cognitive impairment: When nutrition helps brain energy rescue-a report from the EuGMS 2020 Congress. Eur. Geriatr. Med. 2021, 12, 1285–1292. [Google Scholar] [CrossRef]
  60. Barha, C.K.; Falck, R.S.; Best, J.R.; Nagamatsu, L.S.; Hsiung, G.R.; Sheel, A.W.; Hsu, C.L.; Kramer, A.F.; Voss, M.W.; Erickson, K.I.; et al. Reshaping the path of mild cognitive impairment by refining exercise prescription: A study protocol of a randomized controlled trial to understand the “what,” “for whom,” and “how” of exercise to promote cognitive function. Trials 2022, 23, 766. [Google Scholar] [CrossRef]
  61. Williams, C.L.; Tappen, R.M. Exercise training for depressed older adults with Alzheimer’s disease. Aging Ment. Health 2008, 12, 72–80. [Google Scholar] [CrossRef] [PubMed]
  62. Teixeira, C.V.L.; Ribeiro de Rezende, T.J.; Weiler, M.; Magalhaes, T.N.C.; Carletti-Cassani, A.; Silva, T.; Joaquim, H.P.G.; Talib, L.L.; Forlenza, O.V.; Franco, M.P.; et al. Cognitive and structural cerebral changes in amnestic mild cognitive impairment due to Alzheimer’s disease after multicomponent training. Alzheimer’s Dement. 2018, 4, 473–480. [Google Scholar] [CrossRef] [PubMed]
  63. Nayor, M.; Shah, R.V.; Miller, P.E.; Blodgett, J.B.; Tanguay, M.; Pico, A.R.; Murthy, V.L.; Malhotra, R.; Houstis, N.E.; Deik, A.; et al. Metabolic Architecture of Acute Exercise Response in Middle-Aged Adults in the Community. Circulation 2020, 142, 1905–1924. [Google Scholar] [CrossRef]
  64. Lake, S.L.; Guadagni, V.; Kendall, K.D.; Chadder, M.; Anderson, T.J.; Leigh, R.; Rawling, J.M.; Hogan, D.B.; Hill, M.D.; Poulin, M.J. Aerobic exercise training in older men and women-Cerebrovascular responses to submaximal exercise: Results from the Brain in Motion study. Physiol. Rep. 2022, 10, e15158. [Google Scholar] [CrossRef]
  65. Portugal, E.M.; Vasconcelos, P.G.; Souza, R.; Lattari, E.; Monteiro-Junior, R.S.; Machado, S.; Deslandes, A.C. Aging process, cognitive decline and Alzheimer`s disease: Can strength training modulate these responses? CNS Neurol. Disord. Drug Targets 2015, 14, 1209–1213. [Google Scholar] [CrossRef]
  66. Okonkwo, O.C.; Schultz, S.A.; Oh, J.M.; Larson, J.; Edwards, D.; Cook, D.; Koscik, R.; Gallagher, C.L.; Dowling, N.M.; Carlsson, C.M.; et al. Physical activity attenuates age-related biomarker alterations in preclinical AD. Neurology 2014, 83, 1753–1760. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Coutinho, L.A.; Leao, L.L.; Cassilhas, R.C.; de Paula, A.M.B.; Deslandes, A.C.; Monteiro-Junior, R.S. Alzheimer’s disease genes and proteins associated with resistance and aerobic training: An in silico analysis. Exp. Gerontol. 2022, 168, 111948. [Google Scholar] [CrossRef] [PubMed]
  68. Nascimento, C.M.; Pereira, J.R.; de Andrade, L.P.; Garuffi, M.; Talib, L.L.; Forlenza, O.V.; Cancela, J.M.; Cominetti, M.R.; Stella, F. Physical exercise in MCI elderly promotes reduction of pro-inflammatory cytokines and improvements on cognition and BDNF peripheral levels. Curr. Alzheimer Res. 2014, 11, 799–805. [Google Scholar] [CrossRef]
  69. Baker, L.D.; Frank, L.L.; Foster-Schubert, K.; Green, P.S.; Wilkinson, C.W.; McTiernan, A.; Plymate, S.R.; Fishel, M.A.; Watson, G.S.; Cholerton, B.A.; et al. Effects of aerobic exercise on mild cognitive impairment: A controlled trial. Arch. Neurol. 2010, 67, 71–79. [Google Scholar] [CrossRef] [Green Version]
  70. Maass, A.; Duzel, S.; Goerke, M.; Becke, A.; Sobieray, U.; Neumann, K.; Lovden, M.; Lindenberger, U.; Backman, L.; Braun-Dullaeus, R.; et al. Vascular hippocampal plasticity after aerobic exercise in older adults. Mol. Psychiatry 2015, 20, 585–593. [Google Scholar] [CrossRef] [Green Version]
  71. Yu, F.; Vock, D.M.; Zhang, L.; Salisbury, D.; Nelson, N.W.; Chow, L.S.; Smith, G.; Barclay, T.R.; Dysken, M.; Wyman, J.F. Cognitive Effects of Aerobic Exercise in Alzheimer’s Disease: A Pilot Randomized Controlled Trial. J. Alzheimers Dis. 2021, 80, 233–244. [Google Scholar] [CrossRef] [PubMed]
  72. Yoshino, M.; Yoshino, J.; Smith, G.I.; Stein, R.I.; Bittel, A.J.; Bittel, D.C.; Reeds, D.N.; Sinacore, D.R.; Cade, W.T.; Patterson, B.W.; et al. Worksite-based intensive lifestyle therapy has profound cardiometabolic benefits in people with obesity and type 2 diabetes. Cell Metab. 2022, 34, 1431–1441.e5. [Google Scholar] [CrossRef] [PubMed]
  73. Freberg, E.; Taglialatela, G. Exercise as a Potential Therapeutic Strategy to Target the Clinical Link Between Depression and Alzheimer’s Disease: A Narrative Review. J. Alzheimers Dis. 2022, 89, 759–767. [Google Scholar] [CrossRef]
  74. Liu-Ambrose, T.; Best, J.R.; Davis, J.C.; Eng, J.J.; Lee, P.E.; Jacova, C.; Boyd, L.A.; Brasher, P.M.; Munkacsy, M.; Cheung, W.; et al. Aerobic exercise and vascular cognitive impairment: A randomized controlled trial. Neurology 2016, 87, 2082–2090. [Google Scholar] [CrossRef] [Green Version]
  75. Fiatarone, M.A.; O’Neill, E.F.; Ryan, N.D.; Clements, K.M.; Solares, G.R.; Nelson, M.E.; Roberts, S.B.; Kehayias, J.J.; Lipsitz, L.A.; Evans, W.J. Exercise training and nutritional supplementation for physical frailty in very elderly people. N. Engl. J. Med. 1994, 330, 1769–1775. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Teri, L.; Logsdon, R.G.; Uomoto, J.; McCurry, S.M. Behavioral treatment of depression in dementia patients: A controlled clinical trial. J. Gerontol. B Psychol. Sci. Soc. Sci. 1997, 52, P159–P166. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Wu, C.; Yang, L.; Feng, S.; Zhu, L.; Yang, L.; Liu, T.C.; Duan, R. Therapeutic non-invasive brain treatments in Alzheimer’s disease: Recent advances and challenges. Inflamm. Regen. 2022, 42, 31. [Google Scholar] [CrossRef] [PubMed]
  78. Hsu, C.L.; Best, J.R.; Davis, J.C.; Nagamatsu, L.S.; Wang, S.; Boyd, L.A.; Hsiung, G.R.; Voss, M.W.; Eng, J.J.; Liu-Ambrose, T. Aerobic exercise promotes executive functions and impacts functional neural activity among older adults with vascular cognitive impairment. Br. J. Sport. Med. 2018, 52, 184–191. [Google Scholar] [CrossRef]
  79. Yu, F.; Kolanowski, A.M.; Strumpf, N.E.; Eslinger, P.J. Improving cognition and function through exercise intervention in Alzheimer’s disease. J. Nurs. Scholarsh. Off. Publ. Sigma Theta Tau Int. Honor Soc. Nurs. 2006, 38, 358–365. [Google Scholar] [CrossRef]
  80. Wilckens, K.A.; Stillman, C.M.; Waiwood, A.M.; Kang, C.; Leckie, R.L.; Peven, J.C.; Foust, J.E.; Fraundorf, S.H.; Erickson, K.I. Exercise interventions preserve hippocampal volume: A meta-analysis. Hippocampus 2021, 31, 335–347. [Google Scholar] [CrossRef]
  81. Lange-Asschenfeldt, C.; Kojda, G. Alzheimer’s disease, cerebrovascular dysfunction and the benefits of exercise: From vessels to neurons. Exp. Gerontol 2008, 43, 499–504. [Google Scholar] [CrossRef] [PubMed]
  82. Phillips, C.; Baktir, M.A.; Das, D.; Lin, B.; Salehi, A. The Link Between Physical Activity and Cognitive Dysfunction in Alzheimer Disease. Phys. Ther. 2015, 95, 1046–1060. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Huttenrauch, M.; Lopez-Noguerola, J.S.; Castro-Obregon, S. Connecting Mind-Body Therapy-Mediated Effects to Pathological Features of Alzheimer’s Disease. J. Alzheimers Dis. 2021, 82, S65–S90. [Google Scholar] [CrossRef] [PubMed]
  84. Scarmeas, N.; Luchsinger, J.A.; Schupf, N.; Brickman, A.M.; Cosentino, S.; Tang, M.X.; Stern, Y. Physical activity, diet, and risk of Alzheimer disease. JAMA 2009, 302, 627–637. [Google Scholar] [CrossRef] [Green Version]
  85. Saez de Asteasu, M.L.; Martinez-Velilla, N.; Zambom-Ferraresi, F.; Casas-Herrero, A.; Izquierdo, M. Role of physical exercise on cognitive function in healthy older adults: A systematic review of randomized clinical trials. Ageing Res. Rev. 2017, 37, 117–134. [Google Scholar] [CrossRef]
  86. Savage, V.M.; West, G.B. A quantitative, theoretical framework for understanding mammalian sleep. Proc. Natl. Acad. Sci. USA 2007, 104, 1051–1056. [Google Scholar] [CrossRef] [Green Version]
  87. Bishir, M.; Bhat, A.; Essa, M.M.; Ekpo, O.; Ihunwo, A.O.; Veeraraghavan, V.P.; Mohan, S.K.; Mahalakshmi, A.M.; Ray, B.; Tuladhar, S.; et al. Sleep Deprivation and Neurological Disorders. Biomed Res. Int. 2020, 2020, 5764017. [Google Scholar] [CrossRef]
  88. Reddy, O.C.; van der Werf, Y.D. The Sleeping Brain: Harnessing the Power of the Glymphatic System through Lifestyle Choices. Brain Sci. 2020, 10, 868. [Google Scholar] [CrossRef]
  89. Rasch, B.; Born, J. About sleep’s role in memory. Physiol. Rev. 2013, 93, 681–766. [Google Scholar] [CrossRef]
  90. Stickgold, R.; Walker, M.P. Sleep-dependent memory triage: Evolving generalization through selective processing. Nat. Neurosci. 2013, 16, 139–145. [Google Scholar] [CrossRef] [Green Version]
  91. Borges, C.R.; Poyares, D.; Piovezan, R.; Nitrini, R.; Brucki, S. Alzheimer’s disease and sleep disturbances: A review. Arq. Neuropsiquiatr. 2019, 77, 815–824. [Google Scholar] [CrossRef] [PubMed]
  92. Shokri-Kojori, E.; Wang, G.J.; Wiers, C.E.; Demiral, S.B.; Guo, M.; Kim, S.W.; Lindgren, E.; Ramirez, V.; Zehra, A.; Freeman, C.; et al. beta-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc. Natl. Acad. Sci. USA 2018, 115, 4483–4488. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Yulug, B.; Hanoglu, L.; Kilic, E. Does sleep disturbance affect the amyloid clearance mechanisms in Alzheimer’s disease? Psychiatry Clin. Neurosci. 2017, 71, 673–677. [Google Scholar] [CrossRef] [PubMed]
  94. Cordone, S.; Annarumma, L.; Rossini, P.M.; De Gennaro, L. Sleep and beta-Amyloid Deposition in Alzheimer Disease: Insights on Mechanisms and Possible Innovative Treatments. Front. Pharmacol. 2019, 10, 695. [Google Scholar] [CrossRef] [Green Version]
  95. Spinedi, E.; Cardinali, D.P. Neuroendocrine-Metabolic Dysfunction and Sleep Disturbances in Neurodegenerative Disorders: Focus on Alzheimer’s Disease and Melatonin. Neuroendocrinology 2019, 108, 354–364. [Google Scholar] [CrossRef] [Green Version]
  96. Lim, A.S.; Kowgier, M.; Yu, L.; Buchman, A.S.; Bennett, D.A. Sleep Fragmentation and the Risk of Incident Alzheimer’s Disease and Cognitive Decline in Older Persons. Sleep 2013, 36, 1027–1032. [Google Scholar] [CrossRef] [Green Version]
  97. Jackson, M.L.; Gunzelmann, G.; Whitney, P.; Hinson, J.M.; Belenky, G.; Rabat, A.; Van Dongen, H.P. Deconstructing and reconstructing cognitive performance in sleep deprivation. Sleep Med. Rev. 2013, 17, 215–225. [Google Scholar] [CrossRef] [Green Version]
  98. Bombois, S.; Derambure, P.; Pasquier, F.; Monaca, C. Sleep disorders in aging and dementia. J. Nutr. Health Aging 2010, 14, 212–217. [Google Scholar] [CrossRef]
  99. Foley, D.; Ancoli-Israel, S.; Britz, P.; Walsh, J. Sleep disturbances and chronic disease in older adults: Results of the 2003 National Sleep Foundation Sleep in America Survey. J. Psychosom. Res. 2004, 56, 497–502. [Google Scholar] [CrossRef]
  100. Wennberg, A.M.V.; Wu, M.N.; Rosenberg, P.B.; Spira, A.P. Sleep Disturbance, Cognitive Decline, and Dementia: A Review. Semin. Neurol. 2017, 37, 395–406. [Google Scholar]
  101. Deschenes, C.L.; McCurry, S.M. Current treatments for sleep disturbances in individuals with dementia. Curr. Psychiatry Rep. 2009, 11, 20–26. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Tranah, G.J.; Blackwell, T.; Stone, K.L.; Ancoli-Israel, S.; Paudel, M.L.; Ensrud, K.E.; Cauley, J.A.; Redline, S.; Hillier, T.A.; Cummings, S.R.; et al. Circadian activity rhythms and risk of incident dementia and mild cognitive impairment in older women. Ann. Neurol. 2011, 70, 722–732. [Google Scholar] [CrossRef] [PubMed]
  103. Bubu, O.M.; Brannick, M.; Mortimer, J.; Umasabor-Bubu, O.; Sebastiao, Y.V.; Wen, Y.; Schwartz, S.; Borenstein, A.R.; Wu, Y.; Morgan, D.; et al. Sleep, Cognitive impairment, and Alzheimer’s disease: A Systematic Review and Meta-Analysis. Sleep 2017, 40, zsw032. [Google Scholar] [CrossRef]
  104. Ettcheto, M.; Olloquequi, J.; Sanchez-Lopez, E.; Busquets, O.; Cano, A.; Manzine, P.R.; Beas-Zarate, C.; Castro-Torres, R.D.; Garcia, M.L.; Bullo, M.; et al. Benzodiazepines and Related Drugs as a Risk Factor in Alzheimer’s Disease Dementia. Front. Aging Neurosci. 2019, 11, 344. [Google Scholar] [CrossRef] [PubMed]
  105. Rose, K.M.; Lorenz, R. Sleep disturbances in dementia. J. Gerontol. Nurs. 2010, 36, 9–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Bliwise, D.L. Sleep disorders in Alzheimer’s disease and other dementias. Clin. Cornerstone 2004, 6 (Suppl. 1A), S16–S28. [Google Scholar] [CrossRef]
  107. Tractenberg, R.E.; Singer, C.M.; Kaye, J.A. Characterizing sleep problems in persons with Alzheimer’s disease and normal elderly. J. Sleep Res. 2006, 15, 97–103. [Google Scholar] [CrossRef]
  108. Cole, C.S.; Richards, K.C. Sleep and cognition in people with Alzheimer’s disease. Issues Ment. Health Nurs. 2005, 26, 687–698. [Google Scholar] [CrossRef]
  109. Hossain, M.F.; Uddin, M.S.; Uddin, G.M.S.; Sumsuzzman, D.M.; Islam, M.S.; Barreto, G.E.; Mathew, B.; Ashraf, G.M. Melatonin in Alzheimer’s Disease: A Latent Endogenous Regulator of Neurogenesis to Mitigate Alzheimer’s Neuropathology. Mol. Neurobiol. 2019, 56, 8255–8276. [Google Scholar] [CrossRef]
  110. Shukla, M.; Govitrapong, P.; Boontem, P.; Reiter, R.J.; Satayavivad, J. Mechanisms of Melatonin in Alleviating Alzheimer’s Disease. Curr. Neuropharmacol. 2017, 15, 1010–1031. [Google Scholar] [CrossRef] [Green Version]
  111. Cardinali, D.P.; Furio, A.M.; Brusco, L.I. Clinical aspects of melatonin intervention in Alzheimer’s disease progression. Curr. Neuropharmacol. 2010, 8, 218–227. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Wu, Y.H.; Swaab, D.F. The human pineal gland and melatonin in aging and Alzheimer’s disease. J. Pineal Res. 2005, 38, 145–152. [Google Scholar] [CrossRef] [PubMed]
  113. Nous, A.; Engelborghs, S.; Smolders, I. Melatonin levels in the Alzheimer’s disease continuum: A systematic review. Alzheimers Res Ther. 2021, 13, 52. [Google Scholar] [CrossRef] [PubMed]
  114. Zhou, J.N.; Liu, R.Y.; Kamphorst, W.; Hofman, M.A.; Swaab, D.F. Early neuropathological Alzheimer’s changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels. J. Pineal Res. 2003, 35, 125–130. [Google Scholar] [CrossRef]
  115. Reiter, R.J.; Manchester, L.C.; Tan, D.X. Neurotoxins: Free radical mechanisms and melatonin protection. Curr. Neuropharmacol. 2010, 8, 194–210. [Google Scholar] [CrossRef] [Green Version]
  116. Shen, S.; Liao, Q.; Wong, Y.K.; Chen, X.; Yang, C.; Xu, C.; Sun, J.; Wang, J. The role of melatonin in the treatment of type 2 diabetes mellitus and Alzheimer’s disease. Int. J. Biol. Sci. 2022, 18, 983–994. [Google Scholar] [CrossRef]
  117. Rosales-Corral, S.A.; Acuna-Castroviejo, D.; Coto-Montes, A.; Boga, J.A.; Manchester, L.C.; Fuentes-Broto, L.; Korkmaz, A.; Ma, S.; Tan, D.X.; Reiter, R.J. Alzheimer’s disease: Pathological mechanisms and the beneficial role of melatonin. J. Pineal Res. 2012, 52, 167–202. [Google Scholar] [CrossRef]
  118. Rondanelli, M.; Opizzi, A.; Faliva, M.; Mozzoni, M.; Antoniello, N.; Cazzola, R.; Savare, R.; Cerutti, R.; Grossi, E.; Cestaro, B. Effects of a diet integration with an oily emulsion of DHA-phospholipids containing melatonin and tryptophan in elderly patients suffering from mild cognitive impairment. Nutr. Neurosci. 2012, 15, 46–54. [Google Scholar] [CrossRef]
  119. Cardinali, D.P.; Vigo, D.E.; Olivar, N.; Vidal, M.F.; Furio, A.M.; Brusco, L.I. Therapeutic application of melatonin in mild cognitive impairment. Am. J. Neurodegener. Dis. 2012, 1, 280–291. [Google Scholar]
  120. Wade, A.G.; Farmer, M.; Harari, G.; Fund, N.; Laudon, M.; Nir, T.; Frydman-Marom, A.; Zisapel, N. Add-on prolonged-release melatonin for cognitive function and sleep in mild to moderate Alzheimer’s disease: A 6-month, randomized, placebo-controlled, multicenter trial. Clin. Interv. Aging 2014, 9, 947–961. [Google Scholar]
  121. Teter, B.; Ashford, J.W. Neuroplasticity in Alzheimer’s disease. J. Neurosci Res. 2002, 70, 402–437. [Google Scholar] [PubMed]
  122. Merzenich, M.M.; Van Vleet, T.M.; Nahum, M. Brain plasticity-based therapeutics. Front. Hum. Neurosci. 2014, 8, 385. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Voss, P.; Thomas, M.E.; Cisneros-Franco, J.M.; de Villers-Sidani, E. Dynamic Brains and the Changing Rules of Neuroplasticity: Implications for Learning and Recovery. Front. Psychol. 2017, 8, 1657. [Google Scholar] [CrossRef] [Green Version]
  124. Skaper, S.D.; Facci, L.; Zusso, M.; Giusti, P. Synaptic Plasticity, Dementia and Alzheimer Disease. CNS Neurol. Disord. Drug Targets 2017, 16, 220–233. [Google Scholar] [CrossRef] [PubMed]
  125. Chen, Y.; Fu, A.K.Y.; Ip, N.Y. Synaptic dysfunction in Alzheimer’s disease: Mechanisms and therapeutic strategies. Pharmacol. Ther. 2019, 195, 186–198. [Google Scholar] [CrossRef]
  126. Selkoe, D.J. Alzheimer’s disease is a synaptic failure. Science 2002, 298, 789–791. [Google Scholar] [CrossRef] [Green Version]
  127. Vermunt, L.; Sikkes, S.A.M.; van den Hout, A.; Handels, R.; Bos, I.; van der Flier, W.M.; Kern, S.; Ousset, P.J.; Maruff, P.; Skoog, I.; et al. Duration of preclinical, prodromal, and dementia stages of Alzheimer’s disease in relation to age, sex, and APOE genotype. Alzheimers Dement 2019, 15, 888–898. [Google Scholar] [CrossRef]
  128. Morris, J.C.; Storandt, M.; Miller, J.P.; McKeel, D.W.; Price, J.L.; Rubin, E.H.; Berg, L. Mild cognitive impairment represents early-stage Alzheimer disease. Arch. Neurol. 2001, 58, 397–405. [Google Scholar] [CrossRef] [Green Version]
  129. Petersen, R.C.; Smith, G.E.; Waring, S.C.; Ivnik, R.J.; Tangalos, E.G.; Kokmen, E. Mild cognitive impairment: Clinical characterization and outcome. Arch. Neurol. 1999, 56, 303–308. [Google Scholar] [CrossRef]
  130. Davis, M.T.O.C.; Johnson, S.; Cline, S.; Merikle, E.; Martenyi, F.; Simpson, K. Estimating Alzheimer’s Disease Progression Rates from Normal Cognition Through Mild Cognitive Impairment and Stages of Dementia. Curr. Alzheimer Res. 2018, 15, 777–788. [Google Scholar] [CrossRef]
  131. Bahar-Fuchs, A.; Martyr, A.; Goh, A.M.; Sabates, J.; Clare, L. Cognitive training for people with mild to moderate dementia. Cochrane Database Syst. Rev. 2019, 3, CD013069. [Google Scholar] [CrossRef] [PubMed]
  132. Backman, L.; Jones, S.; Berger, A.K.; Laukka, E.J.; Small, B.J. Cognitive impairment in preclinical Alzheimer’s disease: A meta-analysis. Neuropsychology 2005, 19, 520–531. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  133. Forstl, H.; Kurz, A. Clinical features of Alzheimer’s disease. Eur. Arch. Psychiatry Clin. Neurosci. 1999, 249, 288–290. [Google Scholar] [CrossRef]
  134. Llano, D.A.; Kwok, S.S.; Devanarayan, V.; Alzheimer’s Disease Neuroimaging, I. Reported Hearing Loss in Alzheimer’s Disease Is Associated With Loss of Brainstem and Cerebellar Volume. Front. Hum. Neurosci. 2021, 15, 739754. [Google Scholar] [CrossRef]
  135. Ralli, M.; Gilardi, A.; Stadio, A.D.; Severini, C.; Salzano, F.A.; Greco, A.; Vincentiis, M. Hearing loss and Alzheimer’s disease: A Review. Int. Tinnitus J. 2019, 23, 79–85. [Google Scholar] [CrossRef] [PubMed]
  136. Jayakody, D.M.P.; Friedland, P.L.; Martins, R.N.; Sohrabi, H.R. Impact of Aging on the Auditory System and Related Cognitive Functions: A Narrative Review. Front. Neurosci. 2018, 12, 125. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. Mendez, M.F. Degenerative dementias: Alterations of emotions and mood disorders. Handb. Clin. Neurol. 2021, 183, 261–281. [Google Scholar]
  138. Cortes, N.; Andrade, V.; Maccioni, R.B. Behavioral and Neuropsychiatric Disorders in Alzheimer’s Disease. J. Alzheimers Dis. 2018, 63, 899–910. [Google Scholar] [CrossRef] [Green Version]
  139. Pfennig, A.; Littmann, E.; Bauer, M. Neurocognitive impairment and dementia in mood disorders. J. Neuropsychiatry Clin. Neurosci. 2007, 19, 373–382. [Google Scholar] [CrossRef]
  140. Baldwin, S.; Farias, S.T. Neuropsychological assessment in the diagnosis of Alzheimer’s disease. Curr. Protoc. Neurosci. 2009, 49, 10–13. [Google Scholar] [CrossRef] [Green Version]
  141. Mahncke, H.W.; Connor, B.B.; Appelman, J.; Ahsanuddin, O.N.; Hardy, J.L.; Wood, R.A.; Joyce, N.M.; Boniske, T.; Atkins, S.M.; Merzenich, M.M. Memory enhancement in healthy older adults using a brain plasticity-based training program: A randomized, controlled study. Proc. Natl. Acad. Sci. USA 2006, 103, 12523–12528. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  142. Vemuri, P.; Fields, J.; Peter, J.; Kloppel, S. Cognitive interventions in Alzheimer’s and Parkinson’s diseases: Emerging mechanisms and role of imaging. Curr. Opin. Neurol. 2016, 29, 405–411. [Google Scholar] [CrossRef] [PubMed]
  143. Smith, G.E.; Housen, P.; Yaffe, K.; Ruff, R.; Kennison, R.F.; Mahncke, H.W.; Zelinski, E.M. A cognitive training program based on principles of brain plasticity: Results from the Improvement in Memory with Plasticity-based Adaptive Cognitive Training (IMPACT) study. J. Am. Geriatr. Soc. 2009, 57, 594–603. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Clare, L.; Kudlicka, A.; Oyebode, J.R.; Jones, R.W.; Bayer, A.; Leroi, I.; Kopelman, M.; James, I.A.; Culverwell, A.; Pool, J.; et al. Goal-oriented cognitive rehabilitation for early-stage Alzheimer’s and related dementias: The GREAT RCT. Health Technol. Assess. 2019, 23, 1–242. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  145. Perez-Gonzalez, D.; Schreiner, T.G.; Llano, D.A.; Malmierca, M.S. Alzheimer’s Disease, Hearing Loss, and Deviance Detection. Front. Neurosci. 2022, 16, 879480. [Google Scholar] [CrossRef]
  146. Justice, N.J. The relationship between stress and Alzheimer’s disease. Neurobiol. Stress 2018, 8, 127–133. [Google Scholar] [CrossRef]
  147. Avila-Villanueva, M.; Gomez-Ramirez, J.; Maestu, F.; Venero, C.; Avila, J.; Fernandez-Blazquez, M.A. The Role of Chronic Stress as a Trigger for the Alzheimer Disease Continuum. Front. Aging Neurosci. 2020, 12, 561504. [Google Scholar] [CrossRef]
  148. Kudielka, B.M.; Buske-Kirschbaum, A.; Hellhammer, D.H.; Kirschbaum, C. HPA axis responses to laboratory psychosocial stress in healthy elderly adults, younger adults, and children: Impact of age and gender. Psychoneuroendocrinology 2004, 29, 83–98. [Google Scholar] [CrossRef]
  149. Lupien, S.J.; Gaudreau, S.; Tchiteya, B.M.; Maheu, F.; Sharma, S.; Nair, N.P.; Hauger, R.L.; McEwen, B.S.; Meaney, M.J. Stress-induced declarative memory impairment in healthy elderly subjects: Relationship to cortisol reactivity. J. Clin. Endocrinol. Metab. 1997, 82, 2070–2075. [Google Scholar] [CrossRef]
  150. Lupien, S.J.; McEwen, B.S. The acute effects of corticosteroids on cognition: Integration of animal and human model studies. Brain Res. Brain Res. Rev. 1997, 24, 1–27. [Google Scholar] [CrossRef]
  151. Sotiropoulos, I.; Catania, C.; Pinto, L.G.; Silva, R.; Pollerberg, G.E.; Takashima, A.; Sousa, N.; Almeida, O.F. Stress acts cumulatively to precipitate Alzheimer’s disease-like tau pathology and cognitive deficits. J. Neurosci. 2011, 31, 7840–7847. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. Du, X.; Pang, T.Y. Is Dysregulation of the HPA-Axis a Core Pathophysiology Mediating Co-Morbid Depression in Neurodegenerative Diseases? Front. Psychiatry 2015, 6, 32. [Google Scholar]
  153. Canet, G.; Hernandez, C.; Zussy, C.; Chevallier, N.; Desrumaux, C.; Givalois, L. Is AD a Stress-Related Disorder? Focus on the HPA Axis and Its Promising Therapeutic Targets. Front. Aging Neurosci. 2019, 11, 269. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Ennis, G.E.; An, Y.; Resnick, S.M.; Ferrucci, L.; O’Brien, R.J.; Moffat, S.D. Long-term cortisol measures predict Alzheimer disease risk. Neurology 2017, 88, 371–378. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. Ouanes, S.; Popp, J. High Cortisol and the Risk of Dementia and Alzheimer’s Disease: A Review of the Literature. Front. Aging Neurosci. 2019, 11, 43. [Google Scholar] [CrossRef] [Green Version]
  156. Orihashi, R.; Imamura, Y.; Yamada, S.; Monji, A.; Mizoguchi, Y. Association between cortisol and aging-related hippocampus volume changes in community-dwelling older adults: A 7-year follow-up study. BMC Geriatr. 2022, 22, 765. [Google Scholar] [CrossRef]
  157. O’Brien, J.T.; Lloyd, A.; McKeith, I.; Gholkar, A.; Ferrier, N. A longitudinal study of hippocampal volume, cortisol levels, and cognition in older depressed subjects. Am. J. Psychiatry 2004, 161, 2081–2090. [Google Scholar] [CrossRef]
  158. Green, K.N.; Billings, L.M.; Roozendaal, B.; McGaugh, J.L.; LaFerla, F.M. Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer’s disease. J. Neurosci. 2006, 26, 9047–9056. [Google Scholar] [CrossRef] [Green Version]
  159. Pietrzak, R.H.; Laws, S.M.; Lim, Y.Y.; Bender, S.J.; Porter, T.; Doecke, J.; Ames, D.; Fowler, C.; Masters, C.L.; Milicic, L.; et al. Plasma Cortisol, Brain Amyloid-beta, and Cognitive Decline in Preclinical Alzheimer’s Disease: A 6-Year Prospective Cohort Study. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 2017, 2, 45–52. [Google Scholar]
  160. Harrison, N.A.; Cercignani, M.; Voon, V.; Critchley, H.D. Effects of inflammation on hippocampus and substantia nigra responses to novelty in healthy human participants. Neuropsychopharmacology 2015, 40, 831–838. [Google Scholar] [CrossRef] [Green Version]
  161. Fonken, L.K.; Frank, M.G.; Gaudet, A.D.; Maier, S.F. Stress and aging act through common mechanisms to elicit neuroinflammatory priming. Brain. Behav. Immun. 2018, 73, 133–148. [Google Scholar] [CrossRef] [PubMed]
  162. Su, F.; Bai, F.; Zhang, Z. Inflammatory Cytokines and Alzheimer’s Disease: A Review from the Perspective of Genetic Polymorphisms. Neurosci. Bull. 2016, 32, 469–480. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  163. Danucalov, M.A.; Kozasa, E.H.; Ribas, K.T.; Galduroz, J.C.; Garcia, M.C.; Verreschi, I.T.; Oliveira, K.C.; Romani de Oliveira, L.; Leite, J.R. A yoga and compassion meditation program reduces stress in familial caregivers of Alzheimer’s disease patients. Evid Based Complement Altern. Med. 2013, 2013, 513149. [Google Scholar] [CrossRef] [Green Version]
  164. Sampedro-Piquero, P.; Alvarez-Suarez, P.; Begega, A. Coping with Stress During Aging: The Importance of a Resilient Brain. Curr. Neuropharmacol. 2018, 16, 284–296. [Google Scholar] [CrossRef]
  165. Sood, A.; Prasad, K.; Schroeder, D.; Varkey, P. Stress management and resilience training among Department of Medicine faculty: A pilot randomized clinical trial. J. Gen. Intern. Med. 2011, 26, 858–861. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  166. Khalsa, D.S. Stress, Meditation, and Alzheimer’s Disease Prevention: Where The Evidence Stands. J. Alzheimers Dis. 2015, 48, 1–12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  167. Newberg, A.B.; Wintering, N.; Khalsa, D.S.; Roggenkamp, H.; Waldman, M.R. Meditation effects on cognitive function and cerebral blood flow in subjects with memory loss: A preliminary study. Ann. Neurosci. 2012, 19, 81. [Google Scholar] [CrossRef]
  168. Yang, H.; Leaver, A.M.; Siddarth, P.; Paholpak, P.; Ercoli, L.; St Cyr, N.M.; Eyre, H.A.; Narr, K.L.; Khalsa, D.S.; Lavretsky, H. Neurochemical and Neuroanatomical Plasticity Following Memory Training and Yoga Interventions in Older Adults with Mild Cognitive Impairment. Front. Aging Neurosci. 2016, 8, 277. [Google Scholar] [CrossRef] [Green Version]
  169. Farhang, M.; Miranda-Castillo, C.; Rubio, M.; Furtado, G. Impact of mind-body interventions in older adults with mild cognitive impairment: A systematic review. Int. Psychogeriatr. 2019, 31, 643–666. [Google Scholar] [CrossRef] [Green Version]
  170. Wei, L.; Chai, Q.; Chen, J.; Wang, Q.; Bao, Y.; Xu, W.; Ma, E. The impact of Tai Chi on cognitive rehabilitation of elder adults with mild cognitive impairment: A systematic review and meta-analysis. Disabil. Rehabil. 2022, 44, 2197–2206. [Google Scholar] [CrossRef]
  171. Brenes, G.A.; Sohl, S.; Wells, R.E.; Befus, D.; Campos, C.L.; Danhauer, S.C. The Effects of Yoga on Patients with Mild Cognitive Impairment and Dementia: A Scoping Review. Am. J. Geriatr. Psychiatry 2019, 27, 188–197. [Google Scholar] [CrossRef] [PubMed]
  172. Lavretsky, H. Yoga and Meditation Can Help Improve Cognitive Functioning in Older Adults With Mild Cognitive Impairment and Dementia. Am. J. Geriatr. Psychiatry 2019, 27, 198–199. [Google Scholar] [CrossRef] [PubMed]
  173. Innes, K.E.; Selfe, T.K.; Khalsa, D.S.; Kandati, S. Effects of Meditation versus Music Listening on Perceived Stress, Mood, Sleep, and Quality of Life in Adults with Early Memory Loss: A Pilot Randomized Controlled Trial. J. Alzheimers Dis. 2016, 52, 1277–1298. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  174. Rehfeld, K.; Muller, P.; Aye, N.; Schmicker, M.; Dordevic, M.; Kaufmann, J.; Hokelmann, A.; Muller, N.G. Dancing or Fitness Sport? The Effects of Two Training Programs on Hippocampal Plasticity and Balance Abilities in Healthy Seniors. Front. Hum. Neurosci. 2017, 11, 305. [Google Scholar] [CrossRef]
  175. Lyu, J.; Zhang, J.; Mu, H.; Li, W.; Champ, M.; Xiong, Q.; Gao, T.; Xie, L.; Jin, W.; Yang, W.; et al. The Effects of Music Therapy on Cognition, Psychiatric Symptoms, and Activities of Daily Living in Patients with Alzheimer’s Disease. J. Alzheimers Dis. 2018, 64, 1347–1358. [Google Scholar] [CrossRef] [Green Version]
  176. Ito, E.; Nouchi, R.; Dinet, J.; Cheng, C.H.; Husebo, B.S. The Effect of Music-Based Intervention on General Cognitive and Executive Functions, and Episodic Memory in People with Mild Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis of Recent Randomized Controlled Trials. Healthcare 2022, 10, 1462. [Google Scholar] [CrossRef]
  177. Dorris, J.L.; Neely, S.; Terhorst, L.; VonVille, H.M.; Rodakowski, J. Effects of music participation for mild cognitive impairment and dementia: A systematic review and meta-analysis. J. Am. Geriatr. Soc. 2021, 69, 2659–2667. [Google Scholar] [CrossRef]
  178. Kattenstroth, J.C.; Kalisch, T.; Holt, S.; Tegenthoff, M.; Dinse, H.R. Six months of dance intervention enhances postural, sensorimotor, and cognitive performance in elderly without affecting cardio-respiratory functions. Front. Aging Neurosci. 2013, 5, 5. [Google Scholar] [CrossRef] [Green Version]
  179. Kattenstroth, J.C.; Kolankowska, I.; Kalisch, T.; Dinse, H.R. Superior sensory, motor, and cognitive performance in elderly individuals with multi-year dancing activities. Front. Aging Neurosci. 2010, 2, 31. [Google Scholar] [CrossRef] [Green Version]
  180. Zhu, Y.; Gao, Y.; Guo, C.; Qi, M.; Xiao, M.; Wu, H.; Ma, J.; Zhong, Q.; Ding, H.; Zhou, Q.; et al. Effect of 3-Month Aerobic Dance on Hippocampal Volume and Cognition in Elderly People With Amnestic Mild Cognitive Impairment: A Randomized Controlled Trial. Front. Aging Neurosci. 2022, 14, 771413. [Google Scholar] [CrossRef]
  181. Zhu, Y.; Zhong, Q.; Ji, J.; Ma, J.; Wu, H.; Gao, Y.; Ali, N.; Wang, T. Effects of Aerobic Dance on Cognition in Older Adults with Mild Cognitive Impairment: A Systematic Review and Meta-Analysis. J. Alzheimers Dis. 2020, 74, 679–690. [Google Scholar] [CrossRef] [PubMed]
  182. Thumuluri, D.; Lyday, R.; Babcock, P.; Ip, E.H.; Kraft, R.A.; Laurienti, P.J.; Barnstaple, R.; Soriano, C.T.; Hugenschmidt, C.E. Improvisational Movement to Improve Quality of Life in Older Adults With Early-Stage Dementia: A Pilot Study. Front. Sport Act. Living 2021, 3, 796101. [Google Scholar] [CrossRef] [PubMed]
  183. Karkou, V.; Meekums, B. Dance movement therapy for dementia. Cochrane Database Syst. Rev. 2017, 2, CD011022. [Google Scholar] [CrossRef] [PubMed]
  184. Wu, C.C.; Xiong, H.Y.; Zheng, J.J.; Wang, X.Q. Dance movement therapy for neurodegenerative diseases: A systematic review. Front. Aging Neurosci. 2022, 14, 975711. [Google Scholar] [CrossRef]
  185. Kattenstroth, J.C.; Kalisch, T.; Kolankowska, I.; Dinse, H.R. Balance, sensorimotor, and cognitive performance in long-year expert senior ballroom dancers. J. Aging Res. 2011, 2011, 176709. [Google Scholar] [CrossRef] [Green Version]
  186. Kumar, A.M.; Tims, F.; Cruess, D.G.; Mintzer, M.J.; Ironson, G.; Loewenstein, D.; Cattan, R.; Fernandez, J.B.; Eisdorfer, C.; Kumar, M. Music therapy increases serum melatonin levels in patients with Alzheimer’s disease. Altern. Ther. Health Med. 1999, 5, 49–57. [Google Scholar]
  187. Flo, B.K.; Matziorinis, A.M.; Skouras, S.; Sudmann, T.T.; Gold, C.; Koelsch, S. Study protocol for the Alzheimer and music therapy study: An RCT to compare the efficacy of music therapy and physical activity on brain plasticity, depressive symptoms, and cognitive decline, in a population with and at risk for Alzheimer’s disease. PLoS ONE 2022, 17, e0270682. [Google Scholar] [CrossRef]
  188. Guetin, S.; Portet, F.; Picot, M.C.; Pommie, C.; Messaoudi, M.; Djabelkir, L.; Olsen, A.L.; Cano, M.M.; Lecourt, E.; Touchon, J. Effect of music therapy on anxiety and depression in patients with Alzheimer’s type dementia: Randomised, controlled study. Dement Geriatr. Cogn. Disord. 2009, 28, 36–46. [Google Scholar] [CrossRef]
  189. De Souza, L.B.R.; Gomes, Y.C.; de Moraes, M.G.G. The impacts of visual Art Therapy for elderly with Neurocognitive disorder: A systematic review. Dement. Neuropsychol. 2022, 16, 8–18. [Google Scholar] [CrossRef]
  190. Jensen, A.; Bonde, L.O. The use of arts interventions for mental health and wellbeing in health settings. Perspect. Public Health 2018, 138, 209–214. [Google Scholar] [CrossRef]
  191. Windle, G.; Joling, K.J.; Howson-Griffiths, T.; Woods, B.; Jones, C.H.; van de Ven, P.M.; Newman, A.; Parkinson, C. The impact of a visual arts program on quality of life, communication, and well-being of people living with dementia: A mixed-methods longitudinal investigation. Int. Psychogeriatr. 2018, 30, 409–423. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  192. Jeppson, T.A.; Nudo, C.A.; Mayer, J.F. Painting for a Purpose: A Visual Arts Program as a Method to Promote Engagement, Communication, Cognition, and Quality of Life for Individuals With Dementia. Am. J. Speech-Lang. Pathol. 2022, 31, 1687–1701. [Google Scholar] [CrossRef] [PubMed]
  193. Schofield, P. Dementia associated with toxic causes and autoimmune disease. Int. Psychogeriatr. 2005, 17 (Suppl. 1), S129–S147. [Google Scholar] [CrossRef] [PubMed]
  194. Genuis, S.J.; Kelln, K.L. Toxicant exposure and bioaccumulation: A common and potentially reversible cause of cognitive dysfunction and dementia. Behav. Neurol. 2015, 2015, 620143. [Google Scholar] [CrossRef] [Green Version]
  195. Zaganas, I.; Kapetanaki, S.; Mastorodemos, V.; Kanavouras, K.; Colosio, C.; Wilks, M.F.; Tsatsakis, A.M. Linking pesticide exposure and dementia: What is the evidence? Toxicology 2013, 307, 3–11. [Google Scholar] [CrossRef]
  196. Jurewicz, J.; Polanska, K.; Hanke, W. Exposure to widespread environmental toxicants and children’s cognitive development and behavioral problems. Int. J. Occup. Med. Environ. Health 2013, 26, 185–204. [Google Scholar]
  197. Bredesen, D.E. Inhalational Alzheimer’s disease: An unrecognized–and treatable–epidemic. Aging 2016, 8, 304–313. [Google Scholar] [CrossRef]
  198. Vasefi, M.; Ghaboolian-Zare, E.; Abedelwahab, H.; Osu, A. Environmental toxins and Alzheimer’s disease progression. Neurochem. Int. 2020, 141, 104852. [Google Scholar] [CrossRef]
  199. Mir, R.H.; Sawhney, G.; Pottoo, F.H.; Mohi-Ud-Din, R.; Madishetti, S.; Jachak, S.M.; Ahmed, Z.; Masoodi, M.H. Role of environmental pollutants in Alzheimer’s disease: A review. Environ. Sci. Pollut. Res. Int. 2020, 27, 44724–44742. [Google Scholar] [CrossRef]
  200. Shcherbatykh, I.; Carpenter, D.O. The role of metals in the etiology of Alzheimer’s disease. J. Alzheimers Dis. 2007, 11, 191–205. [Google Scholar] [CrossRef]
  201. Arce-Lopez, B.; Alvarez-Erviti, L.; De Santis, B.; Izco, M.; Lopez-Calvo, S.; Marzo-Sola, M.E.; Debegnach, F.; Lizarraga, E.; Lopez de Cerain, A.; Gonzalez-Penas, E.; et al. Biomonitoring of Mycotoxins in Plasma of Patients with Alzheimer’s and Parkinson’s Disease. Toxins 2021, 13, 477. [Google Scholar] [CrossRef] [PubMed]
  202. Killin, L.O.; Starr, J.M.; Shiue, I.J.; Russ, T.C. Environmental risk factors for dementia: A systematic review. BMC Geriatr. 2016, 16, 175. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  203. Zhao, Y.L.; Qu, Y.; Ou, Y.N.; Zhang, Y.R.; Tan, L.; Yu, J.T. Environmental factors and risks of cognitive impairment and dementia: A systematic review and meta-analysis. Ageing Res. Rev. 2021, 72, 101504. [Google Scholar] [CrossRef] [PubMed]
  204. Pisa, D.; Alonso, R.; Rabano, A.; Rodal, I.; Carrasco, L. Different Brain Regions are Infected with Fungi in Alzheimer’s Disease. Sci. Rep. 2015, 5, 15015. [Google Scholar] [CrossRef] [Green Version]
  205. Tran, V.T.A.; Lee, L.P.; Cho, H. Neuroinflammation in neurodegeneration via microbial infections. Front. Immunol. 2022, 13, 907804. [Google Scholar] [CrossRef]
  206. Bakulski, K.M.; Seo, Y.A.; Hickman, R.C.; Brandt, D.; Vadari, H.S.; Hu, H.; Park, S.K. Heavy Metals Exposure and Alzheimer’s Disease and Related Dementias. J. Alzheimers Dis. 2020, 76, 1215–1242. [Google Scholar] [CrossRef]
  207. Huat, T.J.; Camats-Perna, J.; Newcombe, E.A.; Valmas, N.; Kitazawa, M.; Medeiros, R. Metal Toxicity Links to Alzheimer’s Disease and Neuroinflammation. J. Mol. Biol. 2019, 431, 1843–1868. [Google Scholar] [CrossRef]
  208. Aloizou, A.M.; Siokas, V.; Vogiatzi, C.; Peristeri, E.; Docea, A.O.; Petrakis, D.; Provatas, A.; Folia, V.; Chalkia, C.; Vinceti, M.; et al. Pesticides, cognitive functions and dementia: A review. Toxicol. Lett. 2020, 326, 31–51. [Google Scholar] [CrossRef]
  209. Medehouenou, T.C.M.; Ayotte, P.; Carmichael, P.H.; Kroger, E.; Verreault, R.; Lindsay, J.; Dewailly, E.; Tyas, S.L.; Bureau, A.; Laurin, D. Exposure to polychlorinated biphenyls and organochlorine pesticides and risk of dementia, Alzheimer’s disease and cognitive decline in an older population: A prospective analysis from the Canadian Study of Health and Aging. Environ. Health A Glob. Access. Sci. Sour. 2019, 18, 57. [Google Scholar] [CrossRef]
  210. Manivannan, B.; Yegambaram, M.; Supowit, S.; Beach, T.G.; Halden, R.U. Assessment of Persistent, Bioaccumulative and Toxic Organic Environmental Pollutants in Liver and Adipose Tissue of Alzheimer’s Disease Patients and Age-matched Controls. Curr. Alzheimer Res. 2019, 16, 1039–1049. [Google Scholar] [CrossRef]
  211. Yegambaram, M.; Manivannan, B.; Beach, T.G.; Halden, R.U. Role of environmental contaminants in the etiology of Alzheimer’s disease: A review. Curr. Alzheimer Res. 2015, 12, 116–146. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  212. Crous-Bou, M.; Gascon, M.; Gispert, J.D.; Cirach, M.; Sanchez-Benavides, G.; Falcon, C.; Arenaza-Urquijo, E.M.; Gotsens, X.; Fauria, K.; Sunyer, J.; et al. Impact of urban environmental exposures on cognitive performance and brain structure of healthy individuals at risk for Alzheimer’s dementia. Environ. Int. 2020, 138, 105546. [Google Scholar] [CrossRef] [PubMed]
  213. Winstone, J.K.; Pathak, K.V.; Winslow, W.; Piras, I.S.; White, J.; Sharma, R.; Huentelman, M.J.; Pirrotte, P.; Velazquez, R. Glyphosate infiltrates the brain and increases pro-inflammatory cytokine TNFalpha: Implications for neurodegenerative disorders. J. Neuroinflamm. 2022, 19, 193. [Google Scholar] [CrossRef]
  214. Schikowski, T.; Altug, H. The role of air pollution in cognitive impairment and decline. Neurochem. Int. 2020, 136, 104708. [Google Scholar] [CrossRef]
  215. Park, S.Y.; Han, J.; Kim, S.H.; Suk, H.W.; Park, J.E.; Lee, D.Y. Impact of Long-Term Exposure to Air Pollution on Cognitive Decline in Older Adults Without Dementia. J. Alzheimers Dis. 2022, 86, 553–563. [Google Scholar] [CrossRef] [PubMed]
  216. Mortamais, M.; Gutierrez, L.A.; de Hoogh, K.; Chen, J.; Vienneau, D.; Carriere, I.; Letellier, N.; Helmer, C.; Gabelle, A.; Mura, T.; et al. Long-term exposure to ambient air pollution and risk of dementia: Results of the prospective Three-City Study. Environ. Int. 2021, 148, 106376. [Google Scholar] [CrossRef] [PubMed]
  217. Delgado-Saborit, J.M.; Guercio, V.; Gowers, A.M.; Shaddick, G.; Fox, N.C.; Love, S. A critical review of the epidemiological evidence of effects of air pollution on dementia, cognitive function and cognitive decline in adult population. Sci. Total Environ. 2021, 757, 143734. [Google Scholar] [CrossRef]
  218. Singh, N.; Chhillar, N.; Banerjee, B.; Bala, K.; Basu, M.; Mustafa, M. Organochlorine pesticide levels and risk of Alzheimer’s disease in north Indian population. Hum. Exp. Toxicol. 2013, 32, 24–30. [Google Scholar] [CrossRef]
  219. Singh, N.K.; Chhillar, N.; Banerjee, B.D.; Bala, K.; Mukherjee, A.K.; Mustafa, M.D. Mitrabasu, Gene-environment interaction in Alzheimer’s disease. Am. J. Alzheimer’s Dis. Other Dement. 2012, 27, 496–503. [Google Scholar] [CrossRef]
  220. Yan, D.; Zhang, Y.; Liu, L.; Yan, H. Pesticide exposure and risk of Alzheimer’s disease: A systematic review and meta-analysis. Sci. Rep. 2016, 6, 32222. [Google Scholar] [CrossRef] [Green Version]
  221. Tang, B.L. Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease. Toxics 2020, 8, 21. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  222. Queiroz, S.A.L.; Ton, A.M.M.; Pereira, T.M.C.; Campagnaro, B.P.; Martinelli, L.; Picos, A.; Campos-Toimil, M.; Vasquez, E.C. The Gut Microbiota-Brain Axis: A New Frontier on Neuropsychiatric Disorders. Front. Psychiatry 2022, 13, 872594. [Google Scholar] [CrossRef] [PubMed]
  223. Piekut, T.; Hurla, M.; Banaszek, N.; Szejn, P.; Dorszewska, J.; Kozubski, W.; Prendecki, M. Infectious agents and Alzheimer’s disease. J. Integr. Neurosci. 2022, 21, 73. [Google Scholar] [CrossRef]
  224. Chacko, A.; Delbaz, A.; Walkden, H.; Basu, S.; Armitage, C.W.; Eindorf, T.; Trim, L.K.; Miller, E.; West, N.P.; St John, J.A.; et al. Chlamydia pneumoniae can infect the central nervous system via the olfactory and trigeminal nerves and contributes to Alzheimer’s disease risk. Sci. Rep. 2022, 12, 2759. [Google Scholar] [CrossRef]
  225. Hill, J.M.; Clement, C.; Pogue, A.I.; Bhattacharjee, S.; Zhao, Y.; Lukiw, W.J. Pathogenic microbes, the microbiome, and Alzheimer’s disease (AD). Front. Aging Neurosci. 2014, 6, 127. [Google Scholar]
  226. Panza, F.; Lozupone, M.; Solfrizzi, V.; Watling, M.; Imbimbo, B.P. Time to test antibacterial therapy in Alzheimer’s disease. Brain 2019, 142, 2905–2929. [Google Scholar] [CrossRef] [PubMed]
  227. Itzhaki, R.F. Overwhelming Evidence for a Major Role for Herpes Simplex Virus Type 1 (HSV1) in Alzheimer’s Disease (AD); Underwhelming Evidence against. Vaccines 2021, 9, 679. [Google Scholar] [CrossRef] [PubMed]
  228. Wiatrak, B.; Balon, K.; Jawien, P.; Bednarz, D.; Jeskowiak, I.; Szelag, A. The Role of the Microbiota-Gut-Brain Axis in the Development of Alzheimer’s Disease. Int. J. Mol. Sci. 2022, 23, 4862. [Google Scholar] [CrossRef]
  229. Alexandrov, P.; Zhai, Y.; Li, W.; Lukiw, W. Lipopolysaccharide-stimulated, NF-kB-, miRNA-146a- and miRNA-155-mediated molecular-genetic communication between the human gastrointestinal tract microbiome and the brain. Folia Neuropathol. 2019, 57, 211–219. [Google Scholar] [CrossRef]
  230. Kraft, S.; Buchenauer, L.; Polte, T. Mold, Mycotoxins and a Dysregulated Immune System: A Combination of Concern? Int. J. Mol. Sci. 2021, 22, 12269. [Google Scholar] [CrossRef]
  231. Sadrameli, M.; Bathini, P.; Alberi, L. Linking mechanisms of periodontitis to Alzheimer’s disease. Curr. Opin. Neurol. 2020, 33, 230–238. [Google Scholar] [CrossRef] [PubMed]
  232. Beydoun, M.A.; Beydoun, H.A.; Hossain, S.; El-Hajj, Z.W.; Weiss, J.; Zonderman, A.B. Clinical and Bacterial Markers of Periodontitis and Their Association with Incident All-Cause and Alzheimer’s Disease Dementia in a Large National Survey. J. Alzheimers Dis. 2020, 75, 157–172. [Google Scholar] [CrossRef] [PubMed]
  233. Mao, S.; Huang, C.P.; Lan, H.; Lau, H.G.; Chiang, C.P.; Chen, Y.W. Association of periodontitis and oral microbiomes with Alzheimer’s disease: A narrative systematic review. J. Dent. Sci. 2022, 17, 1762–1779. [Google Scholar] [CrossRef] [PubMed]
  234. Cairns, D.M.; Itzhaki, R.F.; Kaplan, D.L. Potential Involvement of Varicella Zoster Virus in Alzheimer’s Disease via Reactivation of Quiescent Herpes Simplex Virus Type 1. J. Alzheimers Dis. 2022, 88, 1189–1200. [Google Scholar] [CrossRef]
  235. Lehrer, S.; Rheinstein, P.H. Vaccination Reduces Risk of Alzheimer’s Disease, Parkinson’s Disease and Other Neurodegenerative Disorders. Discov. Med. 2022, 34, 97–101. [Google Scholar]
  236. Nemergut, M.; Batkova, T.; Vigasova, D.; Bartos, M.; Hlozankova, M.; Schenkmayerova, A.; Liskova, B.; Sheardova, K.; Vyhnalek, M.; Hort, J.; et al. Increased occurrence of Treponema spp. and double-species infections in patients with Alzheimer’s disease. Sci. Total Environ. 2022, 844, 157114. [Google Scholar] [CrossRef]
  237. Hemmat, N.; Asadzadeh, H.; Asadzadeh, Z.; Shadbad, M.A.; Baradaran, B. The Analysis of Herpes Simplex Virus Type 1 (HSV-1)-Encoded MicroRNAs Targets: A Likely Relationship of Alzheimer’s Disease and HSV-1 Infection. Cell. Mol. Neurobiol. 2022, 42, 2849–2861. [Google Scholar] [CrossRef]
  238. Wang, T.; Rumbaugh, J.A.; Nath, A. Viruses and the brain: From inflammation to dementia. Clin. Sci. 2006, 110, 393–407. [Google Scholar] [CrossRef] [Green Version]
  239. Wainberg, M.; Luquez, T.; Koelle, D.M.; Readhead, B.; Johnston, C.; Darvas, M.; Funk, C.C. The viral hypothesis: How herpesviruses may contribute to Alzheimer’s disease. Mol. Psychiatry 2021, 26, 5476–5480. [Google Scholar] [CrossRef]
  240. Linard, M.; Letenneur, L.; Garrigue, I.; Doize, A.; Dartigues, J.F.; Helmer, C. Interaction between APOE4 and herpes simplex virus type 1 in Alzheimer’s disease. Alzheimers Dement 2020, 16, 200–208. [Google Scholar] [CrossRef]
  241. Empting, L.D. Neurologic and neuropsychiatric syndrome features of mold and mycotoxin exposure. Toxicol. Ind. Health 2009, 25, 577–581. [Google Scholar] [CrossRef] [PubMed]
  242. Abbott, A. Are infections seeding some cases of Alzheimer’s disease? Nature 2020, 587, 22–25. [Google Scholar] [CrossRef] [PubMed]
  243. Ganz, T.; Fainstein, N.; Ben-Hur, T. When the infectious environment meets the AD brain. Mol. Neurodegener. 2022, 17, 53. [Google Scholar] [CrossRef]
  244. Rosenblum Lichtenstein, J.H.; Hsu, Y.H.; Gavin, I.M.; Donaghey, T.C.; Molina, R.M.; Thompson, K.J.; Chi, C.L.; Gillis, B.S.; Brain, J.D. Environmental mold and mycotoxin exposures elicit specific cytokine and chemokine responses. PLoS ONE 2015, 10, e0126926. [Google Scholar] [CrossRef] [Green Version]
  245. Ratnaseelan, A.M.; Tsilioni, I.; Theoharides, T.C. Effects of Mycotoxins on Neuropsychiatric Symptoms and Immune Processes. Clin. Ther. 2018, 40, 903–917. [Google Scholar] [CrossRef] [PubMed]
  246. Howes, M.J.; Houghton, P.J. Ethnobotanical treatment strategies against Alzheimer’s disease. Curr. Alzheimer Res. 2012, 9, 67–85. [Google Scholar] [CrossRef] [PubMed]
  247. Abascal, K.; Yarnell, E. Alzheimer’s Disease-Part 2—A Botanical Treatment Plan. Altern. Complement. Ther. 2004, 10, 67–72. [Google Scholar] [CrossRef]
  248. Gregory, J.; Vengalasetti, Y.V.; Bredesen, D.E.; Rao, R.V. Neuroprotective Herbs for the Management of Alzheimer’s Disease. Biomolecules 2021, 11, 543. [Google Scholar] [CrossRef]
  249. Rao, R.V.; Descamps, O.; John, V.; Bredesen, D.E. Ayurvedic medicinal plants for Alzheimer’s disease: A review. Alzheimers Res. Ther. 2012, 4, 22. [Google Scholar] [CrossRef]
  250. Rasoanaivo, P.; Wright, C.W.; Willcox, M.L.; Gilbert, B. Whole plant extracts versus single compounds for the treatment of malaria: Synergy and positive interactions. Malar. J. 2011, 10 (Suppl. 1), S4. [Google Scholar] [CrossRef] [Green Version]
  251. Wagner, H.; Ulrich-Merzenich, G. Synergy research: Approaching a new generation of phytopharmaceuticals. Phytomedicine 2009, 16, 97–110. [Google Scholar] [CrossRef] [PubMed]
  252. Patwardhan, B.; Bodeker, G. Ayurvedic genomics: Establishing a genetic basis for mind-body typologies. J. Altern. Complement. Med. 2008, 14, 571–576. [Google Scholar] [CrossRef]
  253. Parasuraman, S.; Thing, G.S.; Dhanaraj, S.A. Polyherbal formulation: Concept of ayurveda. Pharmacogn. Rev. 2014, 8, 73–80. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  254. Barkat, M.A.; Goyal, A.; Barkat, H.A.; Salauddin, M.; Pottoo, F.H.; Anwer, E.T. Herbal Medicine: Clinical Perspective & Regulatory Status. Comb. Chem. High Throughput Screen. 2020, 24, 1573–1582. [Google Scholar]
  255. Howes, M.J.; Houghton, P.J. Plants used in Chinese and Indian traditional medicine for improvement of memory and cognitive function. Pharm. Biochem. Behav. 2003, 75, 513–527. [Google Scholar] [CrossRef] [PubMed]
  256. Eckert, G.P. Traditional used Plants against Cognitive Decline and Alzheimer Disease. Front. Pharmacol. 2010, 1, 138. [Google Scholar] [CrossRef] [Green Version]
  257. Zieneldien, T.; Kim, J.; Cao, C. The Multifaceted Role of Neuroprotective Plants in Alzheimer’s Disease Treatment. Geriatrics 2022, 7, 24. [Google Scholar] [CrossRef]
  258. Varteresian, T.; Lavretsky, H. Natural products and supplements for geriatric depression and cognitive disorders: An evaluation of the research. Curr. Psychiatry Rep. 2014, 16, 456. [Google Scholar] [CrossRef]
  259. Baker, L.D.; Manson, J.E.; Rapp, S.R.; Sesso, H.D.; Gaussoin, S.A.; Shumaker, S.A.; Espeland, M.A. Effects of cocoa extract and a multivitamin on cognitive function: A randomized clinical trial. Alzheimers Dement 2022. [Google Scholar] [CrossRef]
  260. Wang, Z.; Zhu, W.; Xing, Y.; Jia, J.; Tang, Y. B vitamins and prevention of cognitive decline and incident dementia: A systematic review and meta-analysis. Nutr. Rev. 2022, 80, 931–949. [Google Scholar] [CrossRef]
  261. Smith, A.D.; Refsum, H. Homocysteine, B Vitamins, and Cognitive Impairment. Annu. Rev. Nutr. 2016, 36, 211–239. [Google Scholar] [CrossRef] [PubMed]
  262. Tangvik, R.J.; Bruvik, F.K.; Drageset, J.; Kyte, K.; Hunskar, I. Effects of oral nutrition supplements in persons with dementia: A systematic review. Geriatr. Nurs. 2021, 42, 117–123. [Google Scholar] [CrossRef] [PubMed]
  263. Allen, V.J.; Methven, L.; Gosney, M.A. Use of nutritional complete supplements in older adults with dementia: Systematic review and meta-analysis of clinical outcomes. Clin. Nutr. 2013, 32, 950–957. [Google Scholar] [CrossRef] [PubMed]
  264. Pagano, G.; Aiello Talamanca, A.; Castello, G.; Cordero, M.D.; d’Ischia, M.; Gadaleta, M.N.; Pallardo, F.V.; Petrovic, S.; Tiano, L.; Zatterale, A. Current experience in testing mitochondrial nutrients in disorders featuring oxidative stress and mitochondrial dysfunction: Rational design of chemoprevention trials. Int. J. Mol. Sci. 2014, 15, 20169–20208. [Google Scholar] [CrossRef] [Green Version]
  265. Mantle, D.; Hargreaves, I.P. Mitochondrial Dysfunction and Neurodegenerative Disorders: Role of Nutritional Supplementation. Int. J. Mol. Sci. 2022, 23, 12603. [Google Scholar] [CrossRef]
  266. Saharan, S.; Mandal, P.K. The emerging role of glutathione in Alzheimer’s disease. J. Alzheimers Dis. 2014, 40, 519–529. [Google Scholar] [CrossRef]
  267. Mandal, P.K.; Shukla, D.; Tripathi, M.; Ersland, L. Cognitive Improvement with Glutathione Supplement in Alzheimer’s Disease: A Way Forward. J. Alzheimers Dis. 2019, 68, 531–535. [Google Scholar] [CrossRef] [Green Version]
  268. Arellanes, I.C.; Choe, N.; Solomon, V.; He, X.; Kavin, B.; Martinez, A.E.; Kono, N.; Buennagel, D.P.; Hazra, N.; Kim, G.; et al. Brain delivery of supplemental docosahexaenoic acid (DHA): A randomized placebo-controlled clinical trial. EBioMedicine 2020, 59, 102883. [Google Scholar] [CrossRef]
  269. Cole, G.M.; Frautschy, S.A. DHA may prevent age-related dementia. J. Nutr. 2010, 140, 869–874. [Google Scholar] [CrossRef] [Green Version]
  270. Velazquez, R.; Winslow, W.; Mifflin, M.A. Choline as a prevention for Alzheimer’s disease. Aging 2020, 12, 2026–2027. [Google Scholar] [CrossRef]
  271. Rahman, A.; Jackson, H.; Hristov, H.; Isaacson, R.S.; Saif, N.; Shetty, T.; Etingin, O.; Henchcliffe, C.; Brinton, R.D.; Mosconi, L. Sex and Gender Driven Modifiers of Alzheimer’s: The Role for Estrogenic Control Across Age, Race, Medical, and Lifestyle Risks. Front. Aging Neurosci. 2019, 11, 315. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  272. Jett, S.; Schelbaum, E.; Jang, G.; Boneu Yepez, C.; Dyke, J.P.; Pahlajani, S.; Diaz Brinton, R.; Mosconi, L. Ovarian steroid hormones: A long overlooked but critical contributor to brain aging and Alzheimer’s disease. Front. Aging Neurosci. 2022, 14, 948219. [Google Scholar] [CrossRef] [PubMed]
  273. Scheyer, O.; Rahman, A.; Hristov, H.; Berkowitz, C.; Isaacson, R.S.; Diaz Brinton, R.; Mosconi, L. Female Sex and Alzheimer’s Risk: The Menopause Connection. J. Prev. Alzheimer’s Dis. 2018, 5, 225–230. [Google Scholar] [CrossRef] [PubMed]
  274. Pike, C.J. Sex and the development of Alzheimer’s disease. J. Neurosci. Res. 2017, 95, 671–680. [Google Scholar] [CrossRef] [Green Version]
  275. Kornblith, E.; Bahorik, A.; Boscardin, W.J.; Xia, F.; Barnes, D.E.; Yaffe, K. Association of Race and Ethnicity With Incidence of Dementia Among Older Adults. JAMA 2022, 327, 1488–1495. [Google Scholar] [CrossRef]
  276. Mehta, K.M.; Yeo, G.W. Systematic review of dementia prevalence and incidence in United States race/ethnic populations. Alzheimers Dement 2017, 13, 72–83. [Google Scholar] [CrossRef]
  277. Yeo, G. Association of Race and Ethnicity With Dementia. JAMA 2022, 327, 1454–1455. [Google Scholar] [CrossRef]
  278. Cummings, J.L.; Goldman, D.P.; Simmons-Stern, N.R.; Ponton, E. The costs of developing treatments for Alzheimer’s disease: A retrospective exploration. Alzheimers Dement 2022, 18, 469–477. [Google Scholar] [CrossRef]
  279. Servick, K. Alzheimer’s drug approved despite murky results. Science 2021, 372, 1141. [Google Scholar] [CrossRef]
  280. Zucchella, C.; Sinforiani, E.; Tamburin, S.; Federico, A.; Mantovani, E.; Bernini, S.; Casale, R.; Bartolo, M. The Multidisciplinary Approach to Alzheimer’s Disease and Dementia. A Narrative Review of Non-Pharmacological Treatment. Front. Neurol. 2018, 9, 1058. [Google Scholar] [CrossRef] [Green Version]
  281. Poulos, C.J.; Bayer, A.; Beaupre, L.; Clare, L.; Poulos, R.G.; Wang, R.H.; Zuidema, S.; McGilton, K.S. A comprehensive approach to reablement in dementia. Alzheimer’s Dement. 2017, 3, 450–458. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Identifying and addressing potential contributors to cognitive decline with a personalized, multi-therapeutic approach is supportive of cognitive health. Shown in the figure are the various core strategies for the reversal of AD and MCI and for optimizing brain health.
Figure 1. Identifying and addressing potential contributors to cognitive decline with a personalized, multi-therapeutic approach is supportive of cognitive health. Shown in the figure are the various core strategies for the reversal of AD and MCI and for optimizing brain health.
Ijms 24 01659 g001
Table 1. Criteria for a perfect AD drug. A perfect drug is one that increases and optimizes all parameters on the left as they tend to be lowered or down-regulated in AD. The same drug decreases, lowers, or reduces the parameters on the right side, as these tend to be elevated in AD. The highlighted items indicate the targets of preference for most pharmaceutical companies. While some drugs are designed to target amyloid, others are focused on tau. However, here again, it is a mono-therapeutic strategy, and past single target-based failures have cast doubts on this approach.
Table 1. Criteria for a perfect AD drug. A perfect drug is one that increases and optimizes all parameters on the left as they tend to be lowered or down-regulated in AD. The same drug decreases, lowers, or reduces the parameters on the right side, as these tend to be elevated in AD. The highlighted items indicate the targets of preference for most pharmaceutical companies. While some drugs are designed to target amyloid, others are focused on tau. However, here again, it is a mono-therapeutic strategy, and past single target-based failures have cast doubts on this approach.
APP α-cleavagehomocysteine
NeprilysinAPP β-cleavage
IDEAPP γ-cleavage
Aβ clearanceCaspase-6 cleavage
AutophagyCaspase-3 cleavage
BDNFAPP b-oligomerization
NGFP-tau and PHF
Netrin-1Oxidative damage and ROS production
SIRT1Glial scarring
PP2A activityInflammation
PhagocytosisSynaptoclastic signaling
Insulin sensitivityNeuronal cell death
Axoplasmic transport
Mitochondrial function
Cholinergic neurotransmission
Long-term potentiation
Vit D, B12, and Zinc
Estradiol, progesterone, pregnenolone, DHEA, GABA, free T3, free T4, TSH
Table 2. Reversing AD-associated cognitive health requires addressing potential contributors to cognitive decline with a personalized, multi-therapeutic approach. Each of the strategies mentioned in the table has the ability to improve cognition and brain health, and when practiced together, they create a powerful synergy with sustained improvement.
Table 2. Reversing AD-associated cognitive health requires addressing potential contributors to cognitive decline with a personalized, multi-therapeutic approach. Each of the strategies mentioned in the table has the ability to improve cognition and brain health, and when practiced together, they create a powerful synergy with sustained improvement.
Multi-Therapeutic StrategiesGoals
NutritionImproves cognition and supports brain health by
  • creating insulin sensitivity
  • promoting metabolic flexibility/ ketosis
  • reducing inflammation
  • improving vascular health
  • promoting autophagy
  • increases brain-derived neurotrophic factor (BDNF) that stimulates neuroplasticity
  • increases cerebral blood flow and oxygenation
  • mitigates overall stress
  • optimizes body mass index (BMI)
  • improves insulin sensitivity
  • reduces inflammation
  • stabilizes brain volume and decreases white matter lesions
  • enhances ability to focus, learn, and memorize
  • reduces stress
  • promotes neuroplasticity
  • improves waste-clearing capacity
Stress Management
  • activates parasympathetic arm of HPA axis and balances stress hormones
  • increases cerebral blood flow and oxygenation
  • improves insulin sensitivity
  • reduces inflammation
  • boosts cognitive acuity
Mental exercise
(Brain stimulation)
  • promotes neural connectivity in response to new learning
  • improves mood, thinking, hearing, problem-solving, reasoning, and memory
  • lowers risk of cognitive decline and dementia
  • improves activities of daily living
DetoxificationImproves cognition and supports brain health by
  • treating dementogen exposure and limiting ongoing exposure
  • reducing systemic and brain inflammation
  • optimizing gut, oral and nasal microbiome
  • upregulating the immune system and mitochondrial energetics
Herbs & SupplementsImprove cognition and support brain health by
  • promoting neural connectivity and effective synaptic support
  • optimizing trophic support
  • upregulating the immune system and gut health
  • reducing inflammation
  • boosting cognitive acuity
  • improving vascular health
  • neutralizing free radicals
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Rao, R.V.; Subramaniam, K.G.; Gregory, J.; Bredesen, A.L.; Coward, C.; Okada, S.; Kelly, L.; Bredesen, D.E. Rationale for a Multi-Factorial Approach for the Reversal of Cognitive Decline in Alzheimer’s Disease and MCI: A Review. Int. J. Mol. Sci. 2023, 24, 1659.

AMA Style

Rao RV, Subramaniam KG, Gregory J, Bredesen AL, Coward C, Okada S, Kelly L, Bredesen DE. Rationale for a Multi-Factorial Approach for the Reversal of Cognitive Decline in Alzheimer’s Disease and MCI: A Review. International Journal of Molecular Sciences. 2023; 24(2):1659.

Chicago/Turabian Style

Rao, Rammohan V., Kaavya G. Subramaniam, Julie Gregory, Aida L. Bredesen, Christine Coward, Sho Okada, Lance Kelly, and Dale E. Bredesen. 2023. "Rationale for a Multi-Factorial Approach for the Reversal of Cognitive Decline in Alzheimer’s Disease and MCI: A Review" International Journal of Molecular Sciences 24, no. 2: 1659.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop