The Journal of Prevention of Alzheimer's Disease

Objective: Behavioral and social factors (BSFs) substantially influence the risk, onset, and progression of Alzheimer disease and related dementias (ADRD). A systematic representation of their interplay is essential for advancing prevention and targeted interventions. However, BSF-related knowledge is scattered across heterogeneous sources, limiting scalable evidence synthesis and computational analysis. To address this, we created a Behavioral Social Data and Knowledge Ontology for ADRD (BSOAD) to represent and integrate BSFs with respect to ADRD. Material and Methods: BSOAD was developed following established ontology design principles, prioritizing reuse of existing ontology elements to ensure semantic interoperability. It was built upon the Social Determinants of Health Ontology (SDoHO) and the Drug-Repurposing Oriented Alzheimer Disease Ontology (DROADO). BSF-related classes were enriched with ICD 10 CM Z55 Z65 codes and ADRD related classes with AD Onto. Relationships between BSFs and ADRD were derived through literature mining. Ontology quality was evaluated through Hootation based expert review and an LLM assisted framework assessing structural coverage and semantic coherence. Results: BSO AD contains 2275 classes, 153 object properties, and 49 data properties. Expert review demonstrated strong rational agreement (0.95), with disagreements resolved through discussion. LLM-based evaluation showed high category coverage rates ([≥] 0.97) and robust semantic alignment with the relevant literature (average completeness = 0.79; conciseness = 0.94). Discussion and Conclusion: BSOAD is, to our knowledge, the first ontology to systematically represent BSFs and hierarchically model their interrelationships in ADRD. It establishes a semantic backbone for computational analysis and knowledge integration. The LLM assisted evaluation framework demonstrates the feasibility of scalable, automated ontology assessment.

Improving diversity in U.S. Alzheimers disease (AD) research is a pressing need. By 2050, Hispanic and Latino Americans will comprise 30% of the population. Hispanics are 1.5 times more likely and Blacks are twice as likely to develop AD compared to Whites, yet both remain vastly underrepresented in clinical trials research. Aging and AD research mentorship of underrepresented STEM undergraduates is designed to promote entry into related professions by students committed to decreasing disparities in AD research participation and clinical care. The NIA-funded MADURA program recruited 93 students from backgrounds historically underrepresented in STEM majors and/or from NIH-defined disadvantaged backgrounds. Trainees were placed in aging/AD research labs and received weekly training and mentorship from faculty research PIs and other types of supervisors (postdoctoral researchers, graduate students, research assistant staff...) Our study examined student ratings of the program and mentor behaviors, using a program-specific survey and the Mentoring Competency Assessment-21 (MCA-21). Trainees were highly satisfied with both mentoring relationships and the overall program. Student rated MCA-21 competency areas were quite high for both P.I.s and other types of research mentors. However, there were striking differences in associations between competencies and relationship and program satisfaction, by mentor type. For PI mentors, no MCA-21 competencies were associated with relationship satisfaction, but five of six competencies were associated with relationship satisfaction for other mentor types. Similarly, no PI mentor competencies were significantly correlated with overall placement satisfaction, but all six competencies were correlated with overall placement satisfaction for other mentor types. The authors discuss the likelihood of differing student expectations of faculty PI versus other types of research mentors, recommendations for assessing role-specific student expectations (including functions primarily possible only for senior faculty PIs), and utilizing nearer-peer plus PI faculty mentors to comprehensively address the gamut of mentee needs.

Background and Aims: Plasma phosphorylated tau 217 (p-tau217), including %p-tau217, has emerged as a robust biomarker of Alzheimer's disease (AD) pathology, with increasing interest in its longitudinal behavior. In "Predicting onset of symptomatic Alzheimer's disease with plasma p-tau217 clocks," Petersen et al. applied disease clock models, Sampled Iterative Local Approximation (SILA) and Temporal Integration of Rate Accumulation (TIRA), to estimate age at plasma %p-tau217 positivity and reported that this measure predicts age at onset of symptomatic AD. We aimed to determine whether this apparent predictive performance reflects biomarker information or arises from structural artifacts in the analysis. Methods: We analyzed digitized data from published figures and decomposed the clock-derived predictor into baseline age and estimated time from %p-tau217 positivity. We quantified shared and unique explained variance between baseline age and the clock-derived predictor using commonality analysis. To further disentangle structural and biomarker contributions, we evaluated a null scenario in which the biomarker-derived timing component was replaced with randomly generated values drawn over the observed range, preserving the predictor distribution while removing biomarker information. Results: The reported predictive performance was largely driven by structural artifacts arising from bounded follow up and constraints among the variables. Restriction to individuals who progressed during limited follow up, together with constraints on the allowable timing of events, induced a strong association between baseline age and age at symptom onset. In ADNI, baseline age alone explained substantially more variance in age at onset than the clock-derived predictors (R2=0.78 vs. 0.337 and 0.470 for TIRA and SILA). The estimated time from %p-tau217 positivity contributed minimal additional information, and randomized predictors yielded comparable performance to baseline age alone (R2=0.79). Conclusion: The apparent predictive ability of plasma %p-tau217 disease clocks is driven largely by structural age relationships rather than independent biomarker signal. The plasma %p-tau217 timing component provided minimal predictive value, and its combination with age obscured these structural dependencies. These findings underscore the need for careful evaluation of constructed predictors and outcomes in longitudinal analyses of disease progression.

Alzheimer s disease (AD) and other tauopathies are characterized by the hyperphosphorylation of tau (pTau), leading to its aggregation in the brain, a process strongly predictive of neurodegeneration and future cognitive decline. Currently, tau positron emission tomography (PET) is the only validated method for detecting tau aggregates in vivo. However, its high cost, invasiveness, and limited accessibility restrict its use in clinical settings and preclude large-scale screening. Moreover, existing plasma biomarkers that quantify the level of pTau at specific sites (e.g., pTau217) have limited specificity for confirming AD-related tau aggregation, partly due to the heterogeneous and irregular phosphorylation patterns of pTau. Besides, the concentration of pTau is frequently elevated in the context of isolated amyloid-{beta} pathology, which is less strongly associated with cognitive decline in the absence of aggregated tau. There is therefore an urgent need for a reliable and scalable blood-based biomarker of tau pathology. A key mechanism underlying AD tau pathology is the ability of pathologically active pTau (PA pTau) to bind to and seed normal tau, facilitating prion-like propagation of insoluble tau aggregates. Here, we assessed the diagnostic performance of the VeraBIND Tau assay, the first functional assay to detect PA pTau seeding activity in plasma. Seventy-nine cognitively unimpaired (CU) and 66 cognitively impaired older adults underwent blood sampling, cognitive assessment, amyloid-PET or cerebrospinal fluid (CSF) analysis, and [18F]-MK6240 tau-PET imaging. Plasma pTau217 concentrations were quantified using the Lumipulse platform (Fujirebio). The VeraBIND Tau assay isolated PA pTau from plasma and evaluated its ability to bind recombinant normal tau using a tagged-tau chemiluminescent readout. VeraBIND Tau demonstrated 94.2% sensitivity and 96.1% specificity for predicting tau-PET positivity (AUC=0.97). It outperformed plasma pTau217 in CU individuals (PPV=85.9%), regardless of the pTau217 threshold used (maximal PPV of 57.5% using the 0.256pg/mL pTau217 threshold). This higher VeraBIND Tau diagnostic accuracy was driven by early tau-PET stages (Braak-like tau-PET stages 1-3; AUC=0.96 vs. 0.74 for pTau217, p=0.003). Moreover, both cross-sectional values and annual changes in VeraBIND Tau were significantly correlated with cognitive performance and entorhinal tau-PET signal (all absolute Spearman r[&ge;]0.23, p<0.05). These findings highlight the strong potential of VeraBIND Tau as a scalable and accurate screening tool to detect AD tau pathology in the general population. The assay may also help enrich clinical trials with tau-PET positive CU individuals, enhance clinical diagnostic workflows and support monitoring of tau-targeted therapies. Future work should evaluate its utility in optimizing triage and early-intervention strategies.

INTRODUCTION: Bilingualism is a proposed cognitive reserve factor that delays symptom onset in Alzheimer's disease (AD), though current evidence lacks biomarker confirmation. This retrospective study examined bilingualism's association with symptom onset across AD clinical stages, including biomarker-confirmed cases. METHODS: Participants from the Sant Pau Memory Unit spanning amnestic mild cognitive impairment (MCI), amnestic dementia, and biomarker-confirmed AD were analyzed, with balanced representation of active and passive Spanish-Catalan bilinguals. Linear regression models evaluated associations between bilingualism and reported age at symptom onset, controlling for education, sex, and disease severity. RESULTS: Active bilingualism was associated with delayed symptom onset in amnestic MCI (2.21 years), amnestic dementia (1.42 years), and biomarker-confirmed AD (1.45 years; ps < .05). Higher education was associated with earlier onset, likely representing healthcare seeking behavior. DISCUSSION: Bilingualism protects against earlier symptom manifestation in MCI and AD, supporting bilingualism as a contributor to cognitive reserve.

Background: Evidence regarding dementia prevention strategies has been accumulating. However, disseminating research findings to the public is often difficult, and addressing the evidence-practice gap presents an important challenge. This study examined potential strategies to support sustained engagement in dementia prevention activities. Participants and Setting: Members of senior citizens' clubs in Tottori Prefecture, Japan. Methods: This questionnaire survey collected data on basic demographics, frailty, and subjective cognitive decline (SCD). It also included questions on awareness of the Tottori Method Dementia Prevention Program, interest in experiencing the program if an instructor was dispatched, and the feasibility of engaging in the program through internet-based delivery or printed materials. Results: A total of 9,506 respondents were included in the analysis. Awareness of the dementia prevention program was 11.9%. Overall, 50.4% of the respondents registered a desire to try the program if an instructor was dispatched. The highest proportion of respondents (50.5%) reported willingness to engage in the program if materials summarizing activities that could be completed in approximately 10 min were provided. However, both frailty and SCD were associated with a lower interest in these dementia prevention activities (adjusted odd ratio [95% confidence interval] = 0.77 [0.67-0.89] and 0.86 [0.79-0.95], respectively). Conclusions: To promote sustained engagement in dementia prevention activities, opportunities to experience the program and activities that can be completed in a short time should be availed. However, disseminating research findings to the public remains challenging, and individuals at a higher risk of health problems may be less interested in dementia prevention. Proactive outreach strategies targeting high-risk individuals may be necessary to effectively disseminate the information.

Background Autosomal dominant Alzheimer's disease (ADAD) serves as a model for presymptomatic biomarker discovery. Characterising the temporal profile of plasma biomarker levels in presymptomatic individuals may enhance understanding of disease pathogenesis, inform future clinical trials, and guide clinical interpretation. Methods We evaluated 124 proteins using a NUcleic acid-Linked Immuno-Sandwich Assay (NULISA) panel in 270 plasma samples from a longitudinal cohort study of ADAD, comprising 113 individuals (73 mutation carriers and 40 non-carriers). We determined the plasma proteomic changes that distinguished mutation carriers from non-carriers. We then used predicted age at symptom onset to determine the approximate timing of presymptomatic divergence in biomarker levels in carriers relative to non-carriers. Results Nine proteins (A{beta}42, BACE1, GFAP, pTau181, pTau231, pTau217, MAPT, NfL, and AChE) robustly differed between carriers and non-carriers, cross-sectionally. Longitudinal analyses showed A{beta}42 levels were elevated in carriers at least 26 years before expected symptom onset. Carriers diverged from non-carriers in phosphorylated tau markers at 21-24 years before expected symptoms, total-tau at 19 years, GFAP and BACE1 at 14 years, and NfL at 6 years. Differences in AChE were seen in symptomatic individuals, likely reflecting cholinesterase inhibitor use. Conclusion Multiple plasma proteins are elevated in presymptomatic and symptomatic autosomal dominant AD mutation carriers relative to non-carriers. Changes in eight biomarkers occur sequentially from 26 to 6 years prior to symptom onset. Combining biomarkers may help in staging presymptomatic AD and optimise clinical trial inclusion. Further work is needed to assess how these findings generalise to non-monogenic AD.

Abstract Background: Resilience is acknowledged to be an important component for successful aging in older adults, but there is scant evidence with which to inform public health interventions for this age group. The aim of this study is to determine whether the public health intervention, mindfulness for later life is both feasible and acceptable to older adults. Methods: Participants were recruited from September 2021 to June 2022 through older adult organisations and charities, such as the University of the Third Age, Age UK, and Age Concern, and by adverts distributed through village newsletters and support organisations. Participants were offered six weekly sessions of mindfulness therapy, the program was based on the mindfulness-based stress reduction program, each session was two hours long with 10-15 participants per program. The following two pre-defined indicators of success needed to be met for the program to be deemed feasible: successful uptake (recruitment of 30 participants over nine months) and initial engagement. Results: Thirty-three potential participants were screened for eligibility over nine months, 31 of whom were recruited to the study (103% of the target sample). Of these, 28 participants (90%) completed four or more online sessions. Thus, predefined indicators of feasibility were met. Conclusions: This study supports the feasibility of delivering the mindfulness for later life program as a public health intervention, including recruitment and treatment completion. A full-scale trial to assess the clinical- and cost-effectiveness of the intervention including its long-term effects is warranted.

BackgroundEarly recognition of dementia-related changes is critical for timely intervention. The AD8 Dementia Screening Interview (AD8) detects subtle cognitive and functional changes, yet its broader associations with health and wellbeing among Chinese-speaking older adults remain underexplored. MethodsA cross-sectional study was conducted with 144 community-dwelling Chinese older adults (mean age 73.1 years; 81.3% female). Participants completed sociodemographic, health, functional, and psychosocial measures, including the AD8 and the Geriatric Depression Scale (GDS-15). Exploratory Factor Analysis (EFA) assessed the dimensionality of the AD8, and binary logistic regression examined associations between AD8 items and demographic, health, functional, and psychosocial outcomes. ResultsChronic disease was prevalent (68.1 percent), and 13.2 percent reported a mental health disorder. EFA identified three domains: memory impairment, executive and interest decline, and functional recall difficulties, explaining 61.7 percent of the variance. Logistic regression showed predictive roles for judgment problems (AD8_1), repetition (AD8_3), financial difficulties (AD8_6), tool-use difficulties (AD8_4), and daily memory problems (AD8_8). Financial and executive difficulties were associated with age and mobility challenges, while repetition predicted psychological disorders and hopelessness. Judgment problems were linked to lower life satisfaction and happiness but greater helplessness. Worthlessness was predicted by financial, tool-use, and memory difficulties, whereas intact temporal recall (AD8_5) was protective. Several outcomes including boredom, low energy, and staying home were not significant. ConclusionDistinct AD8 items predicted vulnerabilities across physical, psychological, and social domains. Findings highlight the multidimensional value of the AD8 as a culturally relevant screening and risk stratification tool for community-based assessments of Chinese older adults. Summary Statement Implications for PracticeO_ST_ABSWhat does this research add to existing knowledge in gerontology?C_ST_ABSThis study shows that specific AD8 items identify early multidimensional vulnerability among community-dwelling Chinese-speaking older adults. Difficulties with judgment, repetition, financial management, tool use, and daily memory were associated with functional limitations and psychosocial distress, extending the AD8 beyond dementia screening alone. The identification of three AD8 domains supports a broader understanding of early cognitive change as involving cognitive, functional, and emotional processes. The findings contribute culturally specific evidence from an under-researched population in gerontological research. What are the implications of this new knowledge for nursing care with older people?For nursing practice, the AD8 provides a brief, feasible tool to support holistic assessment in community and aged care settings. Key AD8 indicators can guide nurses in identifying older people at risk of functional decline and emotional vulnerability, enabling earlier, person-centred interventions. The findings highlight the importance of culturally and linguistically appropriate assessment when caring for diverse ageing populations. How could the findings be used to influence policy or practice or research or education?The results support integrating brief cognitive screening into routine nursing assessments and community-based aged care services to promote early identification and ageing in place. Nursing education should emphasise interpreting cognitive screening within psychosocial and cultural contexts. Longitudinal research is needed to assess intervention effectiveness. Key Points[tpltrtarr] Early cognitive changes matter for older Chinese-speaking adults, because difficulties with judgment, repetition, financial management, and tool use (AD8 domains) were consistently linked to poorer functional and psychosocial outcomes. [tpltrtarr]Beyond dementia screening, the AD8 proved useful for detecting vulnerabilities in wellbeing and daily functioning, extending its role beyond diagnostic sensitivity. [tpltrtarr]A cultural focus is vital, as this study is among the first to examine AD8 associations in older Chinese-speaking adults, underscoring the need for culturally tailored screening. [tpltrtarr]The psychosocial impact of cognitive changes was evident, with strong associations to helplessness, worthlessness, and reduced life satisfaction, reinforcing the overlap between cognitive and emotional health. [tpltrtarr]In practice, integrating AD8 screening into community and primary care could help identify at-risk individuals early and support targeted interventions in culturally and linguistically diverse populations.

BACKGROUND: Increasing evidence suggests that accurate prediction of Alzheimer disease (AD) symptom onset requires more than amyloid- and tau-centric biomarkers such as cerebrospinal fluid (CSF) A{beta}42/40, total tau and p-tau181 and plasma p-tau217. Autosomal dominant AD (ADAD), caused by pathogenic PSEN1, PSEN2 and APP mutations with predictable age at symptom onset, presents a unique opportunity to characterize the chronological changes in proteins beyond amyloid and tau and clarify them as early biomarkers of disease onset or as biomarkers related to disease staging and progression monitoring. METHODS: We measured 972 CSF samples corresponding to 484 participants of the Dominantly Inherited Alzheimer Disease Network (DIAN) using the NULISASeq 120 CNS Disease Panel. We first benchmarked the technology against gold-standard measurements followed by the identification of proteins that were differentially abundant in relation to mutation status and symptomatology. Next, we determined the chronological emergence of protein changes in relation to the estimated years to onset (EYO). Finally, we assessed whether specific protein measures improved the prediction of EYO in the ADAD. FINDINGS: NULISA measurements were comparable to those previously published. We demonstrated that known early alterations in CSF amyloid and tau were followed by inflammatory and neurodegenerative responses suggesting that clinical manifestation of AD happens before the inflammatory processes is fully developed. Finally, we found a multi-protein composite approach for predicting EYO that outperformed single biomarker values. INTERPRETATION: Our results suggest that the main CSF proteomic landscape changes in ADAD are due to the presence of a pathogenic mutation and occur prior to symptom onset. Improved performance of multi-protein composite to predict EYO compared to single biomarker values highlights the added value of multiplex proteomic signatures for biomarker panel development. FUNDING: National Institute on Aging, Alzheimers Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea, Spanish Institute of Health Carlos III.

Background and ObjectivesMultifactorial interventions have been reported to be effective in improving cognitive function; however, their long-term effectiveness in community settings remains to be sufficiently examined. This study aimed to investigate the effects of a socially implemented multifactorial intervention program on dementia onset, long-term care insurance certification, and post-intervention cognitive and physical functions. MethodsThis retrospective observational study collected data from three municipalities. The study population comprised individuals suspected of having mild cognitive decline based on cognitive function screening tests conducted by March 31, 2024, and who had been invited to participate in a dementia prevention class, but had not applied for long-term care insurance at the time of the invitation. Participants were classified into class participation and non-participation groups for analysis. Most participants attended the class only once (intervention duration: 4 or 6 months). ResultsData from 104, 218, and 256 individuals were collected from the three municipalities, respectively. No significant association was found between class participation and suppression of dementia onset or long-term care insurance certification in any of the municipalities. Regarding pre-post comparisons among class participants, significant improvements in cognitive function and some physical functions were observed in all the three municipalities. ConclusionsThe multifactorial interventions implemented in community settings showed no effect on dementia onset or health outcomes. However, class participation was associated with improvements in cognitive function and some physical functions. These findings suggest that implementing programs based on evidence can achieve effects similar to those observed in studies conducted under ideal conditions.

ABSTRACT BACKGROUND: Recent studies consisting primarily of white participants have found lowered plasmalogen levels to be associated with lower cognitive function. We explore the association of blood plasmalogen levels with global cognition and brain imaging metrics in older African Americans. METHODS: Included in these cross-sectional analyses were participants in the Minority Aging Research Study (MARS) and the Rush Clinical Core without dementia, available serum lipid levels, and a concurrent cognitive function assessment. A plasmalogen biosynthesis value (PBV) was calculated for each participant utilizing five ratios of four key glycerophospholipids. A linear regression model of global cognition was constructed with PBV, adjusted for sex, age, education, total cholesterol, and body mass index. In participants with 3T MRI brain imaging, the association between PBV and white matter hyperintensities (WMH) was explored. RESULTS: Of the 298 participants, the mean age was 74.6 years, mean education was 15.6 years, and 84% were women. The median PBV was 0.42 (interquartile range: 0.22 to 1.14). A unit higher in PBV was suggestively associated with a 0.17 {beta}-unit higher cognitive z-score (SE =0.09, p = 0.06). In 254 participants with MRI data, an increase in log10 SD of PBV suggested the less white matter hyperintensities (estimate = -0.20, SE = 0.12, p = 0.08). DISCUSSION: In older African Americans, higher PBV was associated with higher level of global cognition, and potentially lower levels of brain white matter hyperintensities. Larger studies are needed in additional cohorts to determine if PBV is associated with annual rate of change in cognitive function.

Introduction: End of life decision making poses unique challenges for individuals with dementia and their family caregivers as cognitive decline shifts decision making responsibility to surrogates. Methods: Using 2010 to 2022 Health and Retirement Study (HRS) exit interview data, we compared advance directive completion, decision making needs near death, involvement of others in decision making, and concordance between expressed preferences and care received among decedents with and without dementia. Analyses incorporated HRS exit interview sampling weights, primary sampling units, and strata to account for the complex multistage probability design of HRS and produce nationally representative estimates of U.S. older adult decedents (50 years or older). Weighted descriptive statistics and design adjusted Wald tests were used to compare groups. Results: Among 5,389 decedents, 1,010 (weighted 17.7%) had dementia prior to death. Decedents with dementia were more likely to have completed advance directives than those without dementia (81.3% vs. 69.1%, p<.001). However, they also had significantly higher decision making needs in the final days of life (54.3% vs. 47.2%, p<.001). Children or grandchildren were more frequently involved in care decisions for decedents with dementia (63.9% vs. 45.6%, p<.001). Despite differences in decision making processes, most decedents in both groups expressed preferences for comfort focused care, and preference care concordance exceeded 90% in both groups. Conclusions: Findings suggested that dementia reshaped the structure and intensity of the shared decision making process by increasing surrogate engagement and decisional demands, underscoring the importance of early advance care planning and structured support for family caregivers to sustain goal concordant care.

Background: Gabapentin prescriptions have increased 123% since 2010, reaching 59 million annually and 15.5 million patients. Recent evidence indicates that concomitant use of gabapentin and dihydropyridine calcium channel blockers (DHP-CCBs) amplifies dementia risk through a dual neuronal calcium signaling blockade mechanism. Whether these cognitive effects are reversible upon discontinuation, and whether the combination accelerates decline in patients with established dementia, remains unknown. Methods: We conducted two complementary studies using the Rutgers Clinical Research Data Warehouse (CRDW; 2015-2024). Study 1: A self-controlled case series (SCCS; N=3,058) comparing cognitive event rates during concomitant gabapentin-DHP-CCB use versus after discontinuation, using strictly duration-matched observation windows. Study 2: A cohort study (N=320) of patients with established dementia initiating gabapentin, comparing outcomes between DHP-CCB, non-DHP-CCB, and no-CCB users. Findings were externally replicated in the NIH All of Us Research Program Controlled Tier (N=8,853). Results: In the CRDW self-controlled analysis, event rates were significantly higher during combination use versus after discontinuation: falls (RR 1.34, 95% CI 1.11-1.61), cognitive symptoms (RR 1.67, 95% CI 1.38-2.01), and composite cognitive endpoint (RR 1.32, 95% CI 1.09-1.59). Effects were greatest when both drugs were discontinued (cognitive symptoms RR 2.21; falls RR 1.76). Protopathic bias was ruled out by monotonically increasing RRs across 0-, 30-, and 60-day lag conditions. In the dementia acceleration cohort, DHP-CCB use tripled encephalopathy risk (HR 3.18, 95% CI 1.36-7.46), with zero events among non-DHP CCB users. External replication in All of Us confirmed all primary outcomes (falls RR 1.53, cognitive symptoms RR 1.26, composite RR 1.42; all p<0.001). A non-DHP CCB negative control in All of Us confirmed mechanistic specificity: cognitive symptom and encephalopathy reversal signals were absent with verapamil/diltiazem. CKD amplified effects in both datasets, consistent with gabapentin accumulation through impaired renal clearance. Conclusions: Cognitive effects associated with concomitant gabapentin-DHP-CCB use appear substantially reversible upon discontinuation, replicated across two independent datasets. The DHP-specific pattern, confirmed through a pharmacological negative control, supports a neuronal L-type calcium channel mechanism. Clinicians should review gabapentin-DHP-CCB combinations in patients with cognitive complaints or falls, as deprescribing - particularly of both agents - may produce meaningful improvement.

Frailty is a geriatric syndrome that reflects a state of increased vulnerability to endogenous and exogenous stressors, exposing individuals to a higher risk of premature death and adverse health outcomes. This work aims at identifying new determinants of frailty and improving screening tools for less studied clinical endpoints. To this end, we analyze a novel cohort provided by the Camara Municipal de Famalicao, comprising 2,862 participants and 6,855 observations across up to four assessment moments, and spanning sociodemographics, anthropometry, functional tests, cognitive assessments, quality of life, and fall history. We combine unsupervised clustering to explore heterogeneity with supervised prediction for falls, hospitalization, and handgrip strength, using explainability approaches to connect model outputs to clinically meaningful patterns. Outcome-agnostic clustering separates functional profiles ranging from robust to vulnerable that align a posteriori with different fall burdens, while outcome-aware clustering further identifies a high-risk subgroup characterized by poorer mobility, endurance and greater reliance on mobility assistance. Supervised models achieve moderate and consistent discrimination for fall prediction (AUROC{approx} 0.66-0.68), and explainability approaches consistently emphasize key drivers including handgrip strength, self-report assessments, and other results from functional tests. Handgrip regression attains MAE{approx} 3.6 kg (R2{approx} 0.49), while a dedicated CatBoost sarcopenia classifier improves detection (AUROC = 0.798, recall = 0.792) at the cost of low precision, consistent with screening-oriented use. Overall, the results support the feasibility of explainable AI for actionable risk stratification in community assessments, while highlighting constraints related to missingness, class imbalance, and selection bias toward an active cohort.

Background: Estimates from high income countries suggest that approximately 40% of dementia cases may be attributable to modifiable risk factors across the life course. However, most evidence informing these estimates originates from high income settings, and population level estimates from sub Saharan Africa remain limited. We aimed to estimate population attributable fractions (PAFs) for modifiable dementia risk factors in the Democratic Republic of the Congo (DRC). Methods: We conducted a cross sectional analysis of community dwelling adults aged 65 years and older enrolled in the Etude du Vieillissement Cognitif et de Demence en Republique Democratique du Congo (EVCD RDC). Prevalence estimates of dementia and associated exposures were derived from prior epidemiological studies in this population. Odds ratios were estimated using logistic regression, and population attributable fractions were calculated by integrating exposure prevalence with effect size estimates. To account for correlations between exposures, communality weights were applied when estimating combined PAFs across risk factors. Findings: Combined modifiable risk factors were estimated to account for 37.3% (95% CI 14.3 to 55.6) of dementia cases in this sample. Poverty had the largest weighted PAF (18.4%, 95% CI 13.3 to 22.8), followed by low educational attainment (11.3%, 95% CI 7.3 to 15.3) and depression (5.8%, 95% CI 2.8 to 8.6). Additional contributors included traumatic events (5.4%), war exposure (2.1%), diabetes (1.3%), and hypertension (1.1%). A hypothetical 15% proportional reduction in these risk factors was estimated to reduce dementia prevalence by 6.4% (95% CI 2.1 to 10.8), corresponding to approximately 10 700 cases prevented in the DRC by 2025. Interpretation: Modifiable risk factors account for a substantial proportion of dementia burden in the DRC, with structural determinants such as poverty and education contributing the largest fractions. Dementia prevention strategies in low and middle income countries may therefore require broader public health approaches that address socioeconomic and structural determinants alongside conventional clinical risk factors.

Background: LLMs enable patient-facing conversational agents, creating a pathway toward digital twins that capture older adults' lived experiences and behavioral responses across time. A central barrier is personality drift---inconsistent trait expression across repeated interactions---which undermines reliability of generated trajectories and intervention-response simulation in geriatric care. Objective: To develop ELDER-SIM, a multi-role elderly-care conversational platform for building personality-stable digital twin agents, and to propose a psychometric validation framework for quantifying personality consistency in LLM-based agents. Methods: ELDER-SIM was implemented via n8n workflow orchestration with local LLM inference (Ollama/vLLM), integrating (1) Big Five (OCEAN) trait specifications, (2) a Cognitive Conceptualization Diagram (CCD) grounded in Beck's CBT framework, and (3) a MySQL-based long-term memory module. Ablation studies across four conditions---Baseline, +Memory, +CCD, and +LoRA (fine-tuned on 19,717 instruction pairs from CHARLS)---were evaluated via Cronbach's $\alpha$, ICC, and role discrimination accuracy. Results: Personality measurement reliability was acceptable to excellent across conditions (Cronbach's : 0.70-0.94), with consistently high test-retest stability (ICC: 0.85- 2 0.96). Role discrimination improved stepwise from 83.3% (Baseline) to 88.9% (+Memory), 94.4% (+CCD), and 97.2% (+LoRA). CCD produced the largest gain in internal consistency (mean 0.702[-&gt;]0.892), while LoRA achieved the highest overall internal consistency ( 0.940) and ICC (0.958). Conclusions: ELDER-SIM provides a psychometrically validated approach for constructing personality-consistent elderly digital twin agents. Structured cognitive modeling and domain adaptation reduce personality drift, supporting reliable longitudinal simulation for elderly mental health care and reproducible in silico evaluation before clinical deployment.

Introduction. Latino families shoulder a disproportionate share of dementia care in the United States, yet encounter multilayered barriers that shape access, timeliness, and quality. This study explores the experiences of Latino care partners, focusing on how system-level, cultural, and linguistic factors shape dementia care. Methods. We conducted a qualitative study using semi-structured interviews with care partners of Latino individuals living with Alzheimer's disease and related dementias (ADRD). Interviews were conducted by phone or videoconference by a bilingual interviewer, and the interviews were recorded and transcribed verbatim. Data was analyzed using reflexive thematic analysis. Results. Twenty-three participants were recruited. Two meta-themes captured participants' experiences. (1) Mismatch Between the Healthcare System and the Lived Realities of Latino Families Affected by Dementia, which included three subthemes: a) Linguistic barriers that referred to the quality and dialect fit (over-literal jargon, unfamiliar regional vocabulary, poor adaptation to literacy); b) Cultural misfit, were dementia-care programs were not culturally or linguistically appropriate, or programs where cultural norms were disregarded; and c) Structural and systemic barriers, such as communication failures (e.g. voicemail loops, no responsiveness) and long waits/fragmented pathways that broke clinical momentum (e.g. months to a year for specialty appointment). The second theme was: The Central Role of the Latino Caregiver in Navigating Dementia Care, where, in the absence of pathway ownership, care partners served as navigators, interpreters, coordinators, and safety monitors, while also bearing the emotional and financial strain. Discussion: The narratives from care partners reveal specific mechanisms (e.g., caregiver hyper-advocacy and "maze-like" coordination failures) that, if addressed, can guide intervention design and policy aimed at redistributing coordination back to the system and improving outcomes for Latino families.

Background and Objectives: In Lewy body disease (LBD), co-occurring Alzheimer's disease (AD) neuropathologic change (ADNC) is associated with worse clinical outcomes. While plasma pTau217 detects ADNC in LBD, its prognostic, monitoring, and risk-stratification utility remains unclear. We evaluated whether plasma pTau217 predicted cognitive and functional decline and risk for progression to MCI or dementia in LBD. Methods: We included 501 participants enrolled in the Stanford Alzheimer's Disease Research Center with plasma pTau217 data who were clinically diagnosed as LBD spectrum (n = 131), AD spectrum (n = 133), or healthy controls (HC; n = 237). To assess prognostic and monitoring utility in LBD, linear mixed-effect models tested continuous baseline and longitudinal (2-5 years) plasma pTau217 as predictors of change in 2-8-year clinical outcome trajectories including: daily functioning (CDR-SB), global cognition (MoCA), and five domain-specific cognitive indices. For risk-stratification in LBD, baseline plasma pTau217 was dichotomized using an amyloid PET-derived, LBD-specific cut-point to examine effects of abnormal versus normal levels on clinical outcomes in separate mixed-effects and survival models. Results: In LBD, higher continuous baseline plasma pTau217 predicted accelerated CDR-SB increase ({beta} = 0.29, p < 0.001), MoCA decline ({beta} = -0.37, p = 0.014), and cognitive index decline (memory, executive function, visuospatial function, processing speed; {beta}s = -2.24 to -0.06, ps [&le;] 0.01). Faster longitudinal pTau217 increase predicted accelerated CDR-SB increase ({beta} = 0.24, p = 0.001). In AD, higher continuous baseline pTau217 predicted accelerated CDR-SB increase and MoCA decline, whereas faster longitudinal increase predicted accelerated cognitive index decline (ps [&le;] 0.04). In HC, higher continuous baseline pTau217 predicted accelerated memory index decline (p = 0.008). In LBD, abnormal baseline pTau217 predicted a 0.87 points/year (95% CI: -1.62, -0.58) faster MoCA decline, 0.85 points/year (95% CI: 0.56, 1.14) faster CDR-SB increase, accelerated decline on cognitive indices, and a three-fold higher risk of progressing to MCI or dementia (HR = 3.41, 95% CI 1.60, 7.28, p = 0.002) compared to normal pTau217. Discussion: Plasma pTau217 is a promising prognostic, monitoring, and risk stratification biomarker of clinical progression in LBD, underscoring its utility in mixed pathology groups for clinical practice and trials.

Background: The role of biological age acceleration (BioAgeAccel) in the dynamic progression from single cardiovascular-kidney-metabolic disease (CKMD) to multimorbidity, and subsequently to dementia and mortality remains elusive. Methods: We conducted a longitudinal study with data of 433,911 UK Biobank participants. Cardiovascular-kidney-metabolic multimorbidity (CKMM) was defined as the coexistence of two or more CKMDs, including cardiovascular disease (CVD), stroke, type 2 diabetes (T2D), and chronic kidney disease. Biological aging was measured via PhenoAge and KDM-BA. Multistate models examined the association between BioAgeAccel and disease transitions, ranging from healthy to the first occurrence of CKMD (FCKMD), then progression to CKMM, dementia, and mortality. Restricted mean survival time estimated the disease transition time or life expectancy between states. Results: BioAgeAccel was significantly associated with increased risks across all disease transitions. Specifically, during CKMM progression, the hazard ratios (HRs) of the transition from healthy to FCKMD were 1.24 [95%CI 1.23-1.25] for PhenoAgeAccel and 1.16 [1.15-1.17] for KDM-BA-Accel. For subsequent transition to CKMM, the HRs were 1.20 [1.18-1.22] and 1.19 [1.17-1.21], respectively. In dementia-related transitions, PhenoAgeAccel showed the higher risk for CKMM to dementia (HR=1.13 [1.04-1.22]) than for the transition from healthy or from FCKMD to dementia. These associations were further moderated by age, physical activity, educational, and lifestyle factors. BioAgeAccel also accelerated disease progression and reduced life expectancy; for example, during CKMM progression, BioAgeAccel shortened the time between disease transitions by about 1.09 years from healthy to FCKMD, and an additional 1.75 years to CKMM. Regarding life expectancy, individuals with CKMM experienced an average reduction of about 1.36 years under PhenoAge, while those with dementia showed a decrease of about 0.77 years. Among individuals with CVD or T2D as the initial diagnosis, the impact of BioAgeAccel on progression to CKMM or dementia was stronger. Conclusions: BioAgeAccel exerts significant promotive role in the onset of CKMD and their subsequent progression to CKMM, dementia, and mortality, helping identify high-risk individuals. Implementing biological age assessments and health lifestyle interventions in middle-aged populations serves as an effective strategy for alleviating the burden of CKMDs and dementia.