Background and Objectives: Functional difficulties are hallmark signs of incident cognitive decline and progression to dementia, but are challenging to measure in clinic. Passive smartphone monitoring enables continuous tracking of everyday behaviors and may improve the status quo of dementia risk assessment, but acceptability is understudied. This study evaluated older adults’ attitudes toward personal smartphone monitoring for dementia risk and identified barriers and facilitators to acceptability. Research Design and Methods: Seventeen older adults completed a semi-structured interview followed by a Likert-rating to measure acceptability. Transcripts were analyzed using hybrid inductive-deductive thematic analysis. Exploratory correlations examined associations between acceptability ratings and participant features. Results: Participants identified unique benefits of smartphone monitoring including enhanced scope of measurement, greater ecological validity and personalization, and improved accessibility. Potential disadvantages were confounding variables that threaten validity and concerns about privacy/data security. Preferences for clinical implementation that may improve acceptability included options for extended monitoring, assurances of privacy safeguards, control over data, and continued face-to-face interactions with one’s medical team. Most participants (13/17) were likely or extremely likely to participate in future smartphone monitoring research; higher likelihood was associated with lower depression (r=-.49, p=.046) and White vs. non-White race (U=57.50, n1=10, n2=7 p=.025). Discussion and Implications: Findings offer insights to enhance acceptability of smartphone monitoring including transparent review of procedures, privacy safeguards, and existing evidence. Outstanding requirements for clinical implementation include streamlining results to minimize physician burden and accounting for confounders that threaten data integrity. Our small, research-savvy cohort necessitates follow-up in other settings.

BACKGROUND:Reports of neuropsychiatric symptoms (NPS) from informants, often patients' caregivers and families, and from clinicians are both important for accurate detection of symptoms. However, informant/caregiver report and clinician assessments of NPS often differ. METHODS:We examined agreement between informant/caregiver and clinician report of NPS in the National Alzheimer's Coordinating Center Uniform Data Set. Participants were age ≥ 50 at baseline with mild cognitive impairment (MCI) or dementia (N = 27,225). At each visit, informants reported NPS using the Neuropsychiatric Inventory questionnaire (NPI-Q). Study clinicians provided clinical assessment per study protocol. Agreement between informant report and clinician judgment was assessed using Cohen's kappa statistic. Associations between agreement in reporting for each NPS and participant/informant characteristics were examined using random-effects logistic regressions. RESULTS:At baseline, participants were on average 72.9 ± 9.4 years old, 49% male, 76% non-Hispanic White, with 14.8 ± 3.6 years of schooling. Average follow-up was 4.0 ± 2.5 years. Informants were 63.7 ± 13.2 years old, 31% male, with 15.4 ± 2.8 years of schooling. 60% of informants were spouse/partner of the participant. Informants were more likely than clinicians to report the presence of all symptoms except for hallucinations. Agreement between informant and clinician reports of all symptoms was lower in patients with more severe dementia. Over time, agreement between informant and clinician reports of apathy increased. Agreement between informant and clinician reporting of NPS differed by participant's sex and race/ethnicity. Informants who had lower frequency of contact and more distant relationships with the participant were more likely to agree with clinicians' reporting. CONCLUSIONS:Understanding differences between informant and clinician reports of NPS in dementia is essential in obtaining a more complete, accurate picture of behavioral challenges patients face. Considering patient and informant characteristics and dynamics between them would help clinicians better understand potential biases that may affect the accuracy of reported NPS and better manage and treat the symptoms.

Apathy, defined as a significant and sustained reduction in goal-directed behavior associated with impaired daily functioning, is a common and clinically important syndrome in mild and major neurocognitive disorders (NCDs) and is associated with poorer outcomes for patients and carers. Despite growing research, important gaps in knowledge continue to hinder accurate recognition and effective treatment. This International Psychogeriatric Association (IPA) white paper summarizes key scientific and clinical insights from a multidisciplinary Apathy Task Force, with the aim of providing a narrative overview of current knowledge on nomenclature, biomarkers, treatments, and prevention, and of identifying gaps to inform global priorities in research and clinical care, and inform policy. The IPA convened a multidisciplinary task force of apathy researchers during the 2024 and 2025 IPA Congress meetings. Through structured discussions informed by targeted literature review, the group identified key themes and critical gaps across domains relevant to apathy in NCDs. Apathy is highly prevalent across NCDs and evidence demonstrates that it has substantial functional, emotional, and societal impact. Although diagnostic criteria have recently been refined, clinical identification remains challenging. Multiple scales exist to assess apathy, yet inconsistent use across settings and misalignment with updated diagnostic criteria limit comparability. Neuroimaging studies consistently implicate fronto-subcortical network involvement, but no reliable peripheral biomarkers have been established. While select non-pharmacological, pharmacological and neuromodulatory interventions show promising evidence, non-pharmacological are considered central to current management. Clinical guidelines and policy efforts remain limited despite the substantial burden of apathy. Emerging evidence highlights opportunities to improve diagnosis, deepen mechanistic understanding, and develop more treatments that are targeted and scalable. Key priorities identified include increasing awareness of and education around apathy, incorporating apathy into national dementia strategies, improving implementation of effective non-pharmacological interventions, and advancing the development of interventions and biomarkers aligned with contemporary diagnostic criteria. By integrating evidence across clinical, biological, and care domains, this white paper provides a structured framework to guide future research, clinical practice, and policy.

INTRODUCTION/AIMS:Though studies of Veterans with ALS have reported survival rates, scant literature reports longitudinal symptom progression in Veterans using the ALS Functional Rating Scale-revised (ALSFRS-R). In the absence of an existing national database tracking disease progression in Veterans, we sought to use local medical records to characterize a cohort of Veterans with ALS treated at our VA ALS clinic. METHODS:We examined demographic and clinical factors of 216 Veterans with ALS treated at the James J. Peters VA Medical Center (2012-2025) including race, ethnicity, region of symptom onset, and medication use as predictors of diagnostic delay, functional decline (ALS Functional Rating Scale-Revised (ALSFRS-R)), survival, and caregiver burden (Zarit Caregiver Burden Interview). Joint linear mixed modeling estimated longitudinal functional trajectories and survival simultaneously. RESULTS:The cohort was 96.8% male and 74.5% White. Median age at symptom onset was 69.3 years. Mean baseline ALSFRS-R was 30.7. Median survival from symptom onset was 4.4 years. Median age at symptom onset was younger for Black (60.8 years) and Hispanic (62.5 years) Veterans than Whites (70.1 years). Blacks had faster initial ALSFRS-R progression than Whites (mean 1.9 vs. 0.9 points per month). Blacks and Hispanics had 2.8-fold and 2.3-fold higher adjusted mortality hazard than Whites, respectively. Forty-nine percent of caregivers reported high caregiver burden at first assessment, rising to 66.2% at subsequent assessments. DISCUSSION:Racial and ethnic disparities in ALS progression and survival are pronounced in this single-site Veteran cohort. Standardized ALS-specific data collection across the VHA is needed to enable system-wide analyses.

OBJECTIVE:With the expected demographic shift toward those ≥65 years of age in the United States, late onset epilepsy (LOE) poses a significant public health issue, yet it has been historically understudied. We are undertaking an effort in the Epilepsy-Cog study to pool individual participant data from six United States-based prospective cohort studies. In this paper, we outline the process for ascertaining epilepsy, harmonizing, and pooling individual participant data across the six cohorts. METHODS:The Epilepsy-Cog study includes individual participant data from six United States-based longitudinal cohort studies: Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Multi-Ethnic Study of Atherosclerosis, Northern Manhattan Study (NOMAS), Reasons for Geographic and Racial Differences in Stroke, and Washington Heights/Inwood Columbia Aging Project. In all cohorts except NOMAS, prevalent and incident epilepsy were ascertained using Medicare claims-based algorithms. In NOMAS, epilepsy cases were identified through cohort-based reporting and medical record review. To perform cross-cohort harmonization of variables, we used the lowest common denominator approach, assigning response categories or value levels in common across all cohorts. RESULTS:From a total of 68 544 participants across six cohorts, 43 753 participants met eligibility criteria for Epilepsy-Cog. Among them, we identified 551 (1.3%) participants with prevalent epilepsy and 1500 (3.4%) participants with incident epilepsy. We have harmonized demographic characteristics, health behaviors, vascular risk factors (VRFs), one genetic variable, medication use, subjective health status measures, incident events, and cause-of-death variables. SIGNIFICANCE:The Epilepsy-Cog pooled cohort of 43 753 participants with and without epilepsy, combined with harmonized demographic, VRF, and event data, offers a unique resource to yield new insights into LOE.

Introduction:Neuropsychiatric symptoms (NPS) are common in neurocognitive disorders (NCD) and are known to negatively impact patient's functional abilities. However, our understanding of the relationship between individual NPS and functional decline in patients with NCD across the spectrum of cognitive impairment is limited. Here we examine the relationship between specific NPS to characterize their effects on patient's function within and across different etiologies. Method:Longitudinal observational study using the National Alzheimer's Coordinating Center Uniform Data Set (NACCUDS). We examined NPS as characterized by expert clinicians and report its impact on the outcome of functional decline, measured by the Functional Assessment Questionnaire (FAQ), a standardized assessment of activities of daily living, by dementia etiology (Alzheimer's disease (AD, N = 11,044), Lewy Body Disease (LBD, N = 921), and behavioral variant frontal temporal lobe dementia (bvFTD, N = 933)). Results:We find apathy was the most commonly endorsed and the most persistent symptom across dementia types in all groups and was associated with more rapid functional decline in AD and bvFTD. On the contrary, depression, occurring in 40% or more of all groups, was not associated with worsening functional impairment in any group. We identified patterns that indicated higher rates of disinhibition and persistent disinhibition in bvFTD compared to AD and LBD. Psychosis had unique impact on functional decline in AD and LBD as did agitation in AD. Discussion:Differential impact of individual NPS across dementia etiologies and their impact on functional decline may have important consequences for clinical trial designs for the treatment of these symptoms.

Many Veterans who experienced blast-related traumatic brain injuries (TBI) during their military service suffer from chronic cognitive and mental health problems including post-traumatic stress disorder (PTSD). Male rats exposed to repetitive low-level blast injuries designed to mimic the type of blast-related mild TBI that was so common in the conflicts in Iraq and Afghanistan develop delayed and persistent cognitive and PTSD-related traits that remain present for over 1 year after exposure. Boldine, an alkaloid derived from the Chilean Boldo tree (Peumus boldus), is a widely used herbal remedy with anti-oxidant, anti-inflammatory, hepatoprotective, and connexin hemichannel-blocking properties. We studied whether oral administration of boldine prevented development of PTSD-related behavioral traits in rats exposed to repetitive low-level blast. Treatment with boldine prevented appearance of the blast-induced PTSD-like phenotype including object recognition deficits and exaggerated cued fear learning. Boldine also prevented blast-induced elevation of the metabotropic glutamate receptor 2 (mGluR2) and the N-methyl-D-aspartate receptor 2b (NMDAR2b), but did not reverse decreases in the serotonin 5-HT2A receptor. Iba1 immunofluorescence staining suggested that boldine reduced blast-associated microglial process retraction (indicative of activation) in the somatosensory cortex. Transcriptomics analysis of hippocampus mRNA did not identify individual genes that remained significant after FDR correction. Exploratory analysis of 85 nominally significant candidates suggested that boldine induced coordinated transcriptional changes related to GO terms “Cognition” and “Neurotransmitter Transport,” consistent with modulation of activity-regulated transcription factors and neuroimmune signaling. These studies suggest that boldine may be beneficial for the neurobehavioral syndromes that follow blast exposure in military Veterans.

Repetitive low-level blast exposures in rats induce the development of a post-traumatic stress disorder (PTSD)-like phenotype and evolving chronic brain vascular alterations. These alterations included atherogenic-like lesions characterized by increased extravasation of blood elements into the arterial subendothelial layers, nuclear expression of c-Fos in endothelial and vascular smooth muscle cells, vascular hyperplasia, foam cell formation, and ultimately vascular rupture. Foam cells were mainly of macrophage/microglial or of vascular smooth muscle cell origin with upregulated expression of MHC II and of its co-stimulatory molecule CD86, which is characteristic of antigen-presenting cells. Foam cells also upregulated the lysosomal CD68 marker, indicating macrophage/microglial phagocytic and inflammatory activity. Foam cells of vascular smooth muscle cell origin were present at arteriolar bends, kinks, and bifurcations and were associated with a progressive arterial network degeneration in regions with enlarged perivascular spaces. Foam cell inclusions also contained the gelatinase MMP-9, which is involved in extracellular matrix degradation, and the pro-inflammatory cytokine TNF-α that further induces foam cell formation. These findings indicate that the chronic atherogenic lesions associated with blast-induced vascular degeneration may trigger a progressive pro-inflammatory state and expand the progressive vascular degeneration associated with the PTSD-like phenotype.

Neuropsychiatric symptoms (NPS) including depression and apathy, are common in dementia and profoundly affect both patients and caregivers. These symptoms can manifest early and can be indicative of the disease progression. The existing tools for measuring NPS lack objectivity and are not sensitive enough to detect subtle changes in the earlier stages of dementia. Here, we report a preliminary analysis of the associations of speech markers with NPS in older adults from the Mount Sinai Alzheimer’s Disease Research Center (ADRC). Participants aged 60 and above were recruited through the Mount Sinai ADRC. Cognition was measured by the Montreal Cognitive Assessment (MOCA), and NPS by the Geriatric Depression Scale (GDS) and the Neuropsychiatric Inventory (NPI-Q). Speech samples, collected during description of the “cookie theft” picture. Samples were then transcribed manually and processed using automated acoustic and lexical pipelines. Nonparametric partial correlation analysis was used to examine the relationship of the speech markers with the behavioral measures, adjusting for age, sex, education and MOCA score. Participants (N = 54) averaged 79 ± 7.73 years of age, 55.6% were female. They had a mean MOCA score of 24.91 (±4.08), GDS score of 2.6 (±2.59) and NPI-Q score of 2.17(±3.21). Higher GDS scores, indicative of more severe depression, were associated with higher mean pitch values (r = +0.376, p = 0.015). Higher NPI-Q scores, reflecting greater NPS severity, were associated with reduced speech complexity, including using more incomplete (r = + 0.350, P = 0.025) and less-novel (r = +0.313, p = 0.046) words. Higher NPI-Q scores were also correlated with words with higher valence (i.e., more pleasant content, r = +0.363, p = 0.02) and a tendency toward more dominant speech (r = +0.297, p = 0.059). Our preliminary results so far show the potential of speech (both acoustic and lexical features) as a marker for NPS. Specifically, we observed relationships between speech characteristics and self-reported depression symptoms, as well as NPI scores reflecting symptom severity. Further research is necessary to validate and refine these associations, ultimately paving the way of speech analysis as a promising non-invasive objective method for detecting subtle behavioral changes in the early stages of dementia.

In modern war theaters, exposures to blast overpressures are one of the most common causes of brain injury. These pervasive events result in acute and chronic cerebrovascular degenerative processes. Using a rat model of blast-induced mild traumatic brain injury, we identified intramural periarterial hematomas as early primary acute lesions induced by blast exposures. These lesions resulted in intravascular cell death, cell layer reorganization, and plasma leakage into the intraperiarterial basal membranes that constitute the intraperiarterial drainage system (IPAD). Plasma metalloproteases, including MMP-9, in the IPAD basal membranes may degrade extracellular matrix components compromising normal cerebral interstitial fluid drainage, arterial structure and function leading to chronic vascular degenerative processes. Related subacute effects of blast exposure included increased MMP-9 expression in perivascular reactive astrocytes and the extension of astrocytic processes through the layers of affected vessels. These results, in combination with normal levels of proinflammatory cytokines and the absence of proinflammatory MHC II-expressing microglia, suggest an astrocytic role in the clearing of intravascular hematomas and provide further mechanistic evidence that blast-induced vascular degenerative processes may precede the onset of neurovascular inflammation.

The US population aged 90 or older is growing faster than other groups. Yet they are often excluded from research, including clinical trials. It is imperative that we understand cognitive resilience and frailty in this group. Since 2005, the National Institutes of Health (NIH)/National Institute on Aging (NIA) funded Alzheimer’s Disease Research Center (ADRC) program has collected standardized longitudinal clinical data using the Uniform Dataset (UDS) and genetic and biomarker data on participants with normal cognition, Mild Cognitive Impairment (MCI) or dementia. Here we describe data and sample availability in this long-standing project to assess potential to examine cognitive health in those over 90. Data were drawn from the UDS (up to March 2024 data freeze, N=50,259). Individuals who had at least 2 visits after age 90y were included. The first such visit was defined as baseline. Using consensus diagnosis determined from clinician judgment, neuropsychological testing, and standardized scales such as the CDR at baseline, participants’ cognitive status were grouped into cognitively normal (CN, N=1294), MCI ( N =519) and dementia ( N =807). Characteristics of the sample at baseline visit after age 90y, APOE genotype, availability of genomics and autopsy data by cognitive status are presented in Table 1. Mean age was 91y, 60.8% were female. Mean±SD MMSE was 28.4±1.8, 26.3±2.7, and 19.3±6.4 for CN, MCI and dementia, respectively. Participants were followed for an average of 3.5±2.5, 2.6±1.7, and 2.3±1.5 years after baseline. At their last follow-up visit, among those who were baseline CN, 60.1% remained CN, 19.9% progressed to MCI, and 16.4% to dementia. Among baseline MCI, 54.9% progressed to dementia. Dementia diagnosis remained for 99.8% of baseline dementia cases. 746 CN (57.7%), 300 MCI (57.8%), and 584 dementia (72.4%) cases had died. Among those who died, 515 (69.0%), 187 (62.3%), and 376 (64.4%) were autopsied. APOE genotypes will be used to examine the relationship between APOE e4 and cognitive trajectories over time. GWAS data for 938 (72.5%), 349 (67.2%), and 498 (61.7%) cases are available for more in-depth analyses. The availability of genetics and autopsy data enables understanding cognitive resilience and frailty in individuals age 90y or older.

Several disease modifying treatment (DMT) in early AD have shown effectiveness in reducing rate of decline on cognition and function. Earlier analyses using participants who are likely targets for clinical trial and treatment showed treatment effects may have important effects on patients’ work capacity and need for informal care. However, amyloid pathology was not examined. This study explores the relationship between amyloid burden and health-related resource use. Participants enrolled in the Mount Sinai Alzheimer’s Disease Research Center with CDR = 0.5 or 1 and clinical diagnosis of MCI or AD. Health-related resource use was self-reported by participant and/or study partner using the Resource Use Inventory (RUI). Amyloid images received a clinical read by a neuro-radiologist who was blinded to patient characteristics used to determine amyloid status. Two-part or hurdle models were used adjusting for age, sex, race/ethnicity, education, comorbidities, baseline CDR Sum of Boxes (CDR-SB), and years of follow up. Sample included 56 participants (28 amyloid positive, 28 negative) who had 1 or more RUI assessments (average follow up = 2.6±1.5 years). At baseline, average age = 73±8, 17±3 years of schooling, 54% female, 66% White, 20% Black, 11% Hispanic. 91% CDR = 0.5, 13% cognitively normal, 63% MCI, 25% AD; MMSE = 26±3, CDR-SB = 1.8±1.8, comorbidities = 5.5±2.5. There were no statistically significant differences (at p = 0.05) in participants' characteristics except that proportion of participants who were White was higher in those who were amyloid positive (86%) than negative (46%) (p = 0.002). No Hispanic participant was amyloid positive. Follow up was longer in those who were amyloid negative (3±1.4 years) than amyloid positive (2.2±1.4 years). Baseline RUI items were not statistically significantly different by amyloid positivity. At baseline, amyloid positivity was associated with lower likelihood of participation in employment/volunteering. Among those who used help, amyloid positivity was associated with higher home health care hours. Over time, likelihood of receiving informal help increased and participation in employment/volunteering decreased. Data did not reveal any interaction between amyloid positivity and time. Results from this small sample of participants that reflects AD clinical trial populations suggest amyloid burden may be associated with higher health-related resource use.

Environmental pollutants, called perfluoroalkyl substances (PFAS) have been linked to adverse cardiometabolic outcomes, immune dysfunction and cancer risk, but their associations with adult cognition are unknown. Nearly everyone in the United States has detectable levels of PFAS in their blood, but our prior work found that Asian Americans have the highest exposure burden. As Asian Americans fastest growing segment of older adults, examination of relationships between serum PFAS concentrations and cognition in Asian Americans urgently needed. Here, our study examined those associations in older Asian Americans using the National Health and Nutrition Examination Survey (NHANES), and compared findings to a non-Hispanic White sample. Our cross-sectional study used 2011-2014 (NHANES) data and included 57 non-Hispanic Asian and 448 non-Hispanic White participants who took the cognitive assessments in English, to minimize impact of assessment language on scores. Measures included the Animal Fluency test total score and word learning and recall modules from the Consortium to Establish a Registry for Alzheimer’s disease (CERAD) (immediate recall and delayed recall scores). We used linear regression to estimate impact on cognitive functioning measures per interquartile (IQR) increase in log PFOS concentrations adjusting for age, sex, education, BMI, fish consumption, and serum creatinine. To adjust for co-pollutant confounding, we also adjusted for summed concentration of other six other PFASs. We stratified all analyses by race/ethnicity group. Our sample of Asian Americans had median age of 67 [IQR: 63, 74], and 41% were female. The non-Hispanic White sample had median age of 72 [66, 80] and 54% were female. In Asian Americans, an IQR increase in log PFOS was associated with -4.42 (95% CI: -7.02, -1,82, p = 0.002) fewer words listed in the animal fluency test, -1.30 (95% CI: -2.43, -0.18, p = 0.025) words listed in the delayed recall, and -1.67 (95% CI: -3.68, 0.33, p = 0.098) fewer words listed in the immediate recall test ( Table 2 and Figure 1 ). All associations were null for non-Hispanic Whites. Higher blood levels of perfluoroalkyl substances were associated with lower animal fluency scores and delayed recall scores in Asian Americans, but these associations were null for non-Hispanic Whites.

Neuropsychiatric symptoms (NPS) are core features of Alzheimer’s disease (AD) and have significant impact on patients, caregivers, and families. Worse NPS scores are associated with worse function and higher need for care. It is unclear if individual NPS symptoms may differentially affect functional decline and may be more effectively targeted to improve patient outcomes. Data are drawn from participants enrolled in the National Alzheimer’s Coordinating Center Uniform Data Set (9/2005-11/2022). Participants were diagnosed with Mild Cognitive Impairment or AD at baseline, had a primary etiologic diagnosis of AD, and had at least one annual follow-up visit (average follow-up = 4 years). Participants’ function was measured using the Functional Assessment Questionnaire (FAQ). NPS were reported by ADC study clinicians using the “Clinician Judgment of Symptoms” (Form B9) evaluating whether each of the following symptoms manifested as a meaningful change in behavior (yes = 1, no = 0): apathy-withdrawal, depressed mood, visual or auditory hallucinations, delusions, disinhibition, irritability, agitation, and anxiety. Dementia severity was measured using the CDR. Multivariable analyses of the effects of each NPS on decline in function were performed using linear mixed models. Covariates included baseline age, gender, race/ethnicity, education, referral source, number of visits, comorbidities, APOE genotype, and number of medications. Baseline sample characteristics (N = 9,358): mean age = 74±9, 47% male, 78% non-Hispanic white, 11% black, 8% Hispanic, education = 15±4; 52% CDR = 0.5, 35% CDR = 1, and 13% CDR≥2; FAQ = 12±9. Baseline presence of NPS: apathy (34%), depressed mood (33%), anxiety (31%), irritability (28%), agitation (13%), disinhibition (10%), delusions (9%), and hallucinations (5%). Apathy was the most persistent of NPS with 37% of all participants had clinician endorsed apathy in ≥50% all of their visits, followed by depressed mood (28%), irritability (27%), anxiety (21%), agitation (14%), disinhibition (11%), delusions (9%), and hallucinations (5%). Functional decline was faster in those with persistent (≥50% of all visits) apathy, agitation, and delusions. Different behavioral symptoms have differential effects on functional decline, a major driver of caregiver stress and institutionalization. Better understanding of these differential effects on function is crucial in designing trials for treatment in AD. Assessing for these behavioral symptoms should be a standard component of cognitive evaluations.

Heterogeneity in the progression of clinical dementia poses a significant challenge, impeding the effectiveness of current therapies for Alzheimer’s disease (AD). To decipher the molecular mechanisms governing heterogeneity in AD progression that remains a critical knowledge gap precluding rational therapeutic design, we investigated the biochemical and biophysical properties of tau present in the inferior temporal gyrus (ITG) and prefrontal cortex (PFC) brain regions of AD patients who had varying disease progression rates. To explore gene expression changes in the ITG which are associated with tau pathology and cognitive decline, we used RNA sequencing for molecular characterization of patients displaying tau and clinical heterogeneity. Postmortem brain samples from the ITG and PFC of AD (n = 20) and control (n = 8) subjects were used to evaluate the biochemical features of abnormal tau species, specifically those that may influence its propagation and best predict AD progression. Further, we investigated molecular heterogeneity in AD with RNA-seq analyses of ITG tissues with differential seeding potential. The present study integrates tau biochemistry with transcriptional alterations to elucidate the molecular mechanisms of cognitive decline in AD, which is critical for advancing future therapeutic interventions and development of personalized treatments. Biochemical analysis of human postmortem ITG and PFC tissues revealed individual variability in tau seeding, which correlated with cognitive decline, particularly in the ITG, a region known for promoting accelerated tau propagation. Specific hyperphosphorylated high and, intriguingly, low-molecular-weight tau (p-T217, T231, S396 and S396/S404-tau) and their isoforms (3R and 4R-tau) are likely mediators of seeding and cognitive decline. Additionally, RNA-seq transcriptomic analyses showed that cognitive decline during AD progression could be related to tau-mediated failure of neural mechanisms in the ITG, particularly a loss of neural and synaptic plasticity and increased neuroinflammation. These findings provide further insights into multiple molecular mechanisms potentially involved in disease progression, highlight targets for early intervention, and improve patient subtyping, which is critical for developing precision medicines.

There is longstanding evidence that the presence of psychosis in neurocognitive disorders is associated with faster deterioration of cognitive function. These reports also describe greater care partner burden, higher rates of institutionalization and functional decline, especially among ethnoculturally diverse persons. The goal of this study is to examine the association of race/ethnicity with rates of psychosis in neurocognitive disorders among ethnoculturally diverse older persons . Data are from the National Alzheimer’s Coordinating Center Uniform Dataset, a longitudinal dataset with annual patient assessments from ∼40 National Institute of Aging funded Alzheimer’s Disease Research Centers. Participants aged 40-95 years as of June 2023 with mild cognitive impairment (MCI) or dementia were included. Psychosis was defined as clinician diagnosed visual or auditory hallucinations or delusions. Race and ethnicity were self-reports categorized as non-Hispanic White (NHW), NH-Black/African American (AA), Hispanic/Latino, Asian, and American Indian/Native Alaskan (AI/NA). Associations between race/ethnicity and psychosis were estimated using multivariable generalized estimating equation (GEE) models with repeated measures of outcomes and covariates (severity of cognitive impairment, age, sex, history of anti-psychotic medication use and history of mood disorder). Analyses stratified by age of cognitive impairment onset (40-65 years and 65-95 years) were also performed. 25,731 participants had a mean age 72.5±9.7, 51% female, 76% NHW, 12% NH-Black/AA, 8% Hispanic/Latino, 3% Asian and 1% AI/NA (Table 1). At baseline, 15,646 (60.8%) had MCI and 10,085 (39.2%) had dementia. The rate of psychosis was highest among Hispanic/Latino (15.7%), AI/NA (14.7%) and Black/AA (12.5%) (Graph1). In adjusted analysis, NH-Black/AA had significantly greater odds of psychosis (OR 1.73, 95% CI 1.17-2.19), including visual hallucinations (OR 1.33, 95% CI 1.18-1.51), auditory hallucinations (OR 1.69, 95% CI 1.41-2.03) and delusions (OR 1.73, 95% CI 1.56-1.92) ( p<0.05 ) (Table 2). Hispanic/Latino and AI/NA participants had even greater odds of psychosis than NHWs (Table 2). Only Black/AA and Hispanic/Latino participants with early-onset neurocognitive disorder (40-65 years) had greater odds of psychosis than NHWs (Table 2). Black/AA, Hispanic/Latino and AI/NA individuals were more likely to be diagnosed with psychosis in neurocognitive disorders when compared to NHWs. More research is needed to explore psychosocial, neuropathology and genetic factors involved.

Introduction The Montreal Cognitive Assessment’s (MoCA) validity and efficacy in ethnoculturally diverse settings is not clear. The published cutoff point of ≤ 23 yielded a high false-positive rate of cognitive impairment in culturally and linguistically diverse populations in previous studies and their authors identified lower cutoff points as more appropriate for identifying mild cognitive impairment or dementia using the MoCA (Stimmel et al., 2024, Milani et al., 2018). Multiple studies have shown that lower cutoff points could potentially yield fewer false-positive indications of cognitive impairment (Malek-Ahmadi et al., 2024). We aimed to see if similar results would be found in our geriatric veteran patient population in the Bronx, NY, the same geographic location as the population Stimmel et al. studied. Methods Our group performed cognitive assessments using testing with the MoCA on a cohort of more than 150 geriatric veterans that received care at the James J. Peters Department of Veterans Affairs Medical Center in the Bronx, NY. The veterans then underwent neuropsychological testing and were categorized as cognitively normal, having mild cognitive impairment, or having dementia. We analyzed the discrepancy between utilizing the MoCA and utilizing neuropsychological testing for neurocognitive diagnosis in our studied population and identified preliminary optimal MoCA cutoff points for discriminating cognitive impairment. Results Our preliminary results suggest that the published MoCA cutoffs points for mild cognitive impairment and dementia lead to a high number of false-positives in our studied population and are potentially too high. Conclusions The published Montreal Cognitive Assessment cutoffs points might be too high for ethnoculturally diverse populations, as evidenced by our analysis of the discrepancy between utilizing the published cutoff points to categorize our geriatric veteran patient population in the Bronx, New York, as having mild cognitive impairment or dementia and utilizing neuropsychological testing for this categorization. Our results point towards the need for further studies to determine more appropriate MoCA cutoff points in order to enhance diagnostic accuracy and suggest that cutoff points might need to be stratified by race/ethnicity and education.

Introduction: Epilepsy is the third most common neurological disorder in older adults after dementia and stroke. Previous research suggests that vascular risk factors (VRFs) and cardiovascular disease (CVD) are more common in people with epilepsy. Pooling multiple cohorts with detailed characterization of vascular risk factors, CVD, and harmonized epilepsy case ascertainment increases diversity of the sample to be more representative of the US population and increases the numbers of epilepsy cases for greater statistical power. Methods: We pooled individual participant data from five cohorts, including ARIC, CHS, MESA, NOMAS, and WHICAP. For this analysis, we included participants who were 65 years of age or above. In ARIC, CHS, MESA, and WHICAP, which were linked to Medicare Claims, we included participants who had a minimum 2-year continuous Medicare enrollment and ascertained prevalent epilepsy using an algorithm based on ICD codes and antiepileptic medication. In NOMAS, which was not Medicare-linked, prevalent epilepsy cases were ascertained by telephone interview, medical record review, and ICD codes in New York Statewide Planning and Research Cooperative System (SPARCS) data. Risk factors were assessed by self report, blood measures, ECG, physical exams, and medications at cohort baseline. We calculated unadjusted prevalence of epilepsy in each risk factor category and prevalence differences and prevalence ratios adjusted for age, sex, race/ethnicity, and cohort. Results: Among 26,476 participants, 264 had prevalent epilepsy (9.9 cases per 1,000). Unadjusted prevalence of epilepsy was higher in older age groups, women, non-Hispanic Black and Hispanic groups, those with less education, never or current smokers, heavier alcohol drinkers, those with hypertension, diabetes, high cholesterol, underweight, obesity, history of stroke or heart disease, or 2 APOE e4 alleles (Table). Adjusted prevalence of epilepsy was higher among participants in the non-Hispanic Black group (5.3 additional cases per 1,000 [95% CI: 2.1, 8.5]) and among participants who had a history of stroke (12.9 additional cases per 1,000 [95% CI: 3.5, 22.3]). Conclusions: In this pooled cohort analysis, adjusted for age, sex, race/ethnicity, and cohort, prevalence of epilepsy in those over the age of 65 was higher among non-Hispanic Black individuals and among those with a history of stroke.