J. Alzheimers Dis. [JOURNAL]
Sun
200 papers
Systemic interleukin signaling and Alzheimer's disease risk: A two-sample cross-replication Mendelian randomization study.
Ahmed HM, Ali Siddique M, Shaheer Ul Islam M … +3 more , Khan Lodhi AR, Owais M, Rehman UU
J Alzheimers Dis · 2026 Jul · PMID 42116542 · Publisher ↗
BackgroundAlzheimer's disease (AD) is the leading cause of dementia worldwide, yet no disease-modifying therapy exists. Systemic inflammation has been proposed as a causal factor, supported by observational studies repor...
BackgroundAlzheimer's disease (AD) is the leading cause of dementia worldwide, yet no disease-modifying therapy exists. Systemic inflammation has been proposed as a causal factor, supported by observational studies reporting elevated plasma interleukins in AD, though such studies cannot establish causality. Recent evidence instead highlights local neuroinflammation and microglial dysfunction as key mechanisms.ObjectiveThis study aimed to determine whether circulating interleukins and their receptors causally influence AD risk.MethodsWe conducted a two-sample Mendelian randomization (MR) analysis using genetic instruments to test whether genetically predicted levels of eleven circulating interleukins and receptor subunits influence AD risk. Three AD genome-wide association study (GWAS) datasets were analyzed: a primary cohort (n = 487,511) and two replication cohorts (n = 63,926; n = 55,134). Primary analyses used inverse-variance weighted models, with MR-Egger and weighted median as sensitivity methods. Additional analyses assessed heterogeneity, pleiotropy, directionality, and outlier influence. The study was preregistered and followed STROBE-MR guidelines.ResultsNo consistent evidence supported a causal effect of any circulating interleukin or receptor on AD risk. Nominal associations for IL-1 receptor antagonist (MR-Egger, p = 0.0054) and IL-6 receptor subunit alpha (weighted median, p = 0.014) did not survive false discovery rate correction and failed replication.ConclusionsThese findings do not support a causal role for circulating interleukins in AD risk. However, TNF-alpha and other non-interleukin mediators were not assessed, and stage-specific effects cannot be excluded due to limitations of summary-level GWAS data. Future studies including broader cytokine panels, disease-stage stratification, and individual-level analyses are warranted.
Non-economic social deprivation and cognitive functioning later in life: Results from the DELCODE study.
Rodriguez FS, Kleineidam L, Hoffmann W … +26 more , Peters O, Gref D, Droste Zu Senden L, Priller J, Spruth EJ, Altenstein S, Schneider A, Fliessbach K, Rostamzadeh A, Düzel E, Glanz W, Butryn M, Buerger K, Janowitz D, Teipel S, Kilimann I, Laske C, Munk MH, Spottke A, Roy-Kluth N, Wagner M, Wolfsgruber S, Stark M, Stoecklein S, Jessen F, DELCODE study group
J Alzheimers Dis · 2026 Jul · PMID 42115891 · Full text
BackgroundLow socioeconomic status is associated with a higher risk for a number of health conditions, including cognitive impairment.ObjectiveWhile the association with economic indicators has been well researched, aim...
BackgroundLow socioeconomic status is associated with a higher risk for a number of health conditions, including cognitive impairment.ObjectiveWhile the association with economic indicators has been well researched, aim of this paper was to investigate specifically the association between non-economic social deprivation and cognitive functioning later in life.MethodsParticipants without objective cognitive impairment at baseline (n = 91 controls, n = 106 with subjective cognitive decline) of the multicenter DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) filled out a posthoc survey on social deprivation. Factor analysis identified four non-economic domains of social deprivation (Residential area conditions, Accessibility, Neighborhood support, Household distress). Cognition was assessed via the CERAD neuropsychological battery. Analyses were conducted using linear regression models as well as maximum-likelihood mixed-effects models adjusted for age, gender, years of education, marital status, depression, BMI, heart disease, hypercholesterolemia, hypertension, and diabetes.ResultsAt the time of the survey, cognitive functioning was significantly lower among participants with high deprivation ( = -0.21, = 0.037). These participants also had a faster rate of cognitive decline ( = -0.07, = 0.006). Analyses of the deprivation sub-scores revealed statistically significant effects only for Accessibility ( = -0.31, = 0.001; rate of cognitive decline = -0.07, = 0.004).ConclusionsOur findings suggest that non-economic social deprivation, especially in terms of access to a grocery store, pharmacy, postal office, and bus stop, might be relevant for maintaining cognitive functioning in old age. Further research should explore potential mechanisms of how these environmental conditions affect brain aging and neurodegenerative processes.
Comparison of hippocampus, entorhinal cortex, and amygdala volumes in individuals with Alzheimer's disease, mild cognitive impairment, and healthy individuals.
Senol D, Secgin Y, Kaya S … +3 more , Ozturk O, Harmandaoglu O, Alzheimer’s Disease Neuroimaging Initiative
J Alzheimers Dis · 2026 Jul · PMID 42115829 · Publisher ↗
BackgroundMild cognitive impairment (MCI) and Alzheimer's disease (AD) are associated with structural alterations in medial temporal lobe regions, which can be evaluated using volumetric magnetic resonance imaging.Object...
BackgroundMild cognitive impairment (MCI) and Alzheimer's disease (AD) are associated with structural alterations in medial temporal lobe regions, which can be evaluated using volumetric magnetic resonance imaging.ObjectiveIn this study, we aimed to compare the volumes of the hippocampus, amygdala, and entorhinal cortex in individuals diagnosed with MCI and AD with those of healthy controls.MethodsMagnetic resonance images from AD, MCI, and healthy control groups were retrospectively obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including 100 individuals in each group. Volumetric measurements of the right, left, and total hippocampus, amygdala, and entorhinal cortex, as well as their ratios to total brain volume, were obtained using the VolBrain automated segmentation software.ResultsThe volumes of the hippocampus, amygdala, and entorhinal cortex were significantly lower in the AD group compared with both the MCI and control groups (p < 0.05). In comparisons between the MCI and control groups, a statistically significant difference was observed only in the left entorhinal cortex volume, whereas no significant differences were detected in other medial temporal structures.ConclusionsThese findings demonstrate group-level differences in medial temporal lobe volumes, with more pronounced reductions observed in individuals with AD. The isolated reduction observed in the left entorhinal cortex in the MCI group reflects a region- and hemisphere-specific structural difference at the group level, which should be interpreted cautiously and warrants further investigation using longitudinal and clinico-cognitive approaches.
Beyond association: A quantitative analysis of the infectious burden in Alzheimer's disease.
Bender O, Shemesh OA, Bar DZ
J Alzheimers Dis · 2026 Jul · PMID 42115784 · Full text
The etiology of Alzheimer's disease (AD) remains a subject of intense investigation. While the 2024 Lancet Commission report attributes approximately 45% of global dementia cases to 14 modifiable risk factors, it notably...
The etiology of Alzheimer's disease (AD) remains a subject of intense investigation. While the 2024 Lancet Commission report attributes approximately 45% of global dementia cases to 14 modifiable risk factors, it notably excludes infectious agents due to debated causality. This exclusion contrasts with growing evidence that pathogens, specifically Herpes Simplex Virus Type 1 (HSV-1), Porphyromonas gingivalis, and Chlamydia pneumoniae, may contribute to neuroinflammation, tau pathology and amyloidogenesis. This paper evaluates the Pathogen Hypothesis of AD through a quantitative framework. Synthesizing data from nationwide cohort studies, we apply a Population Attributable Fraction (PAF) model to estimate the potential disease burden associated with infectious agents. Our sensitivity analyses, utilizing E-values to quantify robustness against unmeasured confounding, suggest that, under the assumption of causality, infectious agents yield illustrative PAF scenarios ranging from 19% to 31% from single-pathogen models, which expands to 31% to 52% in joint models of sporadic AD cases. We explicitly model the heterogeneity between cohorts and the synergistic interaction with the APOE ε4 allele. Furthermore, we address recent failures in antimicrobial clinical trials (VALAD, GAIN), arguing that these outcomes reflect a need for precision biomarker stratification rather than a refutation of the hypothesis. These findings argue for the integration of precision pathogen suppression into dementia prevention protocols.
The social value of lecanemab for patients with early Alzheimer's disease in Japan.
Igarashi A, Azuma-Kasai M, Tani M … +8 more , Utsumi T, Shibahara H, Inoue S, Rothwell S, Kamanaka G, Sakata Y, Hiyoshi H, Tomita K
J Alzheimers Dis · 2026 Jul · PMID 42108615 · Full text
BackgroundLecanemab is the first approved disease-modified therapy in Japan for patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) or mild AD dementia (AD-D).ObjectiveThis study aims to evaluat...
BackgroundLecanemab is the first approved disease-modified therapy in Japan for patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) or mild AD dementia (AD-D).ObjectiveThis study aims to evaluate the social value of lecanemab in Japan.MethodsThe social value was evaluated using a cost-effectiveness model. The intervention was lecanemab added to the standard of care (SOC), and the comparator was SOC alone. The effect of lecanemab was determined based on the phase III trial and subsequent long-term follow-up observation studies. Health outcomes were quantified in life years and quality-adjusted life years (QALYs). Both patient and caregiver utilities were considered by summing the absolute values of utility for both the caregiver and patient. The base-case analysis was conducted from the public healthcare and long-term care payer's perspectives.ResultsLecanemab extended the time spent in early AD, thereby maintaining quality of life (QOL), reducing caregiver burden, and medical and long-term care resource usage. The incremental QALYs were 1.31 QALYs for MCI due to AD and 0.85 QALYs for mild AD-D, and the incremental cost-effectiveness ratios (ICERs) were JPY 8.5 million /QALY and JPY 7.9 million /QALY ($1 = JPY 150), respectively.ConclusionsThe value-based price or the ICER of lecanemab varied greatly depending on the perspectives and the methods of reflecting caregiver QOL. In AD, where the progression of the illness spans a long period and had a significant impact on families and society, narrowly defined value assessments were not sufficient, indicating the need to consider broader social value.
Cognitive function in immigrants from Mexico and Latin America: The role of age at migration.
Tsotsoros CE, Centeno Román CA, Clark AL … +3 more , De Anda-Duran I, Ajrouch KJ, Vega IE
J Alzheimers Dis · 2026 May · PMID 42104731 · Publisher ↗
BackgroundLatino immigrants in the United States represent diverse national origins, with Mexicans comprising the largest group. Cognitive health disparities among Latino immigrants may reflect differences in migration e...
BackgroundLatino immigrants in the United States represent diverse national origins, with Mexicans comprising the largest group. Cognitive health disparities among Latino immigrants may reflect differences in migration experiences, including age at migration, socioeconomic differences, and acculturation. Whether Mexican immigrants differ from Latin American immigrants in cognitive outcomes remains unclear.ObjectiveThis study examined the independent and interactive effects of Mexican origin and age at migration on cognitive levels and decline compared to other Latin American immigrants. We also test whether socioeconomic and acculturation factors help explain differences in cognitive outcomes.MethodsData came from 2077 Latino immigrants in the Health and Retirement Study (2014-2020). Cognition was assessed using the Telephone Interview for Cognitive Status. Mixed-effects models evaluated the main and interaction effects of origins and age at migration on age-related decline, controlling for demographic, health-related, socioeconomic, and acculturation covariates.ResultsMexican immigrants had significantly lower cognitive levels than Latin American immigrants. However, after adjusting for socioeconomic indicators and language acculturation, Mexican immigrants demonstrated higher cognitive scores. Among Mexicans, late-life migration was associated with significantly poorer cognitive levels, which persisted after accounting for socioeconomic and acculturation factors. No significant differences were observed in rates of cognitive decline by origin or age at migration.ConclusionsLate-life migration is associated with poorer cognitive outcomes among Mexican immigrants. Findings indicate that socioeconomic and acculturation factors mask underlying differences in cognitive performance between Mexican and Latin American immigrants, underscoring the need to consider both migration experiences and social context when evaluating cognitive disparities.
A novel synaptic compartmentalization failure framework for neurodegeneration.
Panigrahi B
J Alzheimers Dis · 2026 Jul · PMID 42104730 · Publisher ↗
Synaptic plasticity relies on precise spatial and temporal compartmentalization of signaling within dendritic spines, presynaptic terminals, and axonal domains. This compartmentalization is usually reinforced through act...
Synaptic plasticity relies on precise spatial and temporal compartmentalization of signaling within dendritic spines, presynaptic terminals, and axonal domains. This compartmentalization is usually reinforced through activity-dependent remodeling of spine geometry, cytoskeletal scaffolds, calcium handling, and local protein synthesis, allowing plasticity signals to remain localized and terminate appropriately. Here, a unifying framework is proposed in which neurodegenerative diseases emerge when the capacity to maintain and renew these compartments declines. Ageing and glial dysregulation may act as major biological drivers of this process by altering dendritic spine structure, calcium homeostasis, metabolic support, neurotransmitter clearance, and activity-dependent synaptic remodeling. In this state, plasticity induction remains largely preserved, but signaling becomes spatially diffuse and temporally prolonged, imposing chronic structural and energetic stress on synapses and axons. Proteins such as tau and alpha synuclein, which normally support cytoskeletal organization and dynamic phase separated assemblies, may become destabilized under these conditions leading to pathological aggregation. This framework provides an explanation for early synaptic dysfunction, selective neuronal vulnerability, long presymptomatic phases, network-level disease propagation, the protective effects of education and cognitive engagement, and the limited efficacy of proteinopathy centric therapeutic strategies. Neurodegeneration may be conceptualized as a failure of synaptic compartmentalization, with protein aggregation arising downstream of this primary vulnerability.
Association between the Dietary Index for Gut Microbiota and cognitive function among older adults in the United States.
Si K, Sun C, Guo H … +2 more , Shi C, Wang Y
J Alzheimers Dis · 2026 Jul · PMID 42104729 · Publisher ↗
BackgroundThe Dietary Index for Gut Microbiota (DI-GM) is a novel index reflecting diet quality relative to gut microbiota health.ObjectiveThe study aims to investigate the relationship between DI-GM and cognitive functi...
BackgroundThe Dietary Index for Gut Microbiota (DI-GM) is a novel index reflecting diet quality relative to gut microbiota health.ObjectiveThe study aims to investigate the relationship between DI-GM and cognitive function in older adults.MethodsData were obtained from 2629 participants aged ≥60 years in the National Health and Nutrition Examination Surveys (NHANES) (2011-2014). Cognitive function was assessed using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), the Animal Fluency Test (AFT), the Digit Symbol Substitution Test (DSST), and a global z score. Multivariable linear regression, restricted cubic splines (RCS), and subgroup analysis were performed. Predictive utility of DI-GM was assessed via the receiver operating characteristic (ROC) analysis against a baseline model. Mediation analysis examined relationships among DI-GM, the Dietary Inflammatory Index (DII), and cognitive outcomes.ResultsHigher DI-GM was associated with higher AFT, DSST, and the global z scores (p < 0.001). After full adjustment, participants with DI-GM (≥ 6) showed higher AFT score (β = 1.11, 95% CI 0.46∼1.75), DSST score (β = 4.95, 95% CI 3.05∼6.86) and z score (β = 0.19, 95% CI 0.10∼0.28), compared to those with DI-GM (0-3). No significant direct association was observed with CERAD (β = 0.45, 95% CI -0.29∼1.18, p = 0.233). RCS indicated linear relationships between DI-GM and cognitive function scores. DI-GM had excellent predictive performances based on the ROC. No significant interactions were detected by subgroup analysis. Furthermore, DII partly mediated the relationship between DI-GM and cognitive function.ConclusionsThe DI-GM showed a linear positive correlation with cognitive function in older adults.
Real-world clinical profile of individuals with cerebrospinal fluid Aβ/pTau181.
Keret O, Xia T, Wilkins S … +7 more , Ncube LNL, Smaw B, Xiong Y, Gandy S, Pereira A, Naasan G, Elahi FM
J Alzheimers Dis · 2026 Jun · PMID 42104723 · Publisher ↗
BackgroundCerebrospinal fluid (CSF) pTau181 is used to support Alzheimer's disease (AD) diagnosis but can also rise in amyloid-negative individuals. This CSF profile (Aβ/pTau181) lies outside the AD continuum and complic...
BackgroundCerebrospinal fluid (CSF) pTau181 is used to support Alzheimer's disease (AD) diagnosis but can also rise in amyloid-negative individuals. This CSF profile (Aβ/pTau181) lies outside the AD continuum and complicates real-world etiologic diagnosis of neurocognitive disorders.ObjectiveTo determine the prevalence and clinical phenotype associated with the Aβ/pTau181 CSF biomarker profile in a real-world memory clinic population.MethodsWe screened the Mount Sinai Hospital database (2015-2024) for patients who underwent ADmark CSF biomarker testing. An Aβ/pTau181 group was classified using assay cutoffs (Amyloid-Total-Tau Index>1.2, pTau181 > 54 pg/mL) and compared to an Aβ group (Amyloid-Total-Tau Index<0.8) matched for pTau181 and total-Tau. Clinical variables were extracted via chart review, limited to notes preceding CSF and blinded to CSF results.ResultsThe Aβ/pTau181 group included 25 individuals (10.1% of the cohort) and had equally impaired cognition but fewer episodic memory complaints. Diagnosis was more often Lewy body or frontotemporal dementia. On neuroimaging, Aβ/pTau181 exhibited less white matter hyperintensity burden and temporoparietal atrophy.ConclusionsCSF Aβ/pTau181 is frequent in real-world evaluations of cognitive impairment and presents with fewer AD phenotypic features. Further research is required to clarify Aβ/pTau181 underlying biology and clinical trajectory.
Early diagnosis of Alzheimer's disease through handwriting analysis and deep learning: A review.
Tang Q, Liu J, Fan C … +3 more , Zhang X, Zhang C, Qi H
J Alzheimers Dis · 2026 Jul · PMID 42104715 · Publisher ↗
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders worldwide, requiring early identification for timely intervention and to slow disease progression. However, existing diagnostic approaches...
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders worldwide, requiring early identification for timely intervention and to slow disease progression. However, existing diagnostic approaches, while effective at later stages, remain limited in detecting early-stage AD. Handwriting analysis has recently emerged as a non-invasive, cost-effective, and ecologically valid digital behavioral biomarker that reflects neurocognitive impairment. This review examines the role of handwriting as a neurocognitive marker for AD, focusing on integrating deep learning methodologies to enhance early diagnostic accuracy. It also elucidates the neurocognitive mechanisms linking handwriting behavior and AD, addressing current methodological and translational challenges. We performed a PRISMA-informed structured literature search and narrative synthesis of handwriting- and drawing-based studies for detecting AD/mild cognitive impairment (MCI), including offline handwriting images and online pen-stroke kinematics captured by digital devices. Task paradigms, data dimensions, preprocessing pipelines, modeling strategies (traditional machine learning and deep learning), evaluation practices, and translational considerations were summarized, and studies were organized by detection purpose and analytic approach. Our findings show that handwriting-based models generally discriminate AD/MCI from healthy controls with accuracy exceeding 80%, while deep learning models (e.g., convolutional neural network and multimodal Transformer fusion) approach 90% in structured tasks like clock drawing and figure copying. Online kinematic markers (e.g., reduced velocity, prolonged in-air time, increased pausing, and pressure instability) recur across studies, and multimodal integration with speech, gait, or facial signals can further improve sensitivity and ecological validity, although most studies are small and single-center.
Association of mitochondrial genome variants with Alzheimer's disease in a Chinese population.
Hao X, Jiao B, Wang Y … +13 more , Xu T, Yang Q, Zhu Y, Liu Y, Zhang C, Liang X, Zhou Y, Liao X, Luo S, Tang B, Li J, Xiao X, Shen L
J Alzheimers Dis · 2026 Jun · PMID 42104711 · Publisher ↗
BackgroundResearch on the mitochondrial genome variants of Alzheimer's disease (AD) in Chinese populations is lacking.ObjectiveThe study aimed to identify mitochondrial DNA (mtDNA) variants associated with AD risk and ex...
BackgroundResearch on the mitochondrial genome variants of Alzheimer's disease (AD) in Chinese populations is lacking.ObjectiveThe study aimed to identify mitochondrial DNA (mtDNA) variants associated with AD risk and explore the relationship between mtDNA variants and plasma biomarkers in AD patients.MethodsWhole genome sequencing was performed in 1509 AD patients and 2010 controls from the Chinese population. mtDNA variants were called according to GATK's best practice mitochondrial pipeline. We evaluated the association of AD risk with mtDNA variants and mitochondrial haplogroup. Common variant (MAF≥0.01) based association analysis and gene-based tests of rare variants (MAF<0.01) were carried out with PLINK 1.9 and SKAT-O, respectively. Spearman correlation analysis was performed to assess the association between the burden of mtDNA variants and plasma biomarker levels.ResultsThe frequency of mitochondrial haplogroup G in AD group was nominally higher than control group (p = 0.019, OR = 1.48). Rare variants of gene were significantly enriched in controls compared to AD patients (p = 2.81 × 10, OR = 0.886). Besides, the control group exhibited considerably lower mRNA expression of in brain regions compared to AD patients in GEO database. Furthermore, the number of mtDNA indel variants per individual correlated positively with plasma Aβ42 levels.ConclusionsMitochondrial haplogroup G may serve as a risk factor for AD, while rare variants of gene acted as protective factor against AD in mainland China. Moreover, mtDNA variants were related to AD plasma biomarker levels. Our findings highlighted the role of mitochondrial genome variants in the pathogenesis of AD.
Methodological considerations on the network meta-analysis of brexpiprazole dosing for agitation in Alzheimer's disease.
Pereira da Silva AM, Haddad Santos D
J Alzheimers Dis · 2026 Jul · PMID 42099051 · Publisher ↗
Abstract loading — click title to view on PubMed.
Corrigendum to "Early cognitive screening for individuals on the dementia continuum: A novel approach amid current trends".
J Alzheimers Dis · 2026 Jun · PMID 42093610 · Publisher ↗
Abstract loading — click title to view on PubMed.
A snapshot of Italian nursing homes for people with dementia: A national survey of 1671 facilities.
Vaccaro R, Lorenzini P, Giaquinto F … +8 more , Matascioli F, Salvi E, Carnevale G, Locuratolo N, Vanacore N, Bacigalupo I, Permanent Table of the National Dementia Plan Study Group *, NHs Study Group *
J Alzheimers Dis · 2026 Jun · PMID 42089822 · Full text
BackgroundNursing homes (NHs) that provide for people with dementia (PWD) are responsible for meeting the needs of patients and their families through medical, personal, and rehabilitative care. However, little is known...
BackgroundNursing homes (NHs) that provide for people with dementia (PWD) are responsible for meeting the needs of patients and their families through medical, personal, and rehabilitative care. However, little is known regarding the Italian facilities.ObjectiveTo describe the characteristics of NHs and to detail the care services and treatments provided.MethodsIn 2023, the Italian National Institute of Health conducted a national survey to assess dementia care services and update the Dementia Observatory's online Map of Services through a detailed facility questionnaire.ResultsOverall, 1671 NHs accommodating PWD participated, representing 46.3% of facilities and 53.1% of beds. Significant disparities emerged when estimating the number of PWD per available NH across macro-area (North 214; Centre 332; South/Islands 850).R2D classification was more frequent in southern than central and northern facilities (28%, 10.9%, and 13.1%, respectively; p<0.001). Northern facilities had more rooms (North: 46, Centre: 28, South and Islands: 29; p<0.001) and beds (North: 87, Centre: 55, South and Islands: 58; p<0.001). Southern NHs had shorter admission wait times and longer stays. Conversely, Northern facilities had more staff, better training, and more digital systems and were more often integrated with day care centers and palliative care services.ConclusionsThis is the first national study assessing the accessibility and affordability of Italian NHs housing PWD. The lack of special units, tailored environments and uneven services distribution and staff highlight the fragmentation of Italy's long-term care system. NH geographical distribution is inconsistent with epidemiological estimates of PWD.
The association of adverse childhood experiences and life course relationship quality with late-life cognitive health: Moderation by race/ethnicity and gender.
Walters ME, Wong R, Scambray KA … +2 more , Antonucci TC, Tarraf W
J Alzheimers Dis · 2026 May · PMID 42083879 · Publisher ↗
BackgroundAdverse childhood experiences (ACEs) may increase Alzheimer's disease risk. How particular ACEs differentially relate to cognition and what role life course relationship quality (LCRQ) plays are unclear.Objecti...
BackgroundAdverse childhood experiences (ACEs) may increase Alzheimer's disease risk. How particular ACEs differentially relate to cognition and what role life course relationship quality (LCRQ) plays are unclear.ObjectiveAssess how ACEs subgroups relate to cognition and whether associations are impacted by LCRQ.MethodsAdults (ages 50-64 at baseline) from the Health and Retirement Study participated (n = 3225; 2006/2008 = baseline; 2018/2020 = follow-up). Latent class and profile analyses identified ACEs and LCRQ subgroups, respectively. Linear and multinomial logistic regressions related ACEs and LCRQ subgroups to global cognition, cognitive impairment, not dementia (CIND), and dementia at follow-up.ResultsWe identified 4 ACEs (High Adversity, Family Disruptions, Elevated Household Trauma, Low Adversity) and 3 LCRQ ("Strong", "Mixed", "Weak" Ties) classes. Racially/ethnically minoritized adults were more likely to belong to Family Disruptions and Weak Ties classes than White adults. Participants with Family Disruptions (versus Low Adversity) had worse cognition (global: b = -0.78, 95% CI [-1.19;-0.37]; CIND: RRR = 1.50, 95% CI [1.13;1.99]); controlling for LCRQ and sociodemographics attenuated associations. Participants with Weak Ties (versus Strong) had worse cognition (global: b = -2.90, 95% CI [-3.53;-2.26]; CIND: RRR = 3.16, 95% CI [2.12;4.70]; dementia: RRR = 3.64, 95% CI [1.92;6.90]); associations were not explained by covariates.ConclusionsFamily Disruptions negatively impacted cognition, but associations were attenuated by sociodemographics. Assessing life course resources as contributors to resilience may help explain the untenable ACEs-cognition association. However, negative LCRQ was consistently harmful to cognition. Targeting life course social relationships may benefit cognition.
Health behavior mechanisms linking childhood socioeconomic status to Alzheimer's disease and related dementia risk: Exploring gender and racial/ethnic differences.
Nah S, Chek CJ, Montoya A … +3 more , Duarte A, Ryan LH, Chopik WJ
J Alzheimers Dis · 2026 May · PMID 42083876 · Publisher ↗
BackgroundLower childhood socioeconomic status (cSES) has been linked to a higher risk of Alzheimer's disease and related dementia (ADRD). Yet, the mechanisms underlying this association remain unclear.ObjectiveThis stud...
BackgroundLower childhood socioeconomic status (cSES) has been linked to a higher risk of Alzheimer's disease and related dementia (ADRD). Yet, the mechanisms underlying this association remain unclear.ObjectiveThis study examined whether poorer health behaviors in adulthood mediate the association between lower cSES and ADRD risk. We further explored whether the mediating effects of health behaviors vary by gender or race/ethnicity.MethodsData were drawn from 26,631 participants in the Health and Retirement Study ( = 61.18 years). Cox proportional hazard models were used to estimate the association between cSES and ADRD risk, as well as the mediating effects of health behaviors, including smoking, heavy drinking, physical activity, and influenza vaccination.ResultsLower cSES was associated with a higher risk of ADRD (hazard ratio = 1.06, [1.02, 1.09]). Lower physical activity mediated this association, accounting for 17.1% of the total effect of cSES on ADRD risk. Subgroup analyses revealed that this mediation was consistent across all gender and racial/ethnic groups, except for foreign-born Hispanics. Smoking mediated the association only for men, explaining 4.2% of the total effect.ConclusionsThese findings suggest that lower cSES may be a risk factor for ADRD partially through lower physical activity across most demographic groups. Interventions promoting physical activity in adulthood could help mitigate the adverse effect of low cSES on ADRD risk. Furthermore, smoking prevention programs may be particularly beneficial for men from lower socioeconomic backgrounds.
Association of childhood residential change with later life memory function and rate of decline in the US Health and Retirement Study.
Alhasan DM, Hamlin AM, Meier HC … +4 more , Manning M, Yu X, Gutierrez S, Webster NJ
J Alzheimers Dis · 2026 May · PMID 42083869 · Publisher ↗
BackgroundChildhood residential change may affect later-life memory function and risk for Alzheimer's disease. However, few studies have examined this relationship, particularly in minoritized racial/ethnic groups.Object...
BackgroundChildhood residential change may affect later-life memory function and risk for Alzheimer's disease. However, few studies have examined this relationship, particularly in minoritized racial/ethnic groups.ObjectiveTo assess the association between number of residences and moving due to financial difficulties in childhood with memory trajectories in later life.MethodsData were from the U.S. Health and Retirement Study. Childhood residential change was measured by the self-reported number of residences before age 16 (0-1, 2, 3, 4 or more; n = 4704). Moving due to financial difficulties before age 16 was categorized as yes versus no (n = 4651). Memory function was measured using composite memory z-scores incorporating direct and proxy assessments from 1996-2016. We utilized mixed-effects linear regression models with subject-specific random slopes and intercepts adjusting for sociodemographic characteristics to estimate associations between residential change and memory overall and by race/ethnicity and parental education.ResultsThe mean age at baseline was 57.6 ± 6.1 years, 78.7% self-identified as non-Hispanic (NH) White, 15.7% as NH-Black, and 5.6% as Other/Unknown. Descriptively, NH-Black adults reported fewer residential changes and had lower baseline memory performance compared to NH-White participants. More frequent residential change in childhood was associated with a slower rate of memory decline but not baseline memory function. Moving due to financial difficulties during childhood was not associated with initial memory levels or rates of memory decline. We did not observe effect modification by race/ethnicity or parental education.ConclusionsResults suggest that childhood residential change may contribute to later life memory trajectories.
The long arm of divorce and death: Loss, loneliness, and cognition in mid and later life.
Stokes JE, Pugh EA, Briggs E … +3 more , Lee G, Leggett AN, López-Anuarbe M
J Alzheimers Dis · 2026 May · PMID 42083861 · Publisher ↗
BackgroundEarly life adversities can have lifelong consequences for health, including for cognitive functioning and Alzheimer's disease and related dementias. Moreover, early-life disadvantages stemming from parental dea...
BackgroundEarly life adversities can have lifelong consequences for health, including for cognitive functioning and Alzheimer's disease and related dementias. Moreover, early-life disadvantages stemming from parental death and divorce have been linked with later life social, mental, and physical well-being outcomes, including social isolation. Therefore, loneliness stands out as an intervenable aspect of well-being that may mediate long-term consequences of early life exposure to parental death and divorce for midlife and older adults' cognitive decline.ObjectiveThe present study aims to determine whether early life exposures to parental death and/or divorce are associated with cognitive functioning in later life, and whether loneliness in midlife mediates such effects.MethodsWe used the 2014-2020 Health and Retirement Study (HRS), 2015 HRS Life History data and longitudinal structural equation modeling to address our research questions.ResultsEarly-life exposure to parental divorce, but not death, was associated with greater loneliness in late midlife and older age, and loneliness predicted more rapid declines to cognitive functioning over time. Mediation was statistically significant (p < 0.05).ConclusionsAlthough racial/ethnic minorities had higher exposure to both parental death and divorce, the effects of parental death and divorce were similar across race/ethnicity. Our results underscore the long-term impacts of parental divorce on well-being and health in adulthood and highlight loneliness as a critical determinant of cognitive declines and disparities in later life.
Resting after learning facilitates memory consolidation and reverses spatial reorientation impairments in female 3xTg-AD mice.
Stimmell AC, Alday LJ, Salvador EM … +7 more , Marquez Diaz J, Moseley SC, Cushing SD, Zheng Y, Ogg JD, Ragsdale SM, Wilber AA
J Alzheimers Dis · 2026 Jun · PMID 42081596 · Full text
BackgroundSleep is an essential component of memory consolidation and waste clearance, including pathology associated with Alzheimer's disease (AD). Facilitation of sleep decreases amyloid-β (Aβ) and tau accumulation and...
BackgroundSleep is an essential component of memory consolidation and waste clearance, including pathology associated with Alzheimer's disease (AD). Facilitation of sleep decreases amyloid-β (Aβ) and tau accumulation and is important for memory consolidation.ObjectiveWe previously found that 6-month female 3xTg-AD mice were impaired at spatial reorientation learning and memory. Given the association between sleep and AD, we assessed the impact of added rest on impaired spatial reorientation that we previously observed.MethodsWe randomly assigned 3xTg-AD mice to a sleep (n = 7; 50-60 min pre- & post-task induced rest) or a non-sleep group (n = 7; remained in home cage pre- & post- task). Mice in both groups were compared to non-Tg, age-matched, non-sleep controls (n = 6). To confirm that our rest condition induced sleep, we performed the same experiment with rest sessions for both 3xTg-AD and non-Tg mice (n = 5/group) implanted with recording electrodes to capture local field potentials, which were used to classify sleep states. Markers of pathology (AT8, 6E10, M78, and M22) were also assessed in the parietal-hippocampal network, where we previously showed pTau (AT8) positive cell density predicted spatial reorientation ability.ResultsWe found that 3xTg-AD sleep mice were unimpaired at spatial reorientation compared to non-Tg mice and performed better than 3xTg-AD non-sleep mice (replicating our previous work). This recovered behavior was apparent despite no change in the density of pathology-positive cells. Further, theta-gamma coupling during sleep may explain the facilitated cognition in 3xTg-AD sleep mice, suggesting brain activity patterns during sleep may mediate the restored cognition.ConclusionsImproving sleep in early stages of AD pathology offers a promising approach for facilitating memory consolidation and improving cognition.
Choroid plexus volume in Alzheimer's disease: A systematic review and meta-analysis.
Mahmoudi F, Yazdan Panah M, Dehghani Firouzabadi D … +5 more , Vaheb S, Ghoshouni H, Flores Gonzalez R, Shaygannejad V, Mirmosayyeb O
J Alzheimers Dis · 2026 Jul · PMID 42081200 · Full text
BackgroundAlzheimer's disease (AD) is marked by amyloid-β and tau accumulation, processes increasingly linked to impaired protein clearance and neuroinflammation. The choroid plexus (CP), which regulates cerebrospinal fl...
BackgroundAlzheimer's disease (AD) is marked by amyloid-β and tau accumulation, processes increasingly linked to impaired protein clearance and neuroinflammation. The choroid plexus (CP), which regulates cerebrospinal fluid (CSF) production and immune signaling, may contribute to these mechanisms. This review aimed to evaluate alterations in CP volume (CPV) in AD and their clinical significance.MethodsPubMed, Embase, Scopus, and Web of Science were searched up to March 2025. Eligible MRI-based studies comparing CPV between AD patients and healthy controls (HCs), as well as investigations examining associations of CPV with demographic, cognitive, structural, and pathological variables, were included. Random-effects models estimated pooled effect sizes, while narrative synthesis explored associations with clinical and pathological features.ResultsSixteen studies (2004 AD; 883 HCs) met inclusion criteria. Pooled findings demonstrated significantly larger CPV in AD relative to HCs (SMD = 1.05, 95% CI: 0.67 to 1.43; p < 0.01). Narrative review indicated consistent links between CP enlargement and worse cognition, hippocampal and cortical atrophy, ventricular expansion, and increased amyloid and tau deposition. CP changes were also associated with impaired glymphatic clearance and systemic inflammation. Notably, enlargement was observed in mild cognitive impairment, suggesting early involvement in the disease course.ConclusionsCP enlargement may represent a neuroimaging feature of AD, reflecting the interplay between impaired clearance mechanisms and neuroinflammatory processes. Given its visibility on routine MRI, CPV may hold considerable potential as an imaging marker for disease stratification and longitudinal monitoring of AD.
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