High cholesterol contributes to the development and progression of dementia due to both Alzheimer's disease (A.D.) and vascular pathology. However, the effects of lipid-lowering regimen (LLR) on cognitive dysfunction and brain neuropathology are unknown. To investigate the effect of LLR on the conversion from normal to mild cognitive impairment (MCI), indicated by CDR-SOB of >0-2.5 (MCI), and the progression to dementia, indicated by CDR-SOB =>3 (10-year follow-up) and LLR effect on the rate of survival (15-year follow-up). Participants were stratified by age (≤70 years and >70 years), gender, and the presence of at least one copy of the APOE4 allele. We also analyzed the effect of LLR on brain neuropathology in participants, indicated by Braak staging, hippocampal atrophy, and CSF levels of total Tau. The differential effect of LLR, with or without cerebrovascular disease, lacunar infarct, or cystic infarction in the cognitive network, was analyzed. We have analyzed the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS). In participants with CDR-SOB of >0-2.5, the use of hypolipidemic agents was associated with a reduced yearly increase in the CDR-SOB scores by 0.0088 (0.0038, 0.0138) unit (P < 0.001). This effect was more pronounced in participants with CDR-SOB =>3 showing a reduced yearly increase in the CDR-SOB scores by 0.1733 (0.1441, 0.2025) unit (P < 0.001) in LLR-users compared to non-users, and an increased rate of survival [HR: 0.822 (0.746, 0.906). P = 0.001]. The pattern persisted when participants were stratified based on age, gender, and the presence of APOE4. LLR had no significant effect on Braak staging scores, hippocampal atrophy, and total CSF Tau level, and was independent of the presence or absence of cerebrovascular disease, lacunar infarct, and cystic infarction in cognitive network. Our results have implications for delaying cognitive dysfunction and halting the progression of dementia, regardless of the etiology being related to AD or vascular pathology.
Given the growing global public health burden of Alzheimer's disease, this study used the Bayesian network meta-analysis to assess the effects of pharmacological and non-pharmacological interventions on cognitive function in the population with Alzheimer's disease. Two investigators screened the literature from English databases (PubMed, MEDLINE, Embase, Cochrane CENTRAL, and Web of Science) and three major Chinese bibliographical databases (China National Knowledge Infrastructure Database, Wanfang Database, and VIP Database). We assessed the risk of bias and publication bias of the selected literature. Subsequently, a Bayesian network meta-analysis and meta-regression were conducted to further investigate the comparative efficacy of different interventions on cognitive outcomes. A total of 4788 cases were initially identified. Photobiomodulation [SMD=0.66, 95%CrI (0.29, 1.02)], enriching environment [SMD=0.69, 95%CrI (0.08, 1.31)], pharmacological therapy [SMD=0.36, 95%CrI (0.17, 0.55)], cognitive stimulation therapy [SMD=0.32, 95%CrI (0.11, 0.55)] and exercise therapy [SMD=0.28, 95%CrI (0.06, 0.51)] showed considerable enhancements in cognitive function among individuals with Alzheimer's disease. Photobiomodulation and enriching environment stood out, with their effects more potent than those of other therapies, as indicated by the surface under the cumulative ranking curve - photobiomodulation clocked in at 87.3%, while enriching environment scored 83.8%, versus pharmacological therapy's 54.7%. Among the interventions evaluated, photobiomodulation and enriching environment were associated with better improvements in cognitive function than pharmacological therapy. Exercise therapy and cognitive stimulation therapy also demonstrated beneficial effects. Music therapy showed no statistical difference from the control group. In addition, the research developed an innovative approach to contrast pharmacological and non-pharmacological treatments for Alzheimer's disease. PROSPERO 2025 CRD420251075628. Available from https://www.crd.york.ac.uk/PROSPERO/view/CRD420251075628.
Alzheimer's disease (AD) is frequently complicated by vascular co-morbidities. However, the specific mechanistic pathways by which vascular lesions interact with genetic susceptibility to accelerate cognitive decline remain unclear. This study investigated whether cerebral amyloid angiopathy (CAA) and cortical microinfarcts mediate the impact of AD pathology on cognition and evaluated the modifying role of APOE genotype. We conducted a retrospective clinico-pathological study using the National Alzheimer's Coordinating Center (NACC) database. The cohort included autopsy-confirmed participants aged 50 and older. Structural Equation Modeling (SEM) was employed to quantify the pathways linking AD pathology (Thal phase) to CAA severity, microinfarcts, and cognitive performance (CDR-Sum of Boxes). We further assessed the cumulative burden of pathology by comparing "Pure AD" cases against those with a "Triple Hit" of AD, CAA, and microvascular injury. SEM analysis identified a significant statistical mediation pathway wherein parenchymal amyloid is strongly associated with CAA, which correlates with an increased risk of microinfarcts and subsequent cognitive dysfunction. We observed a significant gene-pathology interaction: APOE ε4 carriers demonstrated a steeper trajectory of cognitive decline for a given severity of CAA compared to non-carriers. Furthermore, the "Triple Hit" group exhibited significantly worse cognitive impairment than the "Pure AD" group (P < 0.001), independent of age and education. Vascular pathology is a critical mediator of cognitive failure in AD, particularly in APOE ε4 carriers. The concurrent "Triple Hit" of proteinopathy and vasculopathy is associated with a profound failure of cognitive reserve, likely reflecting a more advanced global disease state. These findings highlight the urgent need to target vascular resilience as a disease-modifying strategy in Alzheimer's disease.
Changes in neuroimaging metrics are among the first detectable pathophysiological alterations in Alzheimer's disease (AD). Proteins are closely linked to fluctuations in neuroimaging metrics. Therefore, the analysis of the proteomic signature associated with neuroimaging metrics holds significant promise for uncovering therapeutic targets that contribute to AD. GWAS data concerning the Brain Imaging Data Structure (BIDs). The AD cohort comprised a total of 401,661 individuals diagnosed with AD, alongside 10,520 control participants. For a bidirectional MR analysis involving neuroimaging metrics, proteomics, and AD, the methods utilized included inverse variance weighted (IVW), MR Egger, weighted median, weighted mode, and the Wald ratio approaches. We identified 12 neuroimaging metrics that demonstrate significant relevance to AD (thickness of the left total hemisphere, volume of the right thalamus, and et al.). These metrics are structural magnetic resonance imaging (MRI) biomarkers that remain stable throughout the entire course of AD, from the preclinical stage through mild cognitive impairment (MCI) to dementia. Additionally, we found a substantial number of 1633 proteins that also show a noteworthy causal relationship with AD. Functional enrichment analysis indicated that these proteins were predominantly focused within various pathways linked to AD, encompassing those involved in the synaptic vesicle cycle, synaptic membranes, neurotransmitter release, and the activity of GABA receptors. In addition, our research indicates that the significant relationships observed between the identified proteins and AD are influenced by neuroimaging metrics. Notably, we found that these neuroimaging metrics play a crucial role in mediating a substantial 67% of the inverse relationship that exists between PTPRC and the phenotypic characteristics associated with AD. This study successfully establishes a connection between proteomic and neuroimaging metrics, as well as the AD that influence them. By creating this relationship, the research offers important information that aids in comprehending the intricate mechanisms involved in AD.
The emergence of disease-modifying therapies targeting amyloid pathology represents a major paradigm shift in the management of Alzheimer disease (AD). However, their implementation poses substantial organizational, infrastructural, and clinical challenges for health systems. To identify the key challenges and establish priority recommendations for the effective incorporation of amyloid-targeting therapies into the Spanish National Health System. This multiphase consensus study was conducted within the Spanish National Health System between September 2024 and July 2025. The study comprised a narrative literature review, qualitative research, regional workshops, and a modified RAND/UCLA Delphi process. A total of 56 experts participated, including a scientific committee of 6 Alzheimer disease specialists and an expert panel of 50 multidisciplinary professionals involved in AD care. Identification of key challenges across the AD care pathway; development, evaluation, and prioritization of consensus-based recommendations; and estimation of patient demand, including projected increases in day hospital activity and magnetic resonance imaging utilization. Ten key challenge areas were identified, encompassing early detection and referral, diagnostic confirmation, assessment of patient eligibility, treatment administration in day hospitals, monitoring of amyloid-related imaging abnormalities, evaluation of treatment effectiveness, infrastructure and capacity, professional training, patient information and support, and health care planning. Of the 43 recommendations assessed, 38 were rated as appropriate and necessary, with 14 prioritized for immediate implementation. Demand estimation models indicated that 11 to 26 patients per 100,000 inhabitants could be treated under current care patterns, increasing to 17 to 115 per 100,000 inhabitants under alternative eligibility scenarios. This consensus defines the clinical, organizational, and infrastructural requirements necessary to integrate amyloid-targeting therapies into routine care within the Spanish National Health System. The prioritized recommendations define immediate actions to address the challenges identified and may serve as a reference for other health systems facing similar implementation processes.
Diet and physical activity have been reported as independent risk factors for dementia, but few published studies have investigated the interactive effects of the two on dementia risk. Understanding their synergism could help shape more effective prevention strategies. Therefore, we assessed the potential interactions between MIND diet adherence and physical activity on the long-term risk of incident dementia in the population-based Rotterdam Study. Between 2009-2013, 5016 participants of the population-based Rotterdam Study were recruited (mean age 69.76 years, 57.9% women). All participants filled in questionnaires regarding their adherence to the MIND diet and time spent on moderate to vigorous physical activity (Metabolic Equivalent of Task [MET] hours per week). Participants were subsequently followed for incident dementia until January 1, 2021. We applied multivariable Cox regression models to assess interaction on both additive and multiplicative scales. Median values were 7.5 for the MIND diet score and 28.0 for MET hours per week. Of all 5016 participants, 2718 (54.2%) adhered to a high MIND diet score (≥7.5), and 2513 (50.1%) reached at least 28.0 MET hours per week. During a mean follow-up of 6.6 years, 365 participants (7.8%) developed dementia. Both higher physical activity and higher MIND-diet score were independently associated with a lower risk of dementia, but there was no significant interaction on the additive scale (RERI [95%CI]=-0.42 [-1.26 to 0.12]), nor on the multiplicative scale (HRinteraction=0.71 [0.46-1.09]). Sex-stratified analysis suggested a negative interaction between exposures in women, but not in men. Better adherence to the MIND-diet and higher levels of physical activity were each associated with a reduced risk of dementia, but overall there was no indication that their joint effects were greater than the product or sum of their individual parts. Potential sex differences warrant further exploration in different populations.
Hydromethylthionine mesylate (HMTM) targets tau pathology and also has tau-independent symptomatic activity. A traditional randomised placebo-controlled trial (RCT) was precluded by loss of blinding due to urinary colouration and therapeutic activity at the minimum dose required to maintain blinding. To evaluate the efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer's disease (AD). Because a traditional RCT was not feasible without loss of blinding, we compared HMTM 16 mg/day in TRx-237-039 with propensity score matched true placebo controls from the FDA-sponsored Critical Path for AD (CPAD) database with the same inclusion/exclusion criteria (protocol TRx-237-080). We also compared HMTM 16 mg/day with matched natural history controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and with a meta-analysis of placebo arms from trials in comparable populations in analyses specified prior to the 104-week database lock of TRx-237-039. Propensity score matching yielded 127 pairs (HMTM n = 127; CPAD placebo n = 127) in the CPAD comparison, and 189 pairs in the ADNI comparison. A total of 218 receiving HMTM 16 mg/day were compared with meta-analytic controls (n = 1805-8567). HMTM 16mg/day MEASUREMENTS: Primary outcomes in TRx-237-080 were change from baseline to 78 weeks in ADAS-Cog13 and whole brain volume (WBV). CDR-Sum of Boxes (CDR-SB) and CDR-Global were analysed at 104 weeks. ADAS-cog11 and WBV were analysed in ADNI comparisons, and ADAS-cog11, ADCS-ADL23, CDR-SB and WBV were analysed in meta-analytic comparisons. Compared with matched CPAD placebo, HMTM 16 mg/day produced statistically significant differences in change on ADAS-Cog13 (p < 0.0001) and WBV at 78 (primary; p < 0.0001) and 104 weeks (p < 0.0001), and CDR-SB differed significantly overall (104-weeks; p < 0.001) and in MCI (p = 0.007). The odds of progressing to a more advanced CDR-Global stage were lower with HMTM (overall OR 0.31) and particularly in MCI (OR 0.15) versus CPAD placebo. Clinical and brain atrophy outcomes were similarly statistically significant in comparisons with ADNI case-matched natural history data and in meta-analytic comparisons. Comparisons of HMTM treatment with CPAD, ADNI, and meta-analytic controls provide evidence consistent with clinical benefit HMTM. It has the potential to offer an accessible oral treatment option which could be delivered with minimal patient/physician burden.
Preclinical Alzheimer's Disease stages represent possible targets for disease-modifying intervention as well as opportunity for early identification of risk for future decline. Recent research has explored the use of objectively-defined subtle cognitive decline (Obj-SCD), an emerging classification that may identify individuals at risk for neurodegeneration before the onset of mild cognitive impairment (MCI). The Edmonds/Thomas actuarial Obj-SCD criteria (> 1 SD below expectations, single cognitive test impaired per domain) aims to capture those who exhibit minimal cognitive difficulties that do not meet a MCI or dementia diagnosis. Given the novelty of the Obj-SCD classification, this narrative review provides an overview of neuroimaging, biomarker, and clinical progression studies to evaluate its biological and clinical significance. Using fluid-based biomarkers, neuroimaging, and longitudinal designs, studies have indicated that the Obj-SCD classification has the potential to capture AD-related pathological changes detectable before the clinical onset of MCI. In particular, recent studies indicate a unique pathological profile of Obj-SCD, differentiating it from the cognitively unimpaired and MCI stages. Studies comparing Obj-SCD and subjective cognitive complaints show that the Obj-SCD criteria may be more closely associated to early AD pathology. While the existing literature is limited, findings uphold Obj-SCD as a sensitive classification able to identify individuals at risk for future cognitive impairment. Studies on Obj-SCD indicate utility in research settings, although it faces challenges regarding its clinical implementation and effectiveness.
Social factors have been linked to cognitive decline and risk of dementia. However, our understanding of their impact on cognition in the context of Alzheimer's disease (AD) pathology is still limited. This study examined whether two structural social factors, relationship status (RS) and living situation (LS), modify the association between AD pathology and cognition. Observational, analysis of existing cohort data. Data were obtained from the National Alzheimer's Coordinating Center (NACC) and the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study. Participants with available data on cognitive performance, AD pathology, and structural social factors. We used the Mini-Mental State Examination (MMSE), a widely used brief screening measure of global cognitive status. For the description of AD, postmortem neuropathology (NACC) reports, or amyloid PET (IDEAS) were used. RS and LS were coded according to the respective datasets. Group comparisons and regression models were used to evaluate interactions between RS or LS with AD pathology on cognition. Across cohorts, up to 31% of individuals were not in a relationship, and up to 22% lived alone. Individuals in a relationship (RS+) or those who lived with someone (LS+) showed poorer cognitive performance than those not in a relationship (RS-) or living alone (LS-) at comparable levels of AD pathology. Interaction analyses indicated that the association between AD pathology and MMSE differed by LS, with LS+ being associated with slightly lower MMSE scores across pathology levels, an effect primarily driven by participants living with someone who is not a partner. In contrast, within the NACC cohort, RS+ individuals showed overall lower MMSE scores, while the association between AD pathology and MMSE was weaker compared to RS- individuals. LS and RS showed differences in how AD pathology related to global cognitive status. Being in a relationship was linked to a weaker association between AD pathology and global cognitive status, whereas living with someone was associated with a lower global cognitive status at comparable levels of pathology. While the direction of these associations remains unclear, our findings suggest that the relationship between AD pathology and cognitive status may vary across different structural social contexts.
Autosomal-dominant Alzheimer's disease (ADAD) offers a model to define early biological changes in Alzheimer's disease due to its predictable age at symptom onset. Although ultrasensitive plasma assays are available, their associations with age in ADAD remain incompletely characterized. To characterize age-related changes in plasma biomarkers and examine associations with cognition in PSEN1 E280A ADAD. Cross-sectional observational study in members of the Colombian PSEN1 E280A kindred. A total of 164 individuals were included, comprising 83 mutation carriers (mean age 34.36±9.82 years; 54% female) and 81 non-carriers (mean age 33.75±9.84 years; 52% female). Plasma Aβ42/Aβ40, phospho-tau217 (p-tau217), brain-derived tau (BD-tau), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were quantified. Sex-adjusted associations with age, divergence ages between groups, classification performance (ROC curves), and associations with cognition (MMSE and CERAD delayed recall) were assessed. All plasma biomarkers were associated with age (p < .01). Divergence between carriers and non-carriers began with Aβ42/Aβ40 before age 18, followed by p-tau217 (26.0 years), GFAP (26.1 years), BD-tau (27.9 years), and NfL (38.7 years). Aβ42/Aβ40 showed the highest discrimination of mutation status (AUC=0.99), followed by p-tau217 (AUC=0.87) and GFAP (AUC=0.84). Among carriers, p-tau217, GFAP, BD-tau, and NfL were associated with MMSE, while p-tau217, GFAP, and NfL predicted CERAD delayed recall. Plasma biomarkers exhibit a temporal cascade in PSEN1 E280A ADAD. P-tau217 and GFAP show the strongest associations with early cognitive decline, suggesting their potential utility for tracking disease progression and monitoring treatment effects in E280A carriers.
Prior meta-analyses have suggested that training utilizing virtual reality (VR) serves as a secure and effective intervention for elderly individuals experiencing mild cognitive impairment (MCI). Nevertheless, the effectiveness of such interventions appears to differ among various populations and cognitive domains. Furthermore, there remains a significant gap in understanding the effectiveness of VR-based training, specifically among individuals diagnosed with Alzheimer's disease (AD). The researchers conducted a comprehensive search of databases, including Web of Science, PubMed, Cochrane Library, and EMBASE up until July 1, 2025, focusing on randomized controlled trials that investigated VR-based training in patients diagnosed with AD. The outcomes measured were categorized and analyzed separately, encompassing overall cognitive performance, distinct cognitive domains, psychosocial function, physical capabilities, and the execution of daily living activities within the context of AD trials. Of the 265 publications identified, 11 (4.15%) randomized controlled trials (RCTs) eventually met all eligibility criteria. Those who received VR-based training showed significantly better global cognitive function [SMD (95%CI) = 0.44 (0.21-0.68)] and Short-term memory [SMD (95%CI) = 0.62 (0.25-0.99)] than the controls. However, no significant improvements were observed in areas such as executive function, spatial memory, activities of daily living, quality of life, balance and coordination, fear of falling, risk of falls, and depression levels. VR-based interventions demonstrated beneficial effects on global cognitive function and short-term memory in AD populations. Due to the small sample size, the current research on evidence for efficacy in people with AD is weak and limited in many indicators.
Plasma brain derived-p-Tau217 (BD-p-Tau217) may outperform total-p-Tau217 in detecting brain amyloid burden and warrants evaluation. To perform head-to-head comparison of plasma BD- as well as total-p-Tau181, p-Tau217 and p-Tau231 for detecting beta-amyloid positivity (Aβ+), evaluate reference ranges for Aβ+, and assess the prognostic utility of BD-p-Tau217 reference ranges. Observational study. Participants recruited from memory clinics and the community in Singapore. 213 participants, including 44 cognitively normal, 107 cognitively impaired no dementia, and 62 dementia (mean [SD] age, 73 [1] years; 121 females). Amyloid status (Aβ- [n = 139] vs Aβ+ [n = 74]) was determined by positron emission tomography (PET). Plasma BD-p-Tau and total-p-Tau were measured using the NULISAseq™ CNS Disease Panel 120. The diagnostic performance for detecting Aβ+, reference ranges (three-range: 95% specificity/95% sensitivity); binary: maximizing Youden index), and the prognostic performance of p-Tau biomarkers were evaluated. Plasma BD-p-Tau217 (AUC = 0.965) outperformed other BD- and total-p-Tau species in detecting PET Aβ+ (AUC = 0.823-0.937; all p ≤ 0.008). Using a three-range reference, BD-p-Tau217 achieved positive predictive value (PPV) and negative predictive value (NPV) of 90% and 97%, respectively. Proportion of participants in the intermediate-risk group was 7% (n = 14). Applying a binary reference, BD-p-Tau217 achieved both a specificity and sensitivity of 92%, with PPV and NPV of 86% and 96%, respectively. BD-p-Tau217-derived high-risk group exhibited faster cognitive decline than the low-risk group. Risk stratification for PET Aβ+ based on plasma BD-p-Tau217 suggests superior diagnostic and prognostic utility, warranting further validation.
Alzheimer's disease (AD) progression varies widely among individuals. Identifying factors influencing timing of pathology and clinical progression is crucial for optimizing early intervention trials. To investigate how the estimated age at amyloid and tau PET positivity, and the time interval between these two key events ("amyloid-tau time interval"), relate to symptom onset and clinical progression, and to assess the effects of APOE-ε4 status and sex on these associations. This analysis used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Harvard Aging Brain Study (HABS). The ADNI is a multicenter observational cohort conducted at 55 sites across the United States; The HABS is a longitudinal, single-center observational cohort. This study included participants with at least one positive amyloid PET scan (ADNI n = 792; HABS n = 104) or at least one positive tau PET scan (ADNI n = 212; HABS n = 48). All participants had information on sex, APOE-ε4 status, and longitudinal cognitive assessments. We examined the influence of APOE-ε4 status, sex, and their interaction on the estimated age at biomarker positivity and the amyloid-tau time interval. Accelerated Failure Time (AFT) models were used to predict time to symptom onset (CDR > 0) based on estimated biomarker positivity age and the amyloid-tau time interval. Linear mixed-effects (LME) models evaluated differences in the rate of cognitive decline, as measured by CDR-SB, over five years following symptom onset according to estimated biomarker positivity age and amyloid-tau time interval. Additional models included interaction terms with sex or APOE-ε4 status. The amyloid-tau time interval varied markedly between individuals and was shorter in APOE-ε4 carriers, women, and those with older age at amyloid PET positivity. APOE-ε4 carriers and women became amyloid and tau PET positive at younger ages. Following amyloid PET positivity, a shorter time to tau PET positivity predicted earlier symptom onset. After symptom onset, faster cognitive decline was observed in individuals with younger ages at amyloid or tau PET positivity. The time to symptom onset following tau PET positivity, or the rate of cognitive decline after symptom onset, were not influenced by the amyloid-tau time interval. After becoming amyloid PET positive, APOE-ε4 carriers, women and older individuals may have a shorter window for detection and treatment before they become tau PET positive and develop symptoms. These findings should guide the identification of individuals at highest risk of rapid AD progression, enabling more efficient participant selection for clinical trials.
The objective of this study was to provide a multimodal biomarker characterization of amnestic objective subtle cognitive decline (obj-SCD) in aging and preclinical Alzheimer's disease (AD). Prospective observational study; data from the Alzheimer's and Families+ (ALFAs+) cohort, including cognitively unimpaired (CU) individuals with available baseline CSF biomarkers (normal or AD continuum profiles) and longitudinal neuropsychological assessment (2 time points, 3-year follow-up). Amnestic obj-SCD was defined using robust longitudinal neuropsychological references with multivariate base rate thresholds of significant decline (Free and Cued Selective Reminding Test, Memory Binding Test, Wechsler Memory Scale IV: Logical Memory). Study outcomes included plasma p-tau217, NfL, and GFAP; CSF p-tau181/Aβ42, NfL, and GFAP; Aβ and tau PET; and MRI Grey Matter volume (GMv). The associations of amnestic obj-SCD with fluid (plasma and CSF) and neuroimaging biomarkers (PET and GMv) were evaluated using mixed-effects and voxel-wise linear regression models, respectively. 350 CU individuals were included (mean age 61 years; 60% female; mean education 14 years; 35% CSF Aβ-positive). Amnestic obj-SCD was identified in 10% of the sample, associated with greater AD pathology (higher plasma p-tau217, CSF p-tau181/Aβ42, global Aβ PET, medial temporal tau PET), neurodegeneration (higher plasma and CSF NfL, reduced GMv in cingulate cortex, longitudinal GMv reductions in hippocampus) and inflammation (higher plasma and CSF GFAP, longitudinal GMv increases in neocortical brain regions). These findings highlight the need for standardized clinical staging criteria to enhance early detection and risk stratification in aging and preclinical AD.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment. Despite extensive research, the precise molecular mechanisms driving AD pathogenesis remain incompletely understood. This study sought to identify robust molecular targets and cellular basis underlying AD progression. We performed a systematic analysis of cross-regional transcriptomic datasets from AD patients, integrating differential expression analysis across 14 Gene Expression Omnibus (GEO) datasets with cross-regional intersection mapping. Single-nucleus RNA sequencing (snRNA-seq) was employed to resolve cell-type-specific expression patterns. Furthermore, cellular communication analysis and functional enrichment of astrocyte-specific genes were conducted. The biological role of the identified candidate was validated in vitro using Aβ42 oligomer-treated primary astrocytes via siRNA-mediated knockdown and plasmid-driven overexpression, with autophagic activity assessed through LC3-II and p62 expression. The transmembrane glycoprotein receptor CD44 was identified as consistently upregulated across AD-vulnerable brain regions, including the temporal cortex, frontal cortex, entorhinal cortex, and hippocampus. snRNA-seq analysis identified this upregulation primarily to astrocytes. Intercellular signaling analysis indicated that the CD44-SPP1 axis enhanced astrocyte-glial crosstalk. Functional enrichment analysis linked astrocytic CD44 to the modulation of autophagy pathways. In vitro experiments demonstrated that CD44 knockdown promoted autophagic activation (increased LC3-II and decreased p62), whereas CD44 overexpression suppressed autophagic activity. Our findings establish CD44 as a pivotal regulator of astrocytic autophagy in AD, highlighting its potential as a novel therapeutic target.
Optimal dementia risk reduction strategies benefit from sufficient public knowledge of risk factors and risk perception, but current public awareness is uncertain. In a systematic literature review on public knowledge and perception of dementia risk factors, we searched relevant databases for original research articles until 2024. When possible, we pooled study results using random effects meta-analysis, and explored sources of heterogeneity through meta-regression. Qualitative studies and studies about risk perception were analysed using narrative synthesis. Of 4996 articles screened, 155 were eligible for inclusion. Of these, 125 reported on knowledge of risk factors and 50 on risk perception, jointly providing data from 164,644 participants in 41 countries across 6 continents. Recognition of the 28 queried risk and protective factors was moderate, somewhat higher for lifestyle factors (medians: 38.5-71.5%) than for cardiovascular (9.9-66.9%) and environmental (25.4-44.4%) factors, but with large heterogeneity across queried factors. With the exception of physical activity (71.5%, IQR:46.9-88.3%), social isolation (66.6% [23.7-84.0%]) and traumatic brain injury (65.0% [18.0-76.7%]), recognition of all established modifiable risk factors for dementia from prespecified lists was below 50%, lowest for education (19.5% [7.8-54.9%]), air pollution (25.4% [16.3-41.0%]), and obesity (30.4% [27.0-43.0%]). Recall of risk factors (7 studies) was markedly lower than recognition. Meta-regression analyses showed no consistent differences by year of publication, or by participants' age, gender, and educational attainment. Among 23 qualitative studies, limited knowledge emerged particularly regarding dementia-specific risk factors like hearing loss. Perceived risk was measured inconsistently across studies, but was generally moderate to high, along with notable worry about dementia in a large part of the older population. Knowledge of dementia risk and protective factors in the general population remains limited. These findings call for population-level interventions, including educational campaigns, to enhance preventive strategies.
Alzheimer's disease and other dementias (ADODs) are increasingly becoming a major public health concern in rapidly ageing Asia. We compared the disease burden across Japan, China, and India at different demographic stages. The Global Burden of Disease Study of 2023 was used to analyze the incidence, prevalence, mortality, and disability-adjusted life years (DALYs) in 1990-2023. Decomposition analysis identified drivers of DALYs trends. DALYs associated risk factors were quantified. The Auto-Regressive Integrated Moving Average model was used to predict future disease burden. In 2023, China had the highest absolute burden, with age-standardized incidence and prevalence rates of 156.63 (95% uncertainty interval [UI]: 136.58-175.49) and 918.83(95% UI: 784.59-1,058.24) per 100,000, respectively. Japan recorded the highest age-standardized mortality rate (31.25 [8.47-71.42] per 100,000). India had the highest annual increase in mortality and DALYs, with estimated annual percentage changes of 0.91 (95% confidence interval [95% CI] 0.80-1.03) and 0.51 (0.45-0.56), respectively. Decomposition analysis revealed distinct drivers: Japan was dominated by epidemiological changes; China was driven by both aging and epidemiological changes; India was mainly due to population growth and epidemiological changes. Ambient particulate matter was the leading risk factor across all countries, though India faced a unique household air pollution burden. DALYs are predicted to increase in all three countries significantly by 2038. The ADODs burden remains substantial, driven by distinct demographic and epidemiological factors in Japan, China, and India. Tailored strategies for prevention and management are essential to address the growing burden.
Emerging evidence point to a bidirectional relationship between sleep disturbances and Alzheimer's disease (AD). Poor sleep may be an overlooked risk factor for older women, who are disproportionately affected by AD and report worse subjective sleep quality than men. High genetic AD risk-characterized by the polygenic hazard score (PHS), including apolipoprotein (APOE) ε4 carriership-may further compound the effects of disrupted sleep on AD, particularly for older women. This study examined the moderating effect of genetic AD risk on subjective sleep as it related to memory and tau burden in a sample of older women. The sample consisted of older women (≥65 years old) from the Women Inflammation Tau Study. Participants completed the Pittsburgh Sleep Quality Index (PSQI), Rey Auditory Learning Test, and Brief Visuospatial Memory Test-Revised. They also underwent [18]F-MK6240 positron emission tomography. Tau burden was calculated in composite regions across Braak stages. Genetic risk groups were characterized by PHS stratified at the 75th percentile. PSQI global score × PHS group interactions on memory composite scores (N = 69) and tau burden (N = 63) were examined. PSQI global score × PHS group interactions were observed on visual memory and pathological tau in Braak regions III/IV (ps<0.10). Poorer subjective sleep was associated with worse visual memory and greater limbic tau deposition only among higher genetic risk women (ps<0.04). No significant associations were observed for verbal memory or tau in Braak regions I/II or V/VI. Older women with elevated genetic AD risk and subjective sleep difficulties may be at greater risk for visual memory deficits and tau burden in regions affected in early AD. This suggests that sleep complaints may represent a promising AD risk factor. Improving sleep may be a potential intervention target for AD mitigation and prevention, particularly for older women.
Patient safety critically influences both quality of life and disease progression in older adults with cognitive impairment, yet large-scale multicenter data remain scarce. This study aims to systematically analyze the types of safety incidents experienced by patients with Alzheimer's disease and related cognitive impairments, and explore the network associations of different safety incidents. Initiated by the Alzheimer's Disease China (ADC), this survey recruited 1057 older individuals with Alzheimer's and related cognitive impairments, along with their families, across 31 provinces, autonomous regions, and municipalities. The safety incidents evaluated in this study included falls, getting lost, medication errors, verbal aggression, physical aggression, household fire, aspiration, and choking. Incidence rates for overall and specific safety incidents were calculated. Correlation analyses and network analysis were performed to examine relationships between safety incidents. A high proportion (73.5%) of participants reported at least one safety incident in the past year, with over one-third (36.0%) experiencing three or more concurrent incidents. Medication errors (55.9%) and verbal aggression (39.6%) were most frequent, followed by falls (32.5%) and physical aggression (22.7%). Incidence rates varied significantly by cognitive impairment stage, care setting, and geographic region. Network analysis highlighted medication errors and getting lost as central nodes bridging other incidents. This study reveals an alarmingly high incidence of safety incidents among cognitively impaired patients, affecting their physical, psychological, and familial well-being. A collaborative, multidisciplinary effort involving healthcare professionals, family caregivers, fire and police emergency responders, and public health policymakers is essential to develop individualized safety strategies aligned with patient needs and contextual considerations.
In the European Union (EU), donanemab is indicated in adults with early symptomatic Alzheimer's disease who are apolipoprotein E ε4 non-carriers or heterozygotes. Among these, patients without superficial siderosis at baseline, uncontrolled hypertension, or anticoagulant use are eligible. To assess efficacy and safety of donanemab in the EU-eligible population. A post-hoc conservative hybrid imputation method was implemented for clinical efficacy analyses during the TRAILBLAZER-ALZ 2 placebo-controlled period. In the 78-week long-term extension (LTE) participants in the early-start (randomised to donanemab) and delayed-start (randomised to placebo with donanemab initiation during the LTE) groups were compared to a propensity-weighted external control. Participants were switched to placebo after meeting amyloid-based treatment course completion criteria. By 76 weeks, donanemab-treated participants in the EU-eligible population had a mean Clinical Dementia Rating Scale (CDR)-Sum of Boxes change from baseline difference from placebo of -0.7 points (95% confidence interval, -1.0, -0.4) and a 40.3% lower risk of disease progression to the next stage (per CDR-Global score). Treatment benefit increased over 154 weeks for non-carriers and heterozygotes, including those meeting treatment course completion criteria by 52 or 76 weeks. In the placebo-controlled period, 119 (19.5%) and 49 (8.0%) donanemab-treated eligible participants experienced amyloid-related imaging abnormalities-edema/effusion and infusion-related reactions, respectively. Safety findings were similar among donanemab-treated participants in the placebo-controlled period and LTE delayed-start group. Consistent with previous TRAILBLAZER-ALZ 2 and LTE findings, donanemab significantly slowed disease progression compared to controls with a manageable safety profile in non-carriers and heterozygotes.