Search Results (89)

Alzheimer’s disease (AD), the most common cause of dementia, is characterized by progressive memory and cognitive decline. Conventional genome-wide association studies (GWAS) comparing AD cases and controls may miss genetic influences that act along a continuum of cognitive function. Using data from 3007 participants in the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study (NIA-LOAD GWAS), we conducted a family-based GWAS of eight quantitative cognitive phenotypes encompassing episodic memory (Logical Memory IA and IIA), working memory (Digit Span Forward, Backward, and Ordering), and semantic fluency (Animal, Fruit and Vegetable, and Vegetable Fluency). Family-based association testing in PLINK v1.9 identified numerous single nucleotide polymorphisms (SNPs) associated with cognitive phenotypes at genome-wide significant (p < 5 × 10⁻⁸) levels. Notably, genome-wide significant variants with cognatic functions were localized to genes implicated in synaptic function, neurodevelopment, and neurodegeneration, including TOMM40 (rs2075650), ERBB4 (rs1521543), APLP2 (rs12281267, rs959354), PTPRD (rs1353983, rs970347, rs1392511), NCAM2 (rs2826728), GRM7 (rs6788201), PAX5 (rs2988003, rs2381595), NRG1 (rs16875655), and NRG3 (rs1937957). Furthermore, the TOMM40 (rs2075650) was significantly associated with AD as a binary outcome (p = 4.60 × 10⁻²⁴) and APLP2 (rs12281267, rs959354), APOE (rs405509), PTPRD (rs1353983, rs970347, rs1392511) were associated with AD (p < 0.001). Additionally, several pathways including the ERBB4 signaling pathway (adjusted p = 2.82 × 10⁻³), driven by ERBB4, NRG1, and NRG3 may contribute to cognitive impairments. This study provides a comprehensive resource of cognitive endophenotype associations in AD families, advancing understanding of the genetic architecture underlying memory, executive function, and cognitive aging, and highlights new therapeutic targets for replication and functional follow-up. Full article

Lipid abnormalities have been observed in brain, cerebrospinal fluid (CSF), and blood in association with late-onset Alzheimer’s disease (LOAD). It is unknown which of these abnormalities are precursors to LOAD and which are concomitants of illness or its treatment. Inherent abnormalities can be identified in induced pluripotent stem cell (iPSC)-derived brain cells. These cells lack markers associated with aging and environmental exposures. The iPSC lines of patients with LOAD or healthy individuals were differentiated to astrocytes. Astrocytes are crucial to neural activity and health, and altered astrocyte functions are associated with LOAD pathology. Lipidomics analyses were performed on whole-cell and mitochondria-enriched fractions. Large reductions in cholesterol esters (CEs) and imbalances in fatty acids (FAs) were observed in LOAD-associated cells or their mitochondria. There were only modest differences in other lipid classes, including membrane structural lipids. The findings identify abnormalities in CEs, as well as in FAs, as inherent abnormalities and likely precursors to LOAD. These differences implicate mechanisms contributing to disease pathogenesis. Further study may lead to early interventions to prevent or delay LOAD. Full article

This narrative review integrates longitudinal cohort studies, neuroimaging and biomarker research, and major clinical trials to examine how depression and cognitive decline interact across the dementia continuum. Depression and cognitive impairment frequently co-occur in late life and exhibit substantial clinical and biological overlap. Meta-analytic and large population-based cohort studies consistently show that late-life depression increases the risk of mild cognitive impairment and dementia, with stronger associations observed for vascular dementia than for Alzheimer’s disease. Neurobiological studies implicate cerebrovascular pathology, neuroinflammation, hypothalamic–pituitary–adrenal axis dysregulation, and fronto-subcortical circuit dysfunction as key mechanisms linking depressive symptoms to later cognitive decline. In a subset of older adults, new-onset depression—particularly when accompanied by executive dysfunction, subjective cognitive decline, or high white-matter hyperintensity burden—are associated with an increased likelihood of near-term cognitive decline and dementia, although evidence for a definitive prodromal state remains limited. Depression is also highly prevalent as part of the behavioral and psychological symptoms of dementia, occurring in 30–50% of individuals with Alzheimer’s disease and even higher proportions in dementia with Lewy bodies or frontotemporal dementia. Comorbid depression in dementia accelerates cognitive and functional decline, increases neuropsychiatric burden, and worsens quality of life for patients and caregivers. Therapeutically, antidepressant treatment may confer modest benefits on mood and selected cognitive domains (e.g., processing speed and executive function) in non-demented older adults, whereas in established dementia, antidepressant efficacy is limited. In contrast, cholinesterase inhibitors, memantine, and multimodal non-pharmacological interventions yield small but measurable improvements in depressive or apathy-related symptoms. Emerging disease-modifying therapies for Alzheimer’s disease have demonstrated cognitive benefits, but current trial data provide insufficient evidence regarding effects on depressive symptoms, highlighting an important gap for future research. These findings underscore the need for stage-specific, integrative strategies to address the intertwined trajectories of mood and cognition in aging. Full article

Background/Objective: To examine whether patients with late-onset schizophrenia (LOS) and very-late-onset schizophrenia-like psychosis (VLOS) are at a higher risk of developing dementia than patients with early-onset schizophrenia (EOS). Methods: A random sample of incident cases of patients with schizophrenia with an age of onset after age 40 (LOS) and age 60 (VLOS) was selected from a psychiatric case register covering all psychiatric services within the city of The Hague, The Netherlands, between 1997 and 2012. Schizophrenia diagnosis and age of onset were audited by systematic review of all case notes up to 2019. Patients who were initially misclassified as LOS/VLOS in the registry but, after this audit, had an age of onset before age 40, were classified as EOS. The risk of developing dementia was compared between the groups using a logistic regression model with correction for age, gender, and stroke as possible confounders. Results: Our study groups consisted of 74 patients with EOS, 81 with LOS, and 25 with VLOS. Dementia was present in 10 patients at follow-up, 7 out of 106 (6.6%) patients in the combined LOS and VLOS groups, and 3 out of 74 (4.1%) patients in the EOS group. However, after correction for confounders, logistic regression showed no statistically significant higher change in the development of dementia in LOS nor VLOS patients compared to EOS patients, nor with age of onset as a continuous variable. Conclusions: Patients with LOS and VLOS are not at a higher risk of developing dementia compared to patients with EOS. These results do not support the hypothesis that LOS and especially VLOS, are precursors of dementia. Full article

Background: Late-onset depression (LOD) represents a distinct clinical and biological phenotype emerging in the context of global population ageing. This study aims to synthesize current evidence on the epidemiology, risk factors, mechanistic pathways, and therapeutic approaches of LOD, integrating biological, psychological, and social dimensions. Methods: This narrative review synthesizes recent evidence across epidemiology, clinical symptomatology, neurobiology, and treatment. Where conceptually appropriate or empirically overlapping, we incorporate findings from the broader late-life depression (LLD) literature. Results: LOD emerges (as a distinct clinical and biological entity in later life) as a clinically and biologically meaningful presentation of depression in later life, representing a minority of depressive cases. It is defined by prominent apathy, psychomotor slowing, and cognitive impairment, and is closely linked to frailty, medical comorbidity, and heightened dementia risk. Pathophysiological mechanisms converge on vascular, inflammatory, oxidative, and neuroplasticity pathways, while psychosocial adversity further shapes onset and course. Treatment prioritizes efficacy and tolerability amid multiple morbidity; SSRIs and SNRIs are first-line, with pro-dopaminergic or dual-action agents addressing anhedonia and apathy, and neuromodulation or augmentation strategies reserved for resistance. Integrative approaches combining pharmacotherapy, psychotherapy, and lifestyle interventions are essential to optimize outcomes in aging populations. Conclusions: Late-onset depression (is a distinct, biologically and psychosocially driven disorder) represents a biologically and psychosocially enriched subtype in its own within the spectrum of late-life depression, requiring integrated, personalized care. Addressing neurovascular mechanisms, psychosocial adversity, and prevention through coordinated geriatric and psychiatric strategies may improve outcomes in aging populations. Full article

Late-onset sporadic Alzheimer’s disease (LOAD) is the most common form of dementia. The disease is characterized by progressive loss of memory and behavioral changes followed by neurodegeneration of all cortical areas. While the contribution of genetic and environmental factors is important, advanced aging remains the most important disease risk factor. Because LOAD does not naturally occur in most animal species, except humans, studies have traditionally relied on the use of transgenic mouse models recapitulating early-onset familial Alzheimer’s disease (EOAD). Hence, the development of more representative LOAD models through reprograming of patient-derived cells into neuronal, glial, and immune cells became a necessity to better understand the disease’s origin and pathophysiology. Herein, and focusing on neurons, we review current work in the field and compare results obtained with two different reprograming methods to generate LOAD patient’s neuronal cells: the induced pluripotent stem cell and induced neuron technologies. We also evaluate if these models can faithfully mimic cellular and molecular pathologies observed in LOAD patients’ brains. Full article

Disruption of myelin in Alzheimer’s disease has been observed by various approaches including histology, proteomics, and white matter hyperintensities in T2 FLAIR images. Since lipids are essential myelin components, we aimed to monitor N-acylphosphatidylserines (NAPSs), unique brain lipids that are altered by neuronal stress. NAPS 52:1 (PS 36:1-N16:0) was the dominant NAPS in both gray and white matter. Relative levels of NAPS 52:1 were 2.5 times higher in the periventricular white matter (PVWM) than in the hippocampus and were reduced to approximately 50% of control in both brain regions in subjects with late-onset Alzheimer’s disease (LOAD). To monitor potential alterations in metabolic precursors of NAPS 52:1, we also measured the following: (1) phosphatidylcholine (PC) 36:1, which can undergo base exchange with N-acylserine (NASer) 16:0 to form NAPS 52:1; (2) phosphatidylserine (PS) 36:1, which can undergo N-acylation with palmitic acid (FA 16:0); and (3) diacylglycerol 36:1, which can be a precursor for both PC 36:1 and PS 36:1. These analyses found that only the relative levels of PS 36:1 were decreased and only in the PVWM. Next, we evaluated NASer 16:0, which can be released from NAPS 52:1 by phospholipase D. This is an N-acyl amino acid with neuroprotective properties. NASer 16:0 was found to be present at trace levels and could only be reliably monitored in the PVWM in which relative levels were decreased in LOAD subjects. In summary, reductions in NAPSs and NASer in the PVWM are lipid biomarkers of disruptions in myelin in LOAD. These data, in conjunction with our previous report of decrements in the levels of neocortical ether-PS in LOAD, suggest that these combined alterations in serine glycerophospholipid metabolism may contribute to neuronal dysfunction in dementia. Full article

Background/Objectives: Young-onset dementia (YOD) is a form of dementia where symptoms appear before the age of 65 years with a worse course, a poorer prognosis, and a lower survival rate than late-onset dementia. Psychiatric disorders often entail confusion, which delays their diagnosis and management. This study emphasizes the risk factors and confounders that limit opportunities to provide adequate early diagnoses of YOD. Methods: A retrospective, analytical, and observational study was based on the clinical records of 191 patients with a diagnosis of probable YOD in a medium-complexity hospital between 2009 and 2024. Demographic variables and the characteristics of the population were analyzed. An explanatory linear regression analysis was conducted to highlight the time required for diagnosis beginning at the onset of symptoms. Results: A high proportion of initial misdiagnoses were identified, and most patients were initially diagnosed with psychiatric or neurological disorders other than dementia. The main preventable risk factors were high blood pressure (HBP), type 2 diabetes mellitus (T2DM), and traumatic brain injury (TBI). HBP and the presence of irritability were associated with earlier diagnosis, whereas T2DM and the initial diagnosis of an affective or anxiety disorder were associated with a longer delay prior to diagnosis. Conclusions: Due to delays in seeking care and initial misdiagnoses as affective or anxiety disorders, T2DM is associated with a delayed final dementia diagnosis. In contrast, HBP and irritability were linked to shorter diagnostic times. These findings underscore the need for improved diagnostic capacity, adapted clinical tools, and awareness strategies to promote the early recognition of YOD. Full article

The streptozotocin (STZ) experimental model of sporadic Alzheimer’s disease (SAD), the most prevalent form of this type of dementia, has become a valuable tool to study the behavioral and morphological changes that occur during the gradual development of this pathology. We used the STZ experimental model in combination with the novel object recognition test (NORT) and immunohistochemical techniques to evaluate the recognition memory decline and morphological alterations in memory-related structures (hippocampus and cortex). Our analysis included five different time points after intracerebroventricular (ICV) administration of 3 mg/kg of STZ or artificial cerebrospinal fluid (aCSF) as a control. The time points included three distinct stages: early (15 and 30 days), intermediate (60 days), and late (90 and 120 days). We found that recognition memory impairment started in the intermediate stage and persisted through the later stages. Morphologically, we detected significant astrogliosis starting in the early stages, whereas cholinergic changes began in the intermediate stage. No neuronal loss was observed at any of the time points analyzed. Our results further support the hypothesis that astrogliosis constitutes an initial pathological event that may compromise the hippocampal cholinergic system and can contribute to the onset of recognition memory deficits. Full article

This narrative review of Alzheimer’s disease (AD) history, therapy and prevention shows that its conceptualization has changed three times over 100 years. First, AD was a normative creation by Kraepelin in 1910 of a rare presenile dementia characterized by specific histological features. Second, during the 1970s, American neurologists, driven by sociological changes, merged presenile and senile dementias into an Alzheimer-type dementia with the universally accepted clinicopathological diagnostic criteria of McKhann. By the end of the 20th century, AD was divided into early-onset genetic (1%) and late-onset sporadic (99%) forms. In the 21st century, AD was redefined as a biological entity, using biological and neuroimaging markers of amyloid, tau and neurodegeneration, to better address research and clinical trials. This new nosology has been widely criticized, given the absence of curative therapy, the evidence of mixed pathology in most cases and the decline in the dementia/AD incidence in high-income countries. However, there are currently many drugs against AD in the pipeline; prevention appears as medical and social therapy. In summary, the ancient concept of age-related dementia has evolved into AD normative disorders over 100 years. Nowadays, AD requires a conceptual reassessment, although its medical paradigm remains. Awaiting pharmacological breakthroughs, dementia prevention seems the best practical approach. Full article

Background: Epilepsy and cognitive impairment frequently coexist, yet their relationship remains complex and insufficiently understood. This study aims to explore the clinical and electrophysiological features of patients presenting with both conditions in order to identify patterns that may inform more accurate diagnosis and effective management within a personalized medicine framework. Methods: We retrospectively analyzed 14 patients with late-onset epilepsy and coexisting cognitive impairment, including mild cognitive impairment and Alzheimer’s disease. Clinical history, cognitive assessments, neuroimaging, and electroencephalographic recordings were reviewed. EEG abnormalities, seizure types, and treatment responses were systematically documented. Results: Patients were categorized into two groups: (1) those with established Alzheimer’s disease who later developed epilepsy and (2) those in whom epilepsy preceded cognitive impairment. Temporal lobe involvement was a key feature, with EEG abnormalities frequently localizing to the frontal–temporal electrodes and manifesting as background slowing, focal multiform slow waves, and epileptiform discharges. Levetiracetam was the most commonly used antiseizure medication, and it was effective across both groups. Conclusions: This case series highlights the value of EEG in characterizing patients with subclinical and overt epileptic activity and cognitive impairment comorbidity. The inclusion of a substantial number of cases with documented EEG abnormalities provides valuable insight into the interplay between epilepsy and neurodegenerative diseases. By integrating neurophysiological data with clinical and cognitive trajectories, this work aligns with the principles of precision medicine, facilitating a more comprehensive evaluation and tailored management approach. Further longitudinal studies are required to validate prognostic markers and guide optimal therapeutic strategies. Full article

Apolipoprotein A-I (apoA-I)-coated nanoemulsion particles target scavenger receptors. Adsorbed apoA-I (from the bloodstream) mediates/facilitates this targeted molecular contact, which is followed by receptor-mediated endocytosis and subsequent transcytosis of these same nanoemulsion (nanocarrier) particles across the blood–brain barrier (BBB). When the right drugs are added in advance to these high-density lipoprotein (HDL)-like nanocarriers, multifunctional combination treatment is achieved. This medication penetrates the BBB and targets particular cell-surface scavenger receptors, mainly class B type I (SR-BI). As a result, these (drug-carrying) nanoemulsions may find application in the biomedical therapy of complex medical disorders, such as dementia, as well as some aspects of aging. According to recent research, sustained inflammatory stimulation in the gut, such as via serum amyloid A (SAA), may cause the release of proinflammatory cytokines. Thus, using this “HDL-like” nanoemulsion vehicle to target drugs early (or even proactively) toward a major SAA receptor (like SR-BI), which is implicated in SAA-mediated cell-signaling processes that lead to aging and/or cognitive decline (and eventually Alzheimer’s disease or dementia), may be a useful preventive and therapeutic strategy. Full article

Background: The biological mediators for the epidemiologic overlap between osteoporosis and dementia are unclear. We undertook a scoping review of clinical studies to identify genetic and biological factors linked with these degenerative conditions, exploring the mechanisms and pathways connecting both conditions. Methods: Studies selected (1) involved clinical research investigating genetic factors or biomarkers associated with dementia or osteoporosis, and (2) were published in English in a peer-reviewed journal between July 1993 and March 2025. We searched Medline Ovid, Embase, PsycINFO, the Cochrane Library, the Web of Science databases, Google Scholar, and the reference lists of studies following the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR). Results: Twenty-three studies were included in this review. These explored the role of the APOE polymorphism (n = 2) and the APOE4 allele (n = 13), associations between TREM2 mutation and late onset AD (n = 1), and associations between amyloid beta and bone remodeling (n = 1); bone-related biomarkers like DKK1, OPG, and TRAIL as predictors of cognitive change (n = 2); extracellular vesicles as bone–brain communication pathways (1); and the role of dementia-related genes (n = 1), AD-related CSF biomarkers (n = 1), and parathyroid hormone (PTH) (n = 1) in osteoporosis–dementia pathophysiology. Conclusions: Bone-related biomarkers active in the Wnt/β-Catenin pathway (Dkk1 and sclerostin) and the RANKL/RANK/OPG pathway (OPG/TRAIL ratio) present consistent evidence of involvement in AD and osteoporosis development. Reports proposing APOE4 as a causal genetic link for both osteoporosis and AD in women are not corroborated by newer observational studies. The role of Aβ toxicity in osteoporosis development is unverified in a large clinical study. Full article

Alzheimer’s disease (AD) is a leading cause of dementia and a growing public health concern worldwide. Despite decades of research, effective disease-modifying treatments remain elusive, partly due to limitations in current experimental models. The purpose of this review is to critically assess and compare existing murine and alternative models of AD to identify key strengths, limitations, and future directions for model development that can enhance translational relevance and therapeutic discovery. Traditional transgenic mouse models have advanced the understanding of amyloid-beta and tau pathologies, but often fail to capture the complexity of sporadic, late-onset AD. In response, alternative models—including zebrafish, Drosophila melanogaster, Caenorhabditis elegans, non-human primates, and human brain organoids—are gaining traction due to their complementary insights and diverse experimental advantages. This review also discusses innovations in genetic engineering, neuroimaging, computational modelling, and drug repurposing that are reshaping the landscape of AD research. By integrating these diverse approaches, the review advocates for a multi-model, multidisciplinary strategy to improve the predictive power, accelerate clinical translation, and inform personalised therapeutic interventions. Ethical considerations and equitable access to diagnostics and emerging treatments are also emphasised. Ultimately, this work aims to support the development of more accurate, effective, and human-relevant models to combat AD. Full article

Background: Emerging evidence suggests a potential link between heavy metals and Alzheimer’s disease and related dementias (AD/ADRD). This study compiled epidemiological evidence from research published over the past 11 years on the impact of metals on AD/ADRD in women. Women have unique risk factors for late onset of AD/ADRD, in addition to genetic factors, apolipoprotein E allele (APOE4), and longer life expectancy. Furthermore, women are twice likely as men to experience depression, which increases their risk of developing AD/ADRD. Our narrative review underscored the necessity of a sex-specific approach to address women’s vulnerability to AD/ADRD. Methods: Electronic databases, including PubMed, Google Scholar, NIOSH Toxline, and Scopus, were thoroughly searched to identify primary epidemiological studies on older women exposed to metals and published between 2014 to 2024. Results: We identified 34 epidemiological studies that met the inclusion criteria. The findings revealed a complex interplay between environmental metals such as lead (Pb), cadmium (Cd), arsenic (As), manganese (Mn), selenium (Se), iron (Fe), zinc (Zn), copper (Cu), magnesium (Mg), and calcium (Ca) and the risk of AD/ADRD in women. Significant adverse effects were reported for Cu, Cd, As, Pb, and Mn while significant protective effects were found between Se, Fe, and Zn in blood and AD/ADRD among older women. However, some studies also reported no correlations. Conclusions: Overall, our review identified contrasting results regarding the effects of metals on AD/ADRD in women. Future studies should collect additional evidence to understanding the effects of heavy metals on AD/ADRD in women for developing preventive measures. Full article