Babulal, Ganesh M.

Background African American adults experience a disproportionate burden of dementia, shaped by structural and clinical factors that remain unclear. Objective To quantify associations between multimorbidity, polypharmacy, and cognition in the context of neighborhood disadvantage. Methods This study is a cross-sectional analysis of 348 African American adults aged 45–92 years (mean 64.3 years; 73.6% female) from the Aging Research Characterizing Health Exposome via Social drivers (ARCHES) cohort. Comorbidity burden was assessed using a modified Charlson Comorbidity Index (CCI), polypharmacy as ≥5 medications, and neighborhood disadvantage using the Area Deprivation Index (ADI). Linear regression estimated associations with a Preclinical Alzheimer’s Cognitive Composite (PACC). The polypharmacy model included modified CCI as a covariate, and effect modification by ADI was assessed using an interaction term between polypharmacy and ADI. Results Higher modified CCI was associated with lower cognitive performance (B = −0.071; 95% CI: −0.130, −0.012). Polypharmacy was not independently associated with cognition after modified CCI adjustment (B = −0.081; β = −0.057; p = 0.257). No significant ADI interaction was found (p = 0.064).

Background Hearing impairment (HI) has been identified as a potentially modifiable risk factor for dementia, yet its relationship with Alzheimer's disease (AD) neuropathology and the temporal directionality remain unclear, particularly in late life. Objective To examine cross-sectional and longitudinal associations between HI, clinical cognitive status, and AD biomarkers in community-dwelling older adults. Methods We included 474 DRIVES Project participants (mean age 73.5 ± 5.2 years). Hearing was assessed using the NIH Toolbox Words-in-Noise (WIN) test. Clinical cognitive status was assessed using Clinical Dementia Rating (CDR). AD biomarkers included cerebrospinal fluid (CSF) Aβ 42 /Aβ 40 , t-tau/Aβ 42 , and p-tau/Aβ 42 ratios and amyloid PET imaging. Multivariable linear, logistic, Cox proportional hazards, and Fine–Gray competing-risk models were used. Results HI was more prevalent among participants with mild cognitive impairment (MCI; defined as CDR = 0.5) than cognitively normal individuals (50% versus 24%, p < 0.001), and MCI status was independently associated with worse baseline WIN thresholds (β = 1.55 dB SNR; 95% CI 0.72–2.37). HI was not cross-sectionally associated with CSF amyloid or tau ratios or amyloid PET positivity. Longitudinally, baseline MCI was associated with a higher risk of incident HI (Cox HR = 2.63, 95% CI 1.48–4.67; Fine–Gray sHR = 2.79, 95% CI 1.06–7.40), whereas baseline HI was not associated with subsequent CDR progression. Conclusions In older adults, HI was associated with MCI but not core AD biomarkers or future CDR progression, suggesting that late-life HI may reflect cognitive vulnerability or broader brain aging rather than independently driving AD pathology.

Background Black adults experience disproportionately higher rates of Alzheimer's disease and related dementias (ADRD), yet remain underrepresented in blood-based biomarker research. Understanding how plasma biomarkers relate to cognitive performance is essential for equitable detection and monitoring of ADRD. Objective We examined cross-sectional and longitudinal associations of both core and non-core plasma biomarkers and cognition in a community-based cohort of Black adults. Methods Participants from the ARCHES study completed baseline plasma biomarker assessments and neuropsychological testing, including a Preclinical Alzheimer Cognitive Composite (PACC) score and the Montreal Cognitive Assessment (MoCA). Plasma biomarkers reflecting amyloid, tau, neurodegeneration, and astrocytic activation were quantified using immunoprecipitation–mass spectrometry and ultrasensitive immunoassay platforms. Linear regression was used to evaluate cross-sectional associations between biomarkers and cognition. Linear mixed-effects models examined whether baseline biomarker levels were associated with cognitive change over one year, adjusting for age, sex, and education. Results The sample included 334 participants with a mean baseline age of 64.6 years (SD = 10.1; range, 45–92.9). Cross-sectionally, higher brain-derived phosphorylated tau 181 was associated with poorer MoCA score (p = 0.04), and neurofilament light chain (NfL) level was also associated with lower PACC score (p = 0.04). Longitudinally, higher baseline NfL and glial fibrillary acidic protein (GFAP) were associated with faster cognitive decline (p < 0.001 and p = 0.018). Conclusions Non-core NfL and GFAP biomarkers are associated with both cross-sectional and longitudinal cognitive performance. These findings highlight the importance of inclusive biomarker research and suggest non-core biomarkers may be particularly informative for characterizing cognitive aging and decline in this population.

Abstract INTRODUCTION Naturalistic driving provides real‐world behavioral indicators of early cognitive and functional changes. This study integrated naturalistic driving GPS trajectories collected from in‐vehicle sensors with points of interest (POIs) to quantify daily environmental engagement among older adults who were cognitively normal at enrollment. METHODS Data from 438 participants enrolled in the Driving Real‐world in‐Vehicle Evaluation System Project were used to generate daily POI share vectors and model latent engagement patterns using a logistic‐normal hidden Markov model (HMM). Thirteen latent states described distinct modes of environmental interaction. From each participant's inferred state sequence, we derived mobility features – state occupancy, dwell time, transition entropy, and self‐transition probability – and examined their differences across clinical status groups and associations with Preclinical Alzheimer's Cognitive Composite (PACC) performance. RESULTS Transition entropy and several state‐specific occupancy and dwelling metrics differed across clinical groups, but none of the mobility features were significantly associated with PACC scores. DISCUSSION Mobility‐derived behavioral features differentiate clinical status groups and may reflect early functional changes preceding cognitive decline.

ABSTRACT Background Driving supports independence and quality of life in later life but is vulnerable to age‐related and/or disease‐related decline. While cognitive impairment is a well‐recognized risk for unsafe mobility, the contribution of sensorimotor function is less understood. Methods We studied 374 cognitively normal older adults (Clinical Dementia Rating = 0 at baseline) enrolled in the DRIVES Project. A SensoryMotor Impairment Index (SMI) was constructed from six domains (grip strength, gait speed, reaction time, hearing, vision, olfaction) and categorized as 0, 1, 2, or ≥ 3 impairments. Naturalistic driving was continuously monitored using in‐vehicle GPS dataloggers between 2019 and 2025. Linear mixed‐effects models tested whether longitudinal driving trajectories differed by baseline SMI, adjusting for age, sex, race, education, body mass index, and cognition (Preclinical Alzheimer's Cognitive Composite). Results At baseline, participants with higher SMI burden were older and had lower cognitive scores (both p < 0.01). Over time, greater sensorymotor impairment was associated with faster declines in driving exposure and spatial range. Compared with SMI = 0, participants with SMI ≥ 3 showed steeper reductions in nighttime trips (−0.050 vs. −0.037 trips/month), long‐distance trips (> 20 miles; p < 0.001), and maximum trip distance ( p = 0.009), and greater contraction of driving space (entropy and radius of gyration; p < 0.001). Self‐reported driving behaviors showed that participants with higher SMI drove fewer days per‐week and were more likely to avoid night driving ( p < 0.01). Rates of self‐reported adverse driving events (e.g., crashes or citations) did not differ significantly across SMI groups, consistent with compensatory self‐regulatory behaviors. Conclusion Greater sensorymotor impairment predicts accelerated decline in naturalistic driving among cognitively normal older adults, independent of cognition. A composite SMI may provide a feasible, low‐cost approach to identify older drivers at risk for declining mobility and support timely interventions to prolong safe driving.

Abstract INTRODUCTION This ongoing, prospective study examines the effectiveness of methods used to successfully recruit and retain 238 Black older adults in a longitudinal, observational Alzheimer's disease (AD) study. METHODS Recruitment strategies included traditional media, established research registries, speaking engagements, community events, and snowball sampling. Participants were asked to complete an annual office testing session, blood‐based biomarker collection, optional one‐time magnetic resonance imaging (MRI) scan, and community workshop. RESULTS Within the first 22 months of active recruitment, 629 individuals expressed interest in participating, and 238 enrolled in the ongoing study. Of the recruitment methods used, snowball sampling, community events, and speaking engagements were the most effective. DISCUSSION The systemic underrepresentation of Black participants in AD research impacts the ability to generalize research findings and determine the effectiveness and safety of disease‐modifying treatments. Research to slow, stop, or prevent AD remains a top priority but requires diversity in sample representation. Highlights Provide flexible appointments in the evening or weekends, offering transportation assistance, and allowing participants to complete study visits at alternative locations, such as senior centers or community centers. Continuously monitor and analyze recruitment data to identify trends, challenges, and opportunities for improvement. Implement targeted strategies to recruit participants who are underrepresented based on sex, gender, or education to increase representation. Diversify the research team to include members who reflect the racial and cultural backgrounds of the target population, to enhance trust and rapport with prospective participants.

Objective This study was undertaken to evaluate the frequency of modifiable dementia risk factors and their association with cognitive impairment and rate of decline in diverse participants engaged in studies of memory and aging. Methods Modifiable dementia risk factors and their associations with cognitive impairment and cognitive decline were determined in community‐dwelling African American (AA; n = 261) and non‐Hispanic White (nHW; n = 193) participants who completed ≥2 visits at the Mayo Clinic Alzheimer Disease Research Center in Jacksonville, Florida. Risk factors and their associations with cognitive impairment (global Clinical Dementia Rating [CDR] ≥ 0.5) and rates of decline (CDR Sum of Boxes) in impaired participants were compared in AA and nHW participants, controlling for demographics, APOE ɛ4 status, and Area Deprivation Index. Results Hypertension, hypercholesterolemia, obesity, and diabetes were overrepresented in AA participants, but were not associated with cognitive impairment. Depression was associated with increased odds of cognitive impairment in AA (odds ratio [OR] = 4.30, 95% confidence interval [CI] = 2.13–8.67) and nHW participants (OR = 2.79, 95% CI = 1.21–6.44) but uniquely associated with faster decline in AA participants (β = 1.71, 95% CI = 0.69–2.73, p = 0.001). Fewer AA participants reported antidepressant use (9/49, 18%) than nHW counterparts (57/78, 73%, p < 0.001). Vitamin B12 deficiency was also associated with an increased rate of cognitive decline in AA participants (β = 2.65, 95% CI = 0.38–4.91, p = 0.023). Interpretation Modifiable dementia risk factors are common in AA and nHW participants, representing important risk mitigation targets. Depression was associated with dementia in AA and nHW participants, and with accelerated declines in cognitive function in AA participants. Optimizing depression screening and treatment may improve cognitive trajectories and outcomes in AA participants. ANN NEUROL 2024;95:518–529

Psychotic phenomena are among the most severe and disruptive symptoms of dementias and appear in 30% to 50% of patients. They are associated with a worse evolution and great suffering to patients and caregivers. Their current treatments obtain limited results and are not free of adverse effects, which are sometimes serious. It is therefore crucial to develop new treatments that can improve this situation. We review available data that could enlighten the future design of clinical trials with psychosis in dementia as main target. Along with an explanation of its prevalence in the common diseases that cause dementia, we present proposals aimed at improving the definition of symptoms and what should be included and excluded in clinical trials. A review of the available information regarding the neurobiological basis of symptoms, in terms of pathology, neuroimaging, and genomics, is provided as a guide towards new therapeutic targets. The correct evaluation of symptoms is transcendental in any therapeutic trial and these aspects are extensively addressed. Finally, a critical overview of existing pharmacological and non-pharmacological treatments is made, revealing the unmet needs, in terms of efficacy and safety. Our work emphasizes the need for better definition and measurement of psychotic symptoms in dementias in order to highlight their differences with symptoms that appear in non-dementing diseases such as schizophrenia. Advances in neurobiology should illuminate the development of new, more effective and safer molecules for which this review can serve as a roadmap in the design of future clinical trials.

Abstract Sex or gender differences in the risk of Alzheimer's disease and related dementias (ADRD) differ by world region, suggesting that there are potentially modifiable risk factors for intervention. However, few epidemiological or clinical ADRD studies examine sex differences; even fewer evaluate gender in the context of ADRD risk. The goals of this perspective are to: (1) provide definitions of gender, biologic sex, and sexual orientation. and the limitations of examining these as binary variables; (2) provide an overview of what is known with regard to sex and gender differences in the risk, prevention, and diagnosis of ADRD; and (3) discuss these sex and gender differences from a global, worldwide perspective. Identifying drivers of sex and gender differences in ADRD throughout the world is a first step in developing interventions unique to each geographical and sociocultural area to reduce these inequities and to ultimately reduce global ADRD risk. Highlights The burden of dementia is unevenly distributed geographically and by sex and gender. Scientific advances in genetics and biomarkers challenge beliefs that sex is binary. Discrimination against women and sex and gender minority (SGM) populations contributes to cognitive decline. Sociocultural factors lead to gender inequities in Alzheimer's disease and related dementias (ADRD) worldwide.