Search Results (632)

Background/Objectives: Multifactorial prevention of falls in persons with dementia has minimal or non-significant effects. Personalised prevention is recommended. We have previously shown that gait speed, basic activities of daily living (ADL), and depression (high Cornell scores) were independent predictors of falls in persons with mild and moderate cognitive impairment. This study explored person-specific risks of falls related to physical, mental, and cognitive functions and types of dementia: Alzheimer’s disease (AD), vascular dementia (VD), mixed Alzheimer’s disease/vascular dementia (MixADVD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). Methods: The study used data from “The Norwegian Registry of Persons Assessed for Cognitive Symptoms” (NorCog). Differences between the dementia groups and predictors of falls, gait speed, ADL, and Cornell scores were analysed. Results: Among study participants, 537/1321 (40.7%) reported a fall in the past year, with significant variations between dementia diagnoses. Fall incidence increased with age, comorbidity/polypharmacy, depression, and MAYO fluctuation score and with reduced physical activity, gait speed, and ADL. Persons with VD and MixADVD had high fall incidences and impaired gait speed and ADL. Training of physical fitness, endurance, muscular strength, coordination, and balance and optimising treatment of comorbidities and medication enhance gait speed. Improving ADL necessitates, in addition, relief of cognitive impairment and fluctuations. Relief of depression and fluctuations by psychological and pharmacological interventions is necessary to reduce the high fall risk in persons with DLB. Conclusions: The fall incidence and fall predictors varied significantly. Personalised interventions presuppose knowledge of each individual’s fall risk factors. Full article

Background: There is growing interest in the potential role of manganese (Mn) in the development of Alzheimer’s Disease and related dementias (ADRD). Methods: In this nested pilot study of a ferroalloy worker cohort, we investigated the impact of chronic occupational Mn exposure on cognitive function through β-amyloid (Aβ) deposition and multi-omics profiling. We evaluated six male Mn-exposed workers (median age 63, exposure duration 31 years) and five historical controls (median age: 60 years), all of whom had undergone brain PET scans. Exposed individuals showed significantly higher Aβ deposition in exposed individuals (p < 0.05). The average annual cumulative respirable Mn was 329.23 ± 516.39 µg/m³ (geometric mean 118.59), and plasma Mn levels were significantly elevated in the exposed group (0.704 ± 0.2 ng/mL) compared to controls (0.397 ± 0.18 in controls). Results: LC-MS/MS-based pathway analyses revealed disruptions in olfactory signaling, mitochondrial fatty acid β-oxidation, biogenic amine synthesis, transmembrane transport, and choline metabolism. Simoa analysis showed notable alterations in ADRD-related plasma biomarkers. Protein microarray revealed significant differences (p < 0.05) in antibodies targeting neuronal and autoimmune proteins, including Aβ (25–35), GFAP, serotonin, NOVA1, and Siglec-1/CD169. Conclusion: These findings suggest Mn exposure is associated with neurodegenerative biomarker alterations and disrupted biological pathways relevant to cognitive decline. Full article

Alzheimer’s disease (AD) is increasingly recognized as a multifactorial disorder driven by a combination of disruptions in proteostasis and organelle communication. The 2020 Lancet commission reported that approximately 10 million people worldwide were affected by AD in the mid-20th century. AD is the most prevalent cause of dementia. By early 2030, the global cost of dementia is projected to rise by USD 2 trillion per year, with up to 85% of that cost attributed to daily patient care. Several factors have been implicated in the progression of neurodegeneration, including increased oxidative stress, the accumulation of misfolded proteins, the formation of amyloid plaques and aggregates, the unfolded protein response (UPR), and mitochondrial–endoplasmic reticulum (ER) calcium homeostasis. However, the exact triggers that initiate these pathological processes remain unclear, in part because clinical symptoms often emerge gradually and subtly, complicating early diagnosis. Among the early hallmarks of neurodegeneration, elevated levels of reactive oxygen species (ROS) and the buildup of misfolded proteins are believed to play pivotal roles in disrupting proteostasis, leading to cognitive deficits and neuronal cell death. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles is a characteristic feature of AD. These features contribute to chronic neuroinflammation, which is marked by the release of pro-inflammatory cytokines and chemokines that exacerbate oxidative stress. Given these interconnected mechanisms, targeting stress-related signaling pathways, such as oxidative stress (ROS) generated in the mitochondria and ER, ER stress, UPR, and cytosolic chaperones, represents a promising strategy for therapeutic intervention. This review focuses on the relationship between stress chaperone responses and organelle function, particularly the interaction between mitochondria and the ER, in the development of new therapies for AD and related neurodegenerative disorders. Full article

Background/Objectives: Neurodegenerative proteinopathies, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB), are increasingly prevalent worldwide mainly due to population aging. These conditions are marked by complex etiologies, overlapping pathologies, and progressive clinical decline, with significant consequences for patients, caregivers, and healthcare systems. This review aims to synthesize evidence on the healthcare complexities of major neurodegenerative proteinopathies to highlight current knowledge gaps, and to inform future care models, policies, and research directions. Methods: We conducted a comprehensive literature search in PubMed/MEDLINE using combinations of MeSH terms and keywords related to neurodegenerative diseases, proteinopathies, diagnosis, sex, management, treatment, caregiver burden, and healthcare delivery. Studies were included if they addressed the clinical, pathophysiological, economic, or care-related complexities of aging-related neurodegenerative proteinopathies. Results: Key themes identified include the following: (1) multifactorial and unclear etiologies with frequent co-pathologies; (2) long prodromal phases with emerging biomarkers; (3) lack of effective disease-modifying therapies; (4) progressive nature requiring ongoing and individualized care; (5) high caregiver burden; (6) escalating healthcare and societal costs; and (7) the critical role of multidisciplinary and multi-domain care models involving specialists, primary care, and allied health professionals. Conclusions: The complexity and cost of neurodegenerative proteinopathies highlight the urgent need for prevention-focused strategies, innovative care models, early interventions, and integrated policies that support patients and caregivers. Prevention through the early identification of risk factors and prodromal signs is critical. Investing in research to develop effective disease-modifying therapies and improve early detection will be essential to reducing the long-term burden of these disorders. Full article

Alzheimer’s disease (AD) is one of the most common chronic neurodegenerative disorders worldwide. It is characterized by progressive memory loss and cognitive decline, leading to dementia. The pathogenesis of the disease is primarily attributed to two pathological protein structures: amyloid-beta (Aβ) plaques and tau protein neurofibrils. The current treatment strategies for AD are mainly symptomatic, highlighting the urgent need for the development of new, more effective therapies for the disease. The purpose of this paper is to provide a comprehensive and scientific review of the latest research regarding novel therapeutic options in the treatment of AD. In recent years, research has focused on more advanced and diversified strategies, including immunotherapy, gene therapy, tyrosine kinase inhibitors, therapies targeting mitochondrial function, and neurogenesis-related process modulation. One of the most promising treatment strategies for AD is immunotherapy. Intensive research is currently underway on both passive immunization, which involves the administration of monoclonal antibodies, and active immunization through vaccinations that stimulate the body to produce specific antibodies. Further research into novel therapeutic directions is essential, particularly concerning the role of the immune system in the pathogenesis of AD. Immunization appears to be a highly promising approach to developing effective methods for preventing AD or delaying the progression of this disease. Full article

Alzheimer’s disease (AD) is a leading cause of dementia, characterized by progressive cognitive and language impairments that significantly impact communication and quality of life. Neuromodulation techniques, including repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS), have emerged as promising interventions. This study employs bibliometric analysis to evaluate global research trends in neuromodulation treatments for AD-related language impairments. A total of 88 publications from the Web of Science Core Collection (2006–2024) were analyzed using bibliometric methods. Key indicators such as publication trends, citation patterns, collaboration networks, and research themes were examined to map the intellectual landscape of this field. The analysis identified 580 authors across 65 journals, with an average of 34.82 citations per article. Nearly half of the publications were produced after 2021, indicating rapid recent growth. The findings highlight a predominant focus on non-invasive neuromodulation methods, particularly rTMS and tDCS, within neurosciences and neurology. While research activity is increasing, significant challenges persist, including ethical concerns, operational constraints, and the translational gap between research and clinical applications. This study provides insights into the current research landscape and future directions for neuromodulation in AD-related language impairments. The results emphasize the need for novel neuromodulation techniques and interdisciplinary collaboration to enhance therapeutic efficacy and clinical integration. Full article

Alzheimer’s Disease (AD) is the most common type of dementia. The circadian system, which is controlled by the master clock in the Suprachiasmatic Nucleus (SCN) of the hypothalamus, is crucial for various physiological processes. Studies have shown that changes in the circadian rhythms can deteriorate neurodegenerative diseases. Changes in the SCN are associated with cognitive decline in AD. The cognitive impairments in AD, especially memory dysfunctions, may be related to Circadian Rhythm Disturbances (CRDs). Moreover, rhythmic expression of clock genes is disrupted in AD patients. There is a circadian pattern of inflammatory processes in AD, and dysregulation of core clock genes promotes neuroinflammation. The present narrative review addresses the intricate link between CRDs and AD, revisiting the relevant cellular and molecular mechanisms. The association between CRDs and AD highlights the need for further investigation of the underlying mechanisms. Full article

Background: High-density lipoprotein cholesterol (HDL-C) is known for its cardiovascular and neuroprotective effects, but its association with cognitive function remains unclear, particularly in relation to genetic factors such as apolipoprotein E ε4 (APOE4). We aimed to investigate the association between serum HDL-C levels and cognition and to examine the moderating effect of APOE4 on this relationship. Methods: This cross-sectional study included 196 dementia-free older adults (aged 65–90) recruited from a memory clinic and the community. Cognitive function was assessed across multiple domains using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) battery. Serum HDL-C levels were measured, and APOE4 genotyping was performed. Multiple linear regression analyses were conducted, adjusting for age, sex, APOE4 status, education, diagnosis, vascular risk, nutritional status, physical activity, and blood biomarkers. Results: Higher HDL-C levels were significantly associated with better episodic memory (B = 0.109, 95% confidence interval [CI]: 0.029–0.189, p = 0.008) and global cognition (B = 0.130, 95% CI: 0.001–0.261, p = 0.049). These associations were significantly moderated by APOE4 status. In APOE4-positive individuals, HDL-C was strongly associated with both episodic memory (B = 0.357, 95% CI: 0.138–0.575, p = 0.003) and global cognition (B = 0.519, 95% CI: 0.220–0.818, p = 0.002), but no such associations were observed in APOE4-negative participants. Conclusions: This study indicates a significant association between serum HDL-C levels and cognitive function, particularly in episodic memory and global cognition, with APOE4 status potentially moderating this relationship. While these findings may suggest a protective role of HDL-C in individuals at increased genetic risk due to APOE4, they should be interpreted with caution given the cross-sectional design. Future longitudinal and mechanistic studies are warranted to clarify causality and potential clinical implications. Full article

Background: Suicidal behavior presents a significant dilemma in the context of Alzheimer’s disease. Numerous ethical discussions have emerged regarding euthanasia for patients suffering from neurodegenerative conditions, and research indicates an elevated incidence of suicide in the early stages of dementia. However, there remains a gap in knowledge concerning the historical prevalence of suicidal ideations or attempts among individuals diagnosed with Alzheimer’s disease. This study aims to investigate the historical patterns of suicidal behavior and the associated factors across the lifespan in patients with Alzheimer’s disease. Methods: This study is an excerpt from a case–control research study, where the sample size was calculated at 150 participants, with 75 in the case group and 75 in the control group. Here, the descriptive statistics for the first third of the sample, 50 participants, are discussed. Results: Among the participants in the case group, 12.5% reported having suicidal ideation throughout life, compared to 24% in the control group (OR for suicidal ideation = 0.432 [0.095–1.966]). Additionally, among the participants in the case group, 4% reported having attempted suicide at some point in their life, compared to 8% in the control group (OR for suicide attempts = 0.479 [0.41–5.652]). People with Alzheimer’s disease tended to have a worse quality of life but less suicidality. Conclusions: It appears that suicidal behavior is inversely related to the risk of developing suicidal intentions. The odds ratio data demonstrate the need for a larger sample size to determine whether there is a difference in the history of suicide throughout the lives of people with Alzheimer’s disease and among the general population. Full article

Alzheimer’s disease (AD) is the leading cause of dementia, with a prevalence expected to escalate with the aging of the world population as life expectancy increases. In spite of significant progress made in the investigation of the etiology and pathogenesis of the disease, many mechanistic aspects that could support the implementation of novel therapeutic avenues remain unresolved. Research during the last decade has revealed a crucial role for mitochondria-mediated pathways dysregulation as significant contributors to the disease, highlighting the relevance of changes in brain metabolism and bioenergetics as well as the induction of oxidative stress conditions for neurodegeneration. This review summarizes mitochondrial functional changes associated with AD with emphasis in the dysregulation of redox homeostasis and the role of nuclear factor erythroid 2-related factor 2 (Nrf2), not only as a central regulator of the antioxidant response but also as a more recently described modulator of cellular metabolic pathways. Potential therapeutic strategies targeting oxidative stress and mitochondrial dysfunction are also discussed, with particular emphasis on the use of small molecules Nrf2 activators. Exploiting the multifactorial properties of the transcription factor in either novel or combination-based pharmacological approaches targeting multiple genes and pathways may contribute to providing more definitive and precise therapeutic perspectives. Full article

Background: Research concerning the genetic risk for dementia has recently been headed towards new directions. Novel findings from genome-wide association studies have highlighted the association of Alzheimer’s disease incidence with many gene polymorphisms, apart from the Apolipoprotein-E genotype. The identification of additional genetic risk factors has led to the construction of specific genetic risk scores for dementia, considering many different genetic factors and specific biological pathways related to Alzheimer’s disease. Methods: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis method, summarizing existing data regarding genetic risk scores for Alzheimer’s disease and dementia, in order to improve the current understanding of the genetic underpinnings of dementia. In specific, five databases (PubMed/MEDLINE, Embase, Scopus, Web of science, and Cochrane Central) were searched using the keywords “genetic risk score”, “Alzheimer’s disease”, and “dementia” with specific inclusion and exclusion criteria. Results: From the 552 articles identified, we finally included 20 studies for the qualitative analysis. These reports were classified in three different categories of genetic scores: “polygenic risk scores (PRSs)” (including 11 studies), “pathway specific polygenic risk scores (p-PRSs)” (5 studies), and “complex genetic risk scores” (4 studies). Conclusions: Existing genetic risk scores have contributed to better dementia prediction and a better understanding of the underlying pathology. Novel approaches integrating multiple polygenic risk scores might ameliorate the accuracy of genetic risk scores. The combination of polygenic risk scores that are specific to related biological pathways or relevant biomarkers is of utmost importance to achieve a better predictive ability. Full article

Alzheimer’s disease (AD), the leading cause of dementia, remains poorly understood despite decades of intensive research, which continues to hinder the development of effective treatments. As a complex multifactorial disorder, AD lacks a cure to halt the progressive neurodegeneration, and the precise mechanisms underlying its onset and progression remain elusive, limiting therapeutic options. Due to the challenges of studying neuronal cells in vivo, technologies such as clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) and human-induced pluripotent stem cells (hiPSCs) are key for identifying therapeutic targets, although they face technical and ethical hurdles in their early stages. CRISPR/Cas9 and hiPSCs are promising for disease modeling and therapy, but off-target effects and the complexity of gene editing in the brain limit their use. CRISPR technology enables specific genetic modifications in key AD-related genes, such as APP, PSEN1, PSEN2, and APOE, providing valuable insights into disease mechanisms. iPSC-derived neurons, astrocytes, microglia, and 3D organoids can recapitulate key aspects of human AD pathology, but they do not fully replicate the complexity of the human brain, limiting clinical applicability. These technologies advance studies of amyloid processing, tau aggregation, neuroinflammation, and oxidative stress, yet translating them into clinical therapies remains challenging. Despite the promise of CRISPR/Cas9 and iPSCs for precision medicine, gaps in knowledge about their long-term safety and efficacy must be addressed before clinical implementation. Full article

Background/Objectives: Gamma oscillations (30–100 Hz), which are essential for memory, attention, and cortical synchronization, remain underexplored in Alzheimer’s disease (AD) research. While resting-state EEG studies have predominantly examined lower frequency bands (delta to beta), gamma activity may more accurately reflect early synaptic dysfunction and other mechanisms relevant to AD pathophysiology. AD is a common age-related neurodegenerative disorder frequently associated with altered resting-state EEG (rEEG) patterns. This study analyzed gamma power spectral density (PSD) during eyes-open (EOR) and eyes-closed (ECR) resting-state EEG in AD patients compared to cognitively normal (CN) individuals. Methods: rEEG data from 534 participants (269 CN, 265 AD) aged 40–90 were analyzed. Quantitative EEG (qEEG) analysis focused on the gamma band (30–100 Hz) using PSD estimation with the Welch method, coherence matrices, and coherence-based functional connectivity. Data preprocessing and analysis were performed using EEGLAB and Brainstorm in MATLAB R2024b. Group comparisons were conducted using ANOVA for unadjusted models and linear regression with age adjustment using log₁₀-transformed PSD values in Python (version 3.13.2, 2025). Results: AD patients exhibited significantly elevated gamma PSD in frontal and temporal regions during EOR and ECR states compared to CN. During ECR, gamma PSD was markedly higher in the AD group (Mean = 0.0860 ± 0.0590) than CN (Mean = 0.0042 ± 0.0010), with a large effect size (Cohen’s d = 1.960, p < 0.001). Conversely, after adjusting for age, the group difference was no longer statistically significant (β = −0.0047, SE = 0.0054, p = 0.391), while age remained a significant predictor of gamma power (β = −0.0008, p = 0.019). Pairwise coherence matrix and coherence-based functional connectivity were increased in AD during ECR but decreased in EOR relative to CN. Conclusions: Gamma oscillatory activity in the 30–100 Hz range differed significantly between AD and CN individuals during resting-state EEG, particularly under ECR conditions. However, age-adjusted analyses revealed that these differences are not AD-specific, suggesting that gamma band changes may reflect aging-related processes more than disease effects. These findings contribute to the evolving understanding of gamma dynamics in dementia and support further investigation of gamma PSD as a potential, age-sensitive biomarker. Full article

Background/Objectives: We previously demonstrated that nilotinib can sufficiently enter the brain to pharmacologically inhibit discoidin domain receptors (DDR)-1 in patients with Parkinson’s and Alzheimer’s disease. We primarily hypothesized that nilotinib is safe, and may alter disease-related biomarkers to improve, motor, cognitive and/or behavioral features in dementia with Lewy bodies (DLB). Methods: Forty-three participants were randomized 1:1 into nilotinib, 200 mg, or matching placebo in a single-center, phase 2, randomized, double-blind study. Study drug was taken orally once daily for 6 months followed by one-month wash-out. Results: Of 43 individuals enrolled, 14 were women (33%); age (mean ± SD) was 73 ± 8.5 years. Nilotinib was safe and well-tolerated, and more adverse events were noted in the placebo (74) vs. nilotinib (37) groups (p = 0.054). The number of falls were reduced in the nilotinib (six) compared to placebo (21) group (p = 0.006). Cerebrospinal fluid homovanillic acid, a biomarker of dopamine levels, was increased (p = 0.004), while the ratio of pTau181/Aβ42 was reduced (p = 0.034). The Alzheimer’s Disease Assessment Scale—cognition 14 improved by 2.8 pts (p = 0.037), and no differences were observed in Movement Disorders Society–Unified Parkinson’s Disease Rating Scale parts II and III. However, part I (cognition) improved (p = 0.044) in nilotinib compared to placebo. Conclusions: Nilotinib demonstrates favorable safety, biomarkers, and efficacy outcomes in patients with DLB supporting further trials in DLB or advanced Parkinson’s disease with dementia. Full article

Background/Objectives: Alzheimer’s disease (AD) is the leading cause of dementia and is characterized by progressive neurodegeneration, resulting in cognitive impairment and structural brain changes. Although no curative treatment exists, pharmacological therapies like cholinesterase inhibitors and NMDA receptor antagonists may deliver symptomatic relief and modestly delay disease progression. Structural magnetic resonance imaging (sMRI) is a commonly utilized modality for the diagnosis of brain neurological diseases and may indicate abnormalities. However, improving the recognition of discriminative characteristics is the primary difficulty in diagnosis utilizing sMRI. Methods: To tackle this problem, the Fuzzy Optimized Attention Network with Multi-Instance Deep Learning (FOA-MIDL) system is presented for the prodromal phase of mild cognitive impairment (MCI) and the initial detection of AD. Results: An attention technique to estimate the weight of every case is presented: the fuzzy salp swarm algorithm (FSSA). The swarming actions of salps in oceans serve as the inspiration for the FSSA. When moving, the nutrient gradients influence the movement of leading salps during global search exploration, while the followers fully explore their local environment to adjust the classifiers’ parameters. To balance the relative contributions of every patch and produce a global distinct weighted image for the entire brain framework, the attention multi-instance learning (MIL) pooling procedure is developed. Attention-aware global classifiers are presented to improve the understanding of the integral characteristics and form judgments for AD-related categorization. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Australian Imaging, Biomarker, and Lifestyle Flagship Study on Ageing (AIBL) provided the two datasets (ADNI and AIBL) utilized in this work. Conclusions: Compared to many cutting-edge techniques, the findings demonstrate that the FOA-MIDL system may determine discriminative pathological areas and offer improved classification efficacy in terms of sensitivity (SEN), specificity (SPE), and accuracy. Full article