Mary Ganguli

Consumer surveys are increasingly used in business and clinical practice, but less so in human subjects research. Within a longitudinal, population-based study of older adults, we administered a survey to monitor participants' experiences and address potential challenges. We invited participants to provide feedback on their study experience following their annual interviews, using a survey with Likert-scale questions and open-ended comments. In the first round of surveys between 2022 and 2024, 82% responded who were more likely to be White, cognitively normal, and endorse fewer than 5 depression symptoms compared with their counterparts who did not respond. In the open-ended comments, 63.2% mentioned positive overall experience, 44.3% mentioned positive interactions with staff, 19.4% mentioned the study’s COVID-19 guidelines, and 17.4% shared their motivation for study participation. The survey amplified participants' voices and identified aspects of the study important to them. Understanding participants’ experiences and expectations may help with retention.

The Lifestyle for Brain Health (LIBRA) index, a weighted measure of modifiable risk factors for dementia, has been widely applied in European cohorts but less explored in US populations. We applied it to a cohort aged 65+ years, sampled from a relatively low-socioeconomic US region, and compared its predictive validity for incident mild cognitive impairment (MCI) and incident dementia risk. We used both reference factor weights derived from published meta-analyses and cluster-specific factor weights based on estimation results using our own cohort data. We also compared the original LIBRA index with an updated version (LIBRA2), which added three new risk factors including hearing impairment, sleep disturbance, and low social contact. We used joint modeling to account for informative attrition over time. Higher baseline LIBRA indexes were consistently associated with increased dementia risk across factor weight estimation methods. LIBRA2 demonstrated better predictive validity for incident dementia compared to MCI, further improving its performance. Cohort-specific factor weights strengthened associations with cognitive impairment risk but may limit comparability across studies. These findings contribute to valid use of LIBRA for dementia prediction in a late-life US cohort and support the incorporation of additional factors and cohort-specific adjustments to enhance its utility in diverse populations.

Apolipoprotein E (APOE) allele 4 (APOE4), one of the robust genetic risk factors for AD, has also been associated with cognitive decline in terms of memory, executive function, language, and global cognitive function. APOE genotype-stratified analysis can help to identify additional genetic loci which might be masked due to a strong effect of APOE4. We conducted a genome-wide meta-analysis in APOE2 carriers, APOE4 carriers, and APOE 3/3 homozygote groups among 2969 non-Hispanic Whites aged ≥ 65 years using slopes of decline over time across five cognitive domains (attention, language, executive function, memory, and visuospatial function) and global cognitive function. We identified novel genome-wide significant associations for decline in global cognitive function in the intergenic region between RNU7-66P/RNA5SP208 at rs116379916 (p = 1.44 × 10⁻⁹) in the APOE 3/3 group and for decline in language in the intergenic region between LINC0221/DTWD2 at rs13187183 (p = 3.79 × 10⁻⁸) in APOE4 carriers. A previously reported locus for decline in attention near RASEF at rs6559700 (p = 9.95 × 10⁻⁹) was found to be confined to the APOE 3/3 group. We also found two sub-threshold significant associations in the APOE 2 group for decline in attention (IL1RL2/rs77127114; p = 8.64 × 10⁻⁸) and decline in language (YTHDC2/KCNN2, rs116191836; p = 5.66 × 10⁻⁸). Our study points to potential biological pathways pertaining to specific domains within each APOE genotype group, and the findings suggest that immune-related pathways, plasma levels of polysaturated fatty acids, and bitter taste receptors may play roles in cognitive decline. Our findings enhance the understanding of cognitive aging and provide a framework for future studies.

Social support is considered a protective factor against depression, but there are inconsistent findings regarding social support and depression in older adults. We aimed to clarify the association between emotional and instrumental social support and depressive symptoms in older adults cross-sectionally and longitudinally (mean follow-up = 1.96 years). We meta-analyzed raw individual participant level data from adults in mid- and late-life (N = 23,973) who completed questionnaires about physical health, mental health, and social support and completed neuropsychological assessments. These were COSMIC (Cohort Studies of Memory in an International Consortium) cohort studies carried out in Australia, Brazil, China, Germany, Greece, India, Indonesia, Singapore, South Korea, Sweden, and the United States in mostly urban settings. After controlling for depression risk factors, emotional support (B = -0.40, 95%CI: -0.60,-0.21), but not instrumental support (B = 0.17, 95%CI: -0.26,0.59), was associated with lower depressive symptoms cross-sectionally and at follow-up [emotional support (B = -0.37, 95%CI: -0.54,-0.20); instrumental support (B = 0.09, 95%CI: -0.30,0.49)]. Emotional support was associated with lower depressive scores cross-sectionally and longitudinally, while instrumental support was not associated with depressive symptoms. Our findings can help inform the nature of interventions to prevent and reduce risk of depression among older adults.

Identifying mechanisms that compensate for slow gait speed in older adults is crucial. Dopaminergic neurotransmission curbs deleterious associations of cerebrovascular disease with gait, but whether it compensates for peripheral systemic risk factors (PSRF) for gait slowing has not been studied. In this cross-sectional study of community-dwelling older adults, we examined the relationship between nigrostriatal dopaminergic terminal integrity and gait speed in individuals with and without ≥1 PSRF for gait slowing: obesity, joint pain, or reduced muscle strength. The primary outcome was percent difference in gait speed (%DGS) on transition from even to uneven surface. Participants underwent dopaminergic imaging with dihydrotetrabenazine [ ¹¹ C]DTBZ positron emission tomography. Among 197 individuals, (mean (SD) age 74.92 (4.53) years; 61.93% female; 90.86% White), 130 (65.99%) had ≥1 PSRF. Relationship between posterior putamen [ ¹¹ C]DTBZ binding and %DGS was modified by PSRF; in those with ≥1 PSRF (but not in those with no PSRF), posterior putamen [ ¹¹ C]DTBZ binding was associated with %DGS (β=0.198, p=0.03) independent of potential confounders. This cross-sectional study indicates that striatal dopaminergic neurotransmission may offer resilience to effects of PSRF on gait slowing.

Background: The associations between community‐wide social determinants of health and mild cognitive impairment (MCI) among individuals warrant investigation. Methods: Among 2830 dementia‐free individuals aged 65+ years in a community‐based US study, we examined cross‐sectional associations of MCI (Clinical Dementia Rating = 0.5) with the following potential social determinants of health: at the census tract or block group level obtained from public sources: neighborhood disadvantage (Area Deprivation Index, ADI), air pollution with fine particulate matter (PM _2.5 ), greenspace, Walkability Index, ambulatory healthcare availability per square mile, homicide rate; and at the individual participant level, birth/schooling in a southern US state. Results: Unadjusted logistic regression models found higher odds ratios (OR, 95% CI) for MCI with higher ADI (1.01, 1.003–1.02), higher PM _2.5 (1.16, 1.07–1.26), higher homicide rate (1.007, 1.001–1.012), lesser greenspace (0.99, 0.90–0.99), and southern schooling (2.06, 1.6–3.54). Adjusting for age, race, sex, and educational level, ADI remained statistically significant (1.04, 1.01–1.06), while PM _2.5 and Southern state schooling interacted significantly with race and were more strongly affected in Black participants than in White participants. Conclusions: In this cohort, several community‐wide social/environmental factors were associated with MCI. While clinicians should continue to encourage older adults to modify their individual risk factors, policy changes are needed to mitigate social determinants of health in the community.

Background: Depression is a known risk factor for dementia, and social support may lower the risk of depression in older adults. There is, however, a lack of longitudinal analyses examining the association between emotional versus instrumental support and depressive symptoms in older adults. We analyzed the association of emotional and instrumental support with depression symptom scores using data from eight international longitudinal cohorts. This is an individual participant data meta‐analysis on harmonized social support and depression data.Method: We obtained data from eleven COSMIC (Cohort Studies of Memory in an International Consortium) international longitudinal cognitive ageing studies, including data from Australia, Brazil, China, Germany, Greece, India, Indonesia, South Korea, Singapore, Sweden, and the United States. Randomly sampled 27,058 adults in later life (M = 71.7 years), of whom 59.5% were females. Social support was measured using individual items of emotional support (i.e., having a confidante) or instrumental support (i.e., help with daily living activities). Depression was measured using validated scales at baseline and follow‐up (M = 2.02 years). Covariates included age, sex, education, living situation, smoking history, diabetes mellitus, cardiovascular risk, global cognitive function and (where available) history of depression. Depression scores were standardized while other variables were harmonized before analysis.Result: In the fully adjusted cross‐sectional models, having emotional support (B = ‐0.40, 95%CI: ‐0.60,‐0.21), but not instrument support (B = 0.15, 95%CI: ‐0.29,0.58) was associated with lower depressive symptoms. In the fully adjusted longitudinal models, having emotional support (B = ‐0.36, 95%CI: ‐0.53,‐0.19) but not having instrumental support (B = 0.07, 95%CI: ‐0.33,0.46) was associated with lower depressive symptoms at follow‐up.Conclusion: Emotional, but not instrumental support, was associated with lower depressive symptoms cross‐sectionally and at follow‐up in harmonised data from 8 longitudinal ageing studies. Psychosocial interventions targeted at reducing the risk of depression (and therefore dementia) should focus on improving access to emotional support for older adults.

Background: A rare missense APOE variant (L28P; APOE^*4Pittsburgh) has been reported to be a risk factor for Alzheimer’s disease (AD). However, sinceL28P has been observed only among APOE^*4 carriers, its independent genetic association is uncertain. In this study, we re‐evaluated this association in a large case‐control sample of 15,762 U.S. Whites aged ≥60 years and investigated its independent effect.Method: Samples were derived from three sources: University of Pittsburgh, Alzheimer’s Disease Sequencing Project and the Gingko Evaluation Memory Study. Due to variation in the age distribution between cases and controls in the three studies, each study sample was analyzed separately, and the results then combined by meta‐analysis. To distinguish the independent effect of L28P from APOE^*4, we restricted the analysis to subjects with the APOE 3/4 genotype, as L28P has been observed only in the heterozygous state in the APOE^*4‐background and 3/4 is the most common genotype containing the APOE^*4 allele.Result: A total of 80 L28P heterozygotes were observed in the combined case‐control sample, all in those containing only the APOE^*4 allele, confirming the complete linkage disequilibrium between the two sites. The age‐ and sex‐adjusted meta‐analysis odds ratio (OR) was 2.87 (95% CI: 1.34 – 6.13; p = 0.0066). There were a total of 4,138 cases and controls with the 3/4 genotype. The age‐ and sex‐adjusted meta‐analysis OR was 1.53 (95% CI: 0.70 – 3.36; p = 0.28). The lack of significance is mainly due to the low power with the ∼4,100 sample size (12% power at α = 0.80), as compared to the required sample size of ∼151,000 to detect an OR of 1.5 at α = 0.80.Conclusion: Even with non‐significant p‐value, the OR of 1.53 among 3/4 subjects suggests that the effect of L28P on AD risk is independent of APOE^*4. Our genetic finding is reinforced by an earlier experimental finding showing that this mutation leads to significant structural and conformational alterations in ApoE and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress (J Biol Chem 2014; 289:12931). Additional studies in cell‐based systems and animal models will help to delineate its functional significance in the AD etiology.

Background: Although accumulating evidence has shown that individual socioeconomic status affects dementia incidence, it remains unknown whether a higher degree of neighborhood disadvantage which is independent of individual socioeconomic status contributes to the excess risk of dementia among African Americans (AA).Method: In the Monongahela‐Youghiogheny Healthy Aging Team and 15104 Senior Project, two population‐based prospective cohort studies in an economically disadvantaged Rust Belt community, 2733 participants aged 65+ years were assessed for their health history, lifestyle, and cognitive functioning. Mild cognitive impairment (MCI) or dementia was defined as Clinical Dementia Rating score ≥0.5. Each participant was assigned an Area Deprivation Index (ADI) value according to the census block group where one resided, indicating the level of neighborhood disadvantage. In cross‐sectional data, racial differences in the odds of MCI or dementia were assessed using weighted logistic regressions. Inverse probability weighting was used to balance AA and European Americans (EA) with respect to 1) ADI, 2) other confounders (age, sex, APOE*4 genotype, cardiometabolic diseases, individual socioeconomic status, health‐related behaviors, use of regular health services, functional health literacy, and air pollution [PM_2.5]), and 3) ADI and other confounders.Result: The frequency of MCI and dementia were 648 (24%) and 25 (0.9%), respectively. AA had significantly higher proportion of MCI or dementia (35% vs. 24%, p = 0.001) and higher mean ADI (96 vs. 79, p<0.0001) than EA. Being AA was associated with higher odds of MCI or dementia compared to being EA (odds ratio [OR] = 1.71, 95% confidence interval [CI] = 1.26 ‐ 2.33, unadjusted model). After balancing racial groups with respect to ADI only, the difference between AA and EA no longer reached the level of significance. When balancing all other confounders only, the OR was 1.66 (95% CI = 1.04 ‐ 2.67) and the confounders explained 5.2% of the observed disparity. After balancing both ADI and other confounders, the difference again became non‐significant (OR = 1.61, 95% CI = 0.93 ‐ 2.80) and resulted in 11.1% of the MCI or dementia disparity being explained.Conclusion: A higher degree of neighborhood disadvantage may contribute to the excess risk of MCI or dementia found among AA.