Considerations for the use of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) in cross-country comparisons of cognitive aging and dementia.

INTRODUCTION: Informant reports are a critical component of dementia diagnoses, but the comparability of informant reports across countries is not well understood. METHODS: We compared the performance of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) using population-representative surveys in the United States (N = 3183), England (N = 1050), and India (N = 4047). RESULTS: Analyses of regression splines and comparisons of model fit showed strong associations between IQCODE and objective cognition at low cognitive functioning in the United States and England; in India, the association was weaker but consistent over the range of cognition. Associations between IQCODE score and informant generation (analysis of variance [ANOVA] p = 0.001), caregiver status (p < 0.001), and years known by the informant (p = 0.015) were different across countries after adjusting for objective cognition. DISCUSSION: In India, the IQCODE was less sensitive to impairments at the lowest levels of cognitive functioning. Country-specific adjustments to IQCODE scoring based on informant characteristics may improve cross-national comparisons. HIGHLIGHTS: Associations between IQCODE and cognitive testing were similar in the United States and England but differed in India. In India, the IQCODE may be less sensitive to impairments among those with low cognition and no education. Informant characteristics may differentially impact informant reports of decline across countries. Adjustments or culturally sensitive adaptations may improve cross-national comparability.

Measurement of Prevalent Versus Incident Dementia Cases in Epidemiologic Studies.

Because dementia is progressive, incident cases are on average milder than prevalent cases, affecting the performance of cognitive tests and questions on functional limitations (i.e., cognition/functional limitation items) used for dementia assessment. Longitudinal studies assess incident cases, while cross-sectional studies assess prevalent cases, but differences are not typically considered when researchers select items to include in studies. We used longitudinal data from the Religious Orders Study and Memory and Aging Project (ROSMAP) (n = 3,446) collected between 1994 and 2021 to characterize differences in associations between items (cognition: 35 items; functional limitations: 14 items) and incident or prevalent dementia using multinomial regression models with generalized estimating equations, controlling for ROSMAP cohort (Religious Orders Study or Memory and Aging Project), age, sex, race, and education. The association between a given item and incident dementia was significantly weaker than the association between the same item and prevalent dementia for 46 of 49 items. However, there was variability, with larger differences for some items, including naming a pencil (prevalence odds ratio = 0.02 (95% confidence interval: 0.02, 0.03); incidence odds ratio = 0.10 (95% confidence interval: 0.06, 0.17); P for difference < 0.001). Important differences exist in the performance of cognition/functional limitation items for measurement of incident versus prevalent dementia. Differences can inform the choice of items for cross-sectional studies of prevalent cases or longitudinal studies of incident cases, leading to reduced misclassification and increased statistical power.

Linear linking for related traits (LLRT): A novel method for the harmonization of cognitive domains with no or few common items.

Harmonization means to make data comparable. Recent efforts to generate comparable data on cognitive performance of older adults from many different countries around the world have presented challenges for direct comparison. Neuropsychological instruments vary in many respects, including language, administration techniques and cultural differences, which all present important obstacles to assumptions regarding the presence of linking items. Item response theory (IRT) methods have been previously used to harmonize cross-national data on cognition, but these methods rely on linking items to establish the shared metric. We introduce an alternative approach for linking cognitive performance across two (or more) groups when the fielded assessments contain no items that can be reasonably considered linking items: Linear Linking for Related Traits (LLRT). We demonstrate this methodological approach in a sample from a single United States study split by educational attainment, and in two sets of cross-national comparisons (United States to England, and United States to India). All data were collected as part of the Harmonized Cognitive Assessment Protocol (HCAP) and are publicly available. Our method relies upon strong assumptions, and we offer suggestions for how the method can be extended to relax those assumptions in future work.

Cerebral amyloid angiopathy interacts with neuritic amyloid plaques to promote tau and cognitive decline.

Accumulating data suggest that cerebrovascular disease contributes to Alzheimer's disease pathophysiology and progression toward dementia. Cerebral amyloid angiopathy is a form of cerebrovascular pathology that results from the build-up of ß-amyloid in the vessel walls. Cerebral amyloid angiopathy commonly co-occurs with Alzheimer's disease pathology in the ageing brain and increases the risk of Alzheimer's disease dementia. In the present study, we examined whether cerebral amyloid angiopathy influences tau deposition and cognitive decline independently or synergistically with parenchymal ß-amyloid burden. Secondly, we examined whether tau burden mediates the association between cerebral amyloid angiopathy and cognitive decline. We included data from autopsied subjects recruited from one of three longitudinal clinical-pathological cohort studies: the Rush Memory and Aging Project, the Religious Orders Study and the Minority Aging Research Study. Participants completed annual clinical and cognitive evaluations and underwent brain autopsy. Cerebral amyloid angiopathy pathology was rated as none, mild, moderate or severe. Bielschowsky silver stain was used to visualize neuritic ß-amyloid plaques and neurofibrillary tangles. We used linear regression and linear mixed models to test independent versus interactive associations of cerebral amyloid angiopathy and neuritic plaque burden with tau burden and longitudinal cognitive decline, respectively. We used causal mediation models to examine whether tau mediates the association between cerebral amyloid angiopathy and cognitive decline. The study sample included 1722 autopsied subjects (age at baseline = 80.2 ± 7.1 years; age at death = 89.5 ± 6.7 years; 68% females). Cerebral amyloid angiopathy interacted with neuritic plaques to accelerate tau burden and cognitive decline. Specifically, those with more severe cerebral amyloid angiopathy pathology and higher levels of neuritic plaque burden had greater tau burden and faster cognitive decline. We also found that tau mediated the association between cerebral amyloid angiopathy and cognitive decline among participants with higher neuritic plaque burden. In summary, more severe levels of cerebral amyloid angiopathy and higher parenchymal ß-amyloid burden interacted to promote cognitive decline indirectly via tau deposition. These results highlight the dynamic interplay between cerebral amyloid angiopathy and Alzheimer's disease pathology in accelerating progression toward dementia. These findings have implications for Alzheimer's disease clinical trials and therapeutic development.

Sex-specific effects of microglial activation on Alzheimer's disease proteinopathy in older adults.

Females show a disproportionate burden of Alzheimer's disease pathology and higher Alzheimer's disease dementia prevalences compared to males, yet the mechanisms driving these vulnerabilities are unknown. There is sexual dimorphism in immunological functioning, and neuroimmune processes are implicated in Alzheimer's disease genesis. Using neuropathology indicators from human brain tissue, we examined the mediational role of microglial activation on the relationship between amyloid and tau and how it differs by sex. 187 decedents (64% female; 89 mean age at death; 62% non-demented) from the Rush Memory and Aging Project completed neuropathological evaluations with brain tissue quantified for microglial activation, amyloid-ß and tau. Proportion of morphologically activated microglia was determined via immunohistochemistry (HLA-DP-DQ-DR) and morphological staging (stage I, II or III). Amyloid-ß and tau burden were quantified via immunohistochemistry (M00872 or AT8, respectively). Using causal counterfactual modelling, we estimated the mediational effect of microglial activation on the amyloid-ß to tau relationship in the whole sample and stratified by sex (amyloid-ß â†’ microglial activation → tau). Alternative models tested the role of microglia activation as the precipitating event (microglial activation → amyloid-ß â†’ tau). Microglial activation significantly mediated 33% [95% confidence interval (CI) 10-67] of the relationship between amyloid-ß and tau in the whole sample; stratified analyses suggested this effect was stronger and only statistically significant in females. 57% (95% CI 22-100) of the effect of amyloid-ß on tau was mediated through microglial activation in females, compared to 19% (95% CI 0-64) in males. Regional analyses suggested that mediational effects were driven by greater cortical versus subcortical microglial activation. Relationships were independent of cerebrovascular disease indices. Alternative models suggested that in females, microglial activation was a significant exposure both preceding the amyloid-ß to tau relationship (mediational effect: 50%, 95% CI 23-90) and directly related to tau burden (microglia direct effect: 50%, 95% CI 10-77). By contrast, in males, only the direct effect of microglial activation to tau reached significance (74%, 95% CI 32-100) (mediational effect: 26%, 95% CI 0-68). Our models suggest a reciprocal, bidirectional relationship between amyloid-ß and microglial activation that significantly accounts for tau burden in females. By contrast, in males, direct independent (non-mediational) relationships between microglial activation or amyloid-ß with tau were observed. Microglial activation may be disproportionately important for Alzheimer's disease pathogenesis in females. Determining sex-specific vulnerabilities to Alzheimer's disease development both inform fundamental pathophysiology and support precision health approaches for this heterogeneous disease.

Measurement differences in the assessment of functional limitations for cognitive impairment classification across geographic locations.

INTRODUCTION: The measurement of dementia in cross-national contexts relies on the assessment of functional limitations. We aimed to evaluate the performance of survey items on functional limitations across culturally diverse geographic settings. METHODS: We used data from the Harmonized Cognitive Assessment Protocol Surveys (HCAP) in five countries (total N = 11,250) to quantify associations between items on functional limitations and cognitive impairment. RESULTS: Many items performed better in the United States and England compared to South Africa, India, and Mexico. Items on the Community Screening Instrument for Dementia (CSID) had the least variability across countries (SD = 0.73 vs. 0.92 [Blessed] and 0.98 [Jorm IQCODE]), but also the weakest associations with cognitive impairment (median odds ratio [OR] = 2.23 vs. 3.01 [Blessed] and 2.75 [Jorm IQCODE]). DISCUSSION: Differences in cultural norms for reporting functional limitations likely influences performance of items on functional limitations and may affect the interpretation of results from substantive studies. HIGHLIGHTS: There was substantial cross-country variation in item performance. Items from the Community Screening Instrument for Dementia (CSID) had less cross-country variability but lower performance. There was more variability in performance of instrumental activities of daily living (IADL) compared to activities of daily living (ADL) items. Variability in cultural expectations of older adults should be taken into account. Results highlight the need for novel approaches to assessing functional limitations.

The worldwide costs of dementia in 2019.

INTRODUCTION: Dementia is a leading cause of death and disability globally. Estimating total societal costs demonstrates the wide impact of dementia and its main direct and indirect economic components. METHODS: We constructed a global cost model for dementia, presenting costs as cumulated global and regional costs. RESULTS: In 2019, the annual global societal costs of dementia were estimated at US $1313.4 billion for 55.2 million people with dementia, corresponding to US $23,796 per person with dementia. Of the total, US $213.2 billion (16%) were direct medical costs, US $448.7 billion (34%) direct social sector costs (including long-term care), and US $651.4 billion (50%) costs of informal care. DISCUSSION: The huge costs of dementia worldwide place enormous strains on care systems and families alike. Although most people with dementia live in low- and middle-income countries, highest total and per-person costs are seen in high-income countries. HIGHLIGHTS: Global economic costs of dementia were estimated to reach US $1313.4 in 2019. Sixty-one percent of people with dementia live in low-and middle-income countries, whereas 74% of the costs occur in high-income countries. The impact of informal care accounts for about 50% of the global costs. The development of a long-term care infrastructure is a great challenge for low-and middle-income countries. There is a great need for more cost studies, particularly in low- and middle-income countries. Discussions of a framework for global cost comparisons are needed.

AD and non-AD mediators of the pathway between the APOE genotype and cognition.

INTRODUCTION: The apolipoprotein E (APOE) genotype is a driver of cognitive decline and dementia. We used causal mediation methods to characterize pathways linking the APOE genotype to late-life cognition through Alzheimer's disease (AD) and non-AD neuropathologies. METHODS: We analyzed autopsy data from 1671 individuals from the Religious Orders Study, Memory and Aging Project, and Minority Aging Research Study (ROS/MAP/MARS) studies with cognitive assessment within 5 years of death and autopsy measures of AD (amyloid beta (Aß), neurofibrillary tangles), vascular (athero/arteriolo-sclerosis, micro-infarcts/macro-infarcts), and non-AD neurodegenerative neuropathologies (TAR DNA protein 43 [TDP-43], Lewy bodies, amyloid angiopathy, hippocampal sclerosis). RESULTS: The detrimental effect of APOE ε4 on cognition was mediated by summary measures of AD and non-AD neurodegenerative neuropathologies but not vascular neuropathologies; effects were strongest in individuals with dementia. The protective effect of APOE ε2 was partly mediated by AD neuropathology and stronger in women than in men. DISCUSSION: The APOE genotype influences cognition and dementia through multiple neuropathological pathways, with implications for different therapeutic strategies targeting people at increased risk for dementia. HIGHLIGHTS: Both apolipoprotein E (APOE) ε2 and APOE ε4 effects on late-life cognition are mediated by AD neuropathology. The estimated mediated effects of most measures of AD neuropathology were similar. Non-Alzheimer's disease (AD) neurodegenerative pathologies mediate the effect of ε4 independently from AD. Non-AD vascular pathologies did not mediate the effect of the APOE genotype on cognition. The protective effect of APOE ε2 on cognition was stronger in women.

Sex differences in associations between APOE ε2 and longitudinal cognitive decline.

INTRODUCTION: We examined whether sex modifies the association between APOE ε2 and cognitive decline in two independent samples. METHODS: We used observational data from cognitively unimpaired non-Hispanic White (NHW) and non-Hispanic Black (NHB) adults. Linear mixed models examined interactive associations of APOE genotype (ε2 or ε4 carrier vs. ε3/ε3) and sex on cognitive decline in NHW and NHB participants separately. RESULTS: In both Sample 1 (N = 9766) and Sample 2 (N = 915), sex modified the association between APOE ε2 and cognitive decline in NHW participants. Specifically, relative to APOE ε3/ε3, APOE ε2 protected against cognitive decline in men but not women. Among APOE ε2 carriers, men had slower decline than women. Among APOE ε3/ε3 carriers, cognitive trajectories did not differ between sexes. There were no sex-specific associations of APOE ε2 with cognition in NHB participants (N = 2010). DISCUSSION: In NHW adults, APOE ε2 may protect men but not women against cognitive decline. HIGHLIGHTS: We studied sex-specific apolipoprotein E (APOE) ε2 effects on cognitive decline. In non-Hispanic White (NHW) adults, APOE ε2 selectively protects men against decline. Among men, APOE ε2 was more protective than APOE ε3/ε3. In women, APOE ε2 was no more protective than APOE ε3/ε3. Among APOE ε2 carriers, men had slower decline than women. There were no sex-specific APOE ε2 effects in non-Hispanic Black (NHB) adults.

Performance of the Informant Questionnaire on Cognitive Decline for the Elderly (IQCODE) in a nationally representative study in India: the LASI-DAD study.

BACKGROUND: Low and middle-income countries like India anticipate rapid population aging and increases in dementia burden. In India, dementia screening scales originally developed in other contexts need to be assessed for feasibility and validity, given the number of different languages and varying levels of literacy and education. METHOD: Using data from the Longitudinal Aging Study in India-Diagnostic Assessment of Dementia (N = 4,028), we characterize the performance of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). We described patterns and correlates of missingness, evaluated the psychometric properties of the scale, and assessed criterion validity against the Hindi Mental State Examination (HMSE) using linear regression. RESULTS: Several IQCODE items had high levels of missingness, which was associated with urbanicity, respondent's gender, and informant's generation (same vs. younger generation). Full IQCODE scores showed strong criterion validity against the HMSE; each 1-point increase in IQCODE score was associated with a 3.03-point lower score on the HMSE, controlling for age, gender, and urbanicity. The statistically significant association between IQCODE and HMSE was stronger in urban than rural settings (p-value for interaction = 0.04). Associations between IQCODE and HMSE remained unchanged after removing the three items with the highest levels of differential missingness (remembering addresses and telephone numbers, ability to work with familiar machines, ability to learn to use new gadget or machine). CONCLUSION: Findings raise questions about the value of including items with high proportions of missingness, which may signal cultural irrelevance, while removing them did not affect criterion validity.

Differences in the measurement of cognition for the assessment of dementia across geographic contexts: Recommendations for cross-national research.

INTRODUCTION: Most cognitive assessments have been developed in high-income countries but are used in diverse contexts. Differences in culture and context may affect the performance of cognitive items. METHODS: We used the Harmonized Cognitive Assessment Protocol (HCAP) surveys in the United States, Mexico, India, England, and South Africa (combined N = 11,364) to quantify associations across countries between cognitive items and cognitive impairment status using age- and sex-adjusted logistic regression. RESULTS: Associations were stronger in the United States (median odds ratio [OR] across items = 0.17) and England (median OR = 0.19), compared to South Africa (median OR = 0.23), India (median OR = 0.29), and Mexico (median OR = 0.28). Items assessing memory (e.g., delayed recall tasks) had the most consistent associations of the largest magnitudes across contexts. DISCUSSION: Transporting cognitive items among countries and cultures warrants caution. Our results can guide the design of future instruments by identifying items that performed well either in individual contexts or across the range of contexts considered. HIGHLIGHTS: Little quantitative evidence exists to guide the design of cognitive assessments in cross-national studies. The performance of cognitive items for the measurement of dementia varied across countries. Items with lower variation across countries (e.g., delayed word recall) should be used in future cross-national assessments. Across countries, there was variability in the performance of language assessments, with the exception of the animal naming task. Results can be used to design future cross-national or location-specific cognitive assessments.

Animal origin of 13th-century uterine vellum revealed using noninvasive peptide fingerprinting.

Tissue-thin parchment made it possible to produce the first pocket Bibles: Thousands were made in the 13th century. The source of this parchment, often called "uterine vellum," has been a long-standing controversy in codicology. Use of the Latin term abortivum in many sources has led some scholars to suggest that the skin of fetal calves or sheep was used. Others have argued that it would not be possible to sustain herds if so many pocket Bibles were produced from fetal skins, arguing instead for unexpected alternatives, such as rabbit. Here, we report a simple and objective technique using standard conservation treatments to identify the animal origin of parchment. The noninvasive method is a variant on zooarchaeology by mass spectrometry (ZooMS) peptide mass fingerprinting but extracts protein from the parchment surface by using an electrostatic charge generated by gentle rubbing of a PVC eraser on the membrane surface. Using this method, we analyzed 72 pocket Bibles originating in France, England, and Italy and 293 additional parchment samples that bracket this period. We found no evidence for the use of unexpected animals; however, we did identify the use of more than one mammal species in a single manuscript, consistent with the local availability of hides. These results suggest that ultrafine vellum does not necessarily derive from the use of abortive or newborn animals with ultrathin hides, but could equally well reflect a production process that allowed the skins of maturing animals of several species to be rendered into vellum of equal quality and fineness.

The State of US Health, 1990-2016: Burden of Diseases, Injuries, and Risk Factors Among US States.

Introduction: Several studies have measured health outcomes in the United States, but none have provided a comprehensive assessment of patterns of health by state. Objective: To use the results of the Global Burden of Disease Study (GBD) to report trends in the burden of diseases, injuries, and risk factors at the state level from 1990 to 2016. Design and Setting: A systematic analysis of published studies and available data sources estimates the burden of disease by age, sex, geography, and year. Main Outcomes and Measures: Prevalence, incidence, mortality, life expectancy, healthy life expectancy (HALE), years of life lost (YLLs) due to premature mortality, years lived with disability (YLDs), and disability-adjusted life-years (DALYs) for 333 causes and 84 risk factors with 95% uncertainty intervals (UIs) were computed. Results: Between 1990 and 2016, overall death rates in the United States declined from 745.2 (95% UI, 740.6 to 749.8) per 100 000 persons to 578.0 (95% UI, 569.4 to 587.1) per 100 000 persons. The probability of death among adults aged 20 to 55 years declined in 31 states and Washington, DC from 1990 to 2016. In 2016, Hawaii had the highest life expectancy at birth (81.3 years) and Mississippi had the lowest (74.7 years), a 6.6-year difference. Minnesota had the highest HALE at birth (70.3 years), and West Virginia had the lowest (63.8 years), a 6.5-year difference. The leading causes of DALYs in the United States for 1990 and 2016 were ischemic heart disease and lung cancer, while the third leading cause in 1990 was low back pain, and the third leading cause in 2016 was chronic obstructive pulmonary disease. Opioid use disorders moved from the 11th leading cause of DALYs in 1990 to the 7th leading cause in 2016, representing a 74.5% (95% UI, 42.8% to 93.9%) change. In 2016, each of the following 6 risks individually accounted for more than 5% of risk-attributable DALYs: tobacco consumption, high body mass index (BMI), poor diet, alcohol and drug use, high fasting plasma glucose, and high blood pressure. Across all US states, the top risk factors in terms of attributable DALYs were due to 1 of the 3 following causes: tobacco consumption (32 states), high BMI (10 states), or alcohol and drug use (8 states). Conclusions and Relevance: There are wide differences in the burden of disease at the state level. Specific diseases and risk factors, such as drug use disorders, high BMI, poor diet, high fasting plasma glucose level, and alcohol use disorders are increasing and warrant increased attention. These data can be used to inform national health priorities for research, clinical care, and policy.

Mental Health Impacts of COVID-19: Does Prepandemic Cognition and Dementia Status Matter?

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic disrupted daily life and led to sharp shocks in trends for various health outcomes. Although substantial evidence exists linking the pandemic and mental health outcomes and linking dementia and mental health outcomes, little evidence exists on how cognitive status may alter the impact of COVID-19 on mental health. METHODS: We used prepandemic data from the Longitudinal Aging Study in India-Diagnostic Assessment of Dementia study and 9 waves of data from the Real-Time Insights of COVID-19 in India study (N = 1 182). We estimated associations between measures of prepandemic cognition (continuous cognition based on 22 cognitive tests, dementia status) and mental health measures during the pandemic (Patient Health Questionnaire [PHQ]-4 [9 time points], PHQ-9 [2 time points], Beck Anxiety Inventory [3 time points]), adjusting for age, gender, rural/urban residence, state, education, and prepandemic mental health. RESULTS: Summarizing across time points, PHQ-9 score was marginally or significantly associated with prepandemic cognition (PHQ-9 difference: -0.38 [-0.78 to 0.14] points per SD higher cognition; p = .06), and prepandemic dementia (PHQ-9 difference: 0.61 [0.11-1.13] points for those with dementia compared to no dementia; p = .02). Associations with BAI were null, whereas associations with PHQ-4 varied over time (p value for interaction = .02) and were strongest during the delta wave, when pandemic burden was highest. CONCLUSIONS: We present initial evidence that mental health impacts of COVID-19 or other acute stressors may be unequally distributed across strata of cognitive outcomes. In dynamically changing environments, those with cognitive impairment or dementia may be more vulnerable to adverse mental health outcomes.

Prevalence of DSM-5 mild and major neurocognitive disorder in India: Results from the LASI-DAD.

INTRODUCTION: India, with its rapidly aging population, faces an alarming burden of dementia. We implemented DSM-5 criteria in large-scale, nationally representative survey data in India to characterize the prevalence of mild and major Neurocognitive disorder. METHODS: The Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD) (N = 4,096) is a nationally representative cohort study in India using multistage area probability sampling methods. Using neuropsychological testing and informant reports, we defined DSM-5 mild and major neurocognitive disorder, reported its prevalence, and evaluated criterion and construct validity of the algorithm using clinician-adjudicated Clinical Dementia Ratings (CDR)®. RESULTS: The prevalence of mild and major neurocognitive disorder, weighted to the population, is 17.6% and 7.2%. Demographic gradients with respect to age and education conform to hypothesized patterns. Among N = 2,390 participants with a clinician-adjudicated CDR, CDR ratings and DSM-5 classification agreed for N = 2,139 (89.5%) participants. DISCUSSION: The prevalence of dementia in India is higher than previously recognized. These findings, coupled with a growing number of older adults in the coming decades in India, have important implications for society, public health, and families. We are aware of no previous Indian population-representative estimates of mild cognitive impairment, a group which will be increasingly important in coming years to identify for potential therapeutic treatment.

Trajectories and correlates of poor mental health in India over the course of the COVID-19 pandemic: a nationwide survey.

INTRODUCTION: The COVID-19 pandemic had large impacts on mental health; however, most existing evidence is focused on the initial lockdown period and high-income contexts. By assessing trajectories of mental health symptoms in India over 2 years, we aim to understand the effect of later time periods and pandemic characteristics on mental health in a lower-middle income context. METHODS: We used data from the Real-Time Insights of COVID-19 in India cohort study (N=3709). We used covariate-adjusted linear regression models with generalised estimating equations to assess associations between mental health (Patient Health Questionnaire (PHQ-4) score; range 0-12) and pandemic periods as well as pandemic characteristics (COVID-19 cases and deaths, government stringency, self-reported financial impact, COVID-19 infection in the household) and explored effect modification by age, gender and rural/urban residence. RESULTS: Mental health symptoms dropped immediately following the lockdown period but rose again during the delta and omicron waves. Associations between mental health and later pandemic stages were stronger for adults 45 years of age and older (p<0.001). PHQ-4 scores were significantly associated with all pandemic characteristics considered, including estimated COVID-19 deaths (PHQ-4 difference of 0.10 units; 95% CI 0.06 to 0.13), government stringency index (0.14 units; 95% CI 0.11 to 0.18), self-reported major financial impacts (1.20 units; 95% CI 1.09 to 1.32) and COVID-19 infection in the household (0.36 units; 95% CI 0.23 to 0.50). CONCLUSION: While the lockdown period and associated financial stress had the largest mental health impacts on Indian adults, the effects of the pandemic on mental health persisted over time, especially among middle-aged and older adults. Results highlight the importance of investments in mental health supports and services to address the consequences of cyclical waves of infections and disease burden due to COVID-19 or other emerging pandemics.

Body Mass Index and Cognition: Associations Across Mid- to Late Life and Gender Differences.

BACKGROUND: Higher mid-life body mass index (BMI) is associated with lower late-life cognition. Associations between later-life BMI and cognition are less consistent; evidence suggests reverse causation may play a role. We aimed to characterize associations between BMI and cognition across a wide age range during mid- to late life (55-85 years) and examine whether associations vary by gender. METHODS: We used data from the Health and Retirement Study (HRS) (N = 39,153) to examine the association between BMI and 3 cognitive outcomes: cognitive level, cognitive decline, and cognitive impairment. We used a series of linear regression, mixed effects regression, and logistic regression models, adjusting for potential confounders. RESULTS: Higher BMI before age 65 (midlife) was associated with lower cognitive performance, faster rates of cognitive decline, and higher odds of cognitive impairment in late life. Averaging across analyses assessing associations between BMI measured before age 60 and late-life cognition, a 5-unit higher level of BMI was associated with a 0.26 point lower cognitive score. Beyond age 65, associations flipped, and higher BMI was associated with better late-life cognitive outcomes. Associations in both directions were stronger in women. Excluding those with BMI loss attenuated findings among women in older ages, supporting the reverse causation hypothesis. CONCLUSIONS: In this sample, age 65 represented a critical turning point between mid- and late life for the association between BMI and cognition, which has important implications for recruitment strategies for studies focused on risk factors for late-life cognitive outcomes. Evidence of gender differences raises the need to further investigate plausible mechanisms.

The application of cross-sectionally derived dementia algorithms to longitudinal data in risk factor analyses.

PURPOSE: Dementia algorithms are often developed in cross-sectional samples but implemented in longitudinal studies to ascertain incident dementia. However, algorithm performance may be higher in cross-sectional settings, and this may impact estimates of risk factor associations. METHODS: We used data from the Religious Orders Study and the Memory and Aging Project (N = 3460) to assess the performance of example algorithms in classifying prevalent dementia in cross-sectional samples versus incident dementia in longitudinal samples. We used an applied example and simulation study to characterize the impact of varying sensitivity, specificity, and unequal sensitivity or specificity between exposure groups (differential performance) on estimated hazard ratios from Cox models. RESULTS: Using all items, algorithm sensitivity was higher for prevalent (0.796) versus incident dementia (0.719); hazard ratios had slight bias. Sensitivity differences were larger using a subset of items (0.732 vs. 0.600) and hazard ratios were 13%-19% higher across adjustment sets compared to estimates using gold-standard dementia status. Simulations indicated specificity and differential algorithmic performance between exposure groups may have large effects on hazard ratios. CONCLUSIONS: Algorithms developed using cross-sectional data may be adequate for longitudinal settings when performance is high and non-differential. Poor specificity or differential performance between exposure groups may lead to biases.

Trajectories and correlates of poor mental health in India over the course of the COVID-19 pandemic: a nation-wide survey.

Introduction: The COVID-19 pandemic had large impacts on mental health; however, most existing evidence is focused on the initial lockdown period and high-income contexts. By assessing trajectories of mental health symptoms in India over two years, we aim to understand the effect of later time periods and pandemic characteristics on mental health in a lower-middle income context. Methods: We used data from the Real-Time Insights of COVID-19 in India (RTI COVID-India) cohort study (N=3,662). We used covariate-adjusted linear regression models with generalized estimating equations to assess associations between mental health (PHQ-4 score) and pandemic periods as well as pandemic characteristics (COVID-19 cases and deaths, government stringency, self-reported financial impact, COVID-19 infection in the household) and explored effect modification by age, gender, and rural/urban residence. Results: Mental health symptoms dropped immediately following the lockdown period but rose again during the delta and omicron waves. Associations between mental health and later pandemic stages were stronger for adults 45 years of age and older (p<0.001). PHQ-4 scores were significantly and independently associated with all pandemic characteristics considered, including estimated COVID-19 deaths (PHQ-4 difference of 0.041 SD units; 95% Confidence Interval 0.030 - 0.053), government stringency index (0.060 SD units; 0.048 - 0.072), self-reported major financial impacts (0.45 SD units; 0.41-0.49), and COVID-19 infection in the household (0.11 SD units; 0.07-0.16). Conclusion: While the lockdown period and associated financial stress had the largest mental health impacts on Indian adults, the effects of the pandemic on mental health persisted over time, especially among middle-age and older adults. Results highlight the importance of investments in mental health supports and services to address the consequences of cyclical waves of infections and disease burden due to COVID-19 or other emerging pandemics.

Harmonization of Later-Life Cognitive Function Across National Contexts: Results from the Harmonized Cognitive Assessment Protocols (HCAPs).

Background: The Harmonized Cognitive Assessment Protocol (HCAP) is an innovative instrument for cross-national comparisons of later-life cognitive function, yet its suitability across diverse populations is unknown. We aimed to harmonize general and domain-specific cognitive scores from HCAPs across six countries, and evaluate precision and criterion validity of the resulting harmonized scores. Methods: We statistically harmonized general and domain-specific cognitive function across the six publicly available HCAP partner studies in the United States, England, India, Mexico, China, and South Africa (N=21,141). We used an item banking approach that leveraged common cognitive test items across studies and tests that were unique to studies, as identified by a multidisciplinary expert panel. We generated harmonized factor scores for general and domain- specific cognitive function using serially estimated graded-response item response theory (IRT) models. We evaluated precision of the factor scores using test information plots and criterion validity using age, gender, and educational attainment. Findings: IRT models of cognitive function in each country fit well. We compared measurement reliability of the harmonized general cognitive function factor across each cohort using test information plots; marginal reliability was high (r> 0·90) for 93% of respondents across six countries. In each country, general cognitive function scores were lower with older ages and higher with greater levels of educational attainment. Interpretation: We statistically harmonized cognitive function measures across six large, population-based studies of cognitive aging in the US, England, India, Mexico, China, and South Africa. Precision of the estimated scores was excellent. This work provides a foundation for international networks of researchers to make stronger inferences and direct comparisons of cross-national associations of risk factors for cognitive outcomes. Funding: National Institute on Aging (R01 AG070953, R01 AG030153, R01 AG051125, U01 AG058499; U24 AG065182; R01AG051158).