National Alzheimer's Coordinating Center Research Articles

Pure LATE-NC: Frequency, clinical impact, and the importance of considering APOE genotype when assessing this and other subtypes of non-Alzheimer's pathologies.

Pure limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (pure LATE-NC) is a term used to describe brains with LATE-NC but lacking intermediate or severe levels of Alzheimer's disease neuropathologic changes (ADNC). Focusing on pure LATE-NC, we analyzed data from the National Alzheimer's Coordinating Center (NACC) Neuropathology Data Set, comprising clinical and pathological information aggregated from 32 NIH-funded Alzheimer's Disease Research Centers (ADRCs). After excluding subjects dying with unusual conditions, n = 1,926 autopsied subjects were included in the analyses. For > 90% of these participants, apolipoprotein E (APOE) allele status was known; 46.5% had at least one APOE 4 allele. In most human populations, only 15-25% of people are APOE ε4 carriers. ADRCs with higher documented AD risk allele (APOE or BIN1) rates had fewer participants lacking ADNC, and correspondingly low rates of pure LATE-NC. Among APOE ε4 non-carries, 5.3% had pure LATE-NC, 37.0% had pure ADNC, and 3.6% had pure neocortical Lewy body pathology. In terms of clinical impact, participants with pure LATE-NC tended to die after having received a diagnosis of dementia: 56% died with dementia among APOE ε4 non-carrier participants, comparable to 61% with pure ADNC. LATE-NC was associated with increased Clinical Dementia Rating Sum of Boxes (CDR-SOB) scores, i.e. worsened global cognitive impairments, in participants with no/low ADNC and no neocortical Lewy body pathology (p = 0.0023). Among pure LATE-NC cases, there was a trend for higher LATE-NC stages to be associated with worse CDR-SOB scores (p = 0.026 for linear trend of LATE-NC stages). Pure LATE-NC was not associated with clinical features of disinhibition or primary progressive aphasia. In summary, LATE-NC with no or low levels of ADNC was less frequent than pure ADNC but was not rare, particularly among individuals who lacked the APOE 4 allele, and in study cohorts with APOE 4 frequencies similar to those in most human populations.

Frailty Trajectories Preceding Dementia in the US and UK.

An accessible marker of both biological age and dementia risk is crucial to advancing dementia prevention and treatment strategies. Although frailty is a candidate for that role, the nature of the relationship between frailty and dementia is not well understood. To clarify the temporal relationship between frailty and incident dementia by investigating frailty trajectories in the years preceding dementia onset. Participant data came from 4 prospective cohort studies: the English Longitudinal Study of Ageing, the Health and Retirement Study, the Rush Memory and Aging Project, and the National Alzheimer Coordinating Center. Data were collected between 1997 and 2024 and were analyzed from July 2023 to August 2024. The settings were retirement communities, national-level surveys, and a multiclinic-based cohort. Included individuals were 60 years or older and without cognitive impairment at baseline. Included individuals also had data on age, sex, education level, and ethnicity and a frailty index score calculated at baseline. Frailty was the main exposure, with participants' degrees of frailty quantified using retrospectively calculated frailty index scores. Incident all-cause dementia ascertained through physician-derived diagnoses, self- and informant-report, and estimated classifications based on combinations of cognitive tests. The participant number before exclusions was 87 737. After exclusions, data from 29 849 participants (mean [SD] age, 71.6 [7.7] years; 18 369 female [62%]; 257 963 person-years of follow-up; 3154 cases of incident dementia) were analyzed. Bayesian generalized linear mixed regression models revealed accelerations in frailty trajectories 4 to 9 years before incident dementia. Overall, frailty was positively associated with dementia risk (adjusted hazard ratios [aHRs] ranged from 1.18; 95% CI, 1.13-1.24 to 1.73; 95% CI, 1.57-1.92). This association held among participants whose time between frailty measurement and incident dementia exceeded the identified acceleration period (aHRs ranged from 1.18; 95% CI, 1.12-1.23 to 1.43; 95% CI, 1.14-1.80). These findings suggest that frailty measurements may be used to identify high-risk population groups for preferential enrolment into clinical trials for dementia prevention and treatment. Frailty itself may represent a useful upstream target for behavioral and societal approaches to dementia prevention.

Metabolic syndrome and mobility dysfunction in older adults with and without histories of traumatic brain injury: The mediating role of cognition.

Older adults are more susceptible than the general population to developing metabolic syndrome (i.e., three or more cardiovascular risk factors [MetS]), physical limitations, and traumatic brain injury (TBI). Recent research has demonstrated that cognition may moderate the negative association between MetS and mobility dysfunction in older adults. This study sought to determine if cognition mediates the relationship between MetS and mobility dysfunction and if this relationship differs in older adults with a history of TBI. Participants (N = 20,156) were from the National Alzheimer's Coordinating Center's Uniform Data Set. Mediation models were tested to assess if processing speed, executive functioning, immediate memory, and delayed memory would independently mediate the association between MetS and mobility dysfunction. Investigation of mediation models revealed that MetS had a significant indirect effect on mobility dysfunction through processing speed (b = .0674, 95% CI [.0412, .0953]) and executive functioning (b = .0354, 95% CI [.0228, .0493]). When TBI was included in the model as a moderator, MetS was not found to moderate the mediating effects of any of the cognitive variables. There were no significant indirect effects for immediate or delayed memory in either model. Findings elucidate potential pathways by which MetS contributes to mobility dysfunction in older adults through specific reductions in processing speed and executive functioning capabilities. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Motor signs and incident dementia with Lewy bodies in older adults with mild cognitive impairment.

Motor signs may herald incident dementia and allow the earlier detection of high-risk individuals and the timely implementation of preventive interventions. The current study was performed to investigate the prognostic properties of motor signs with respect to incident dementia with Lewy bodies (DLB) in older adults with mild cognitive impairment (MCI). Emphasis was placed on sex differences. The specificity of these associations was explored. We analyzed data from the National Alzheimer's Coordinating Center Uniform Data Set. Participants 55 + years old with a diagnosis of MCI were included in the analysis. Those with Parkinson's disease (PD) or other parkinsonian disorders at baseline and those with PD dementia at follow-up were excluded. UPDRS III was used to assess the presence or absence of motor signs in nine domains: hypophonia; masked facies; resting tremor; action/postural tremor; rigidity; bradykinesia; impaired chair rise; impaired posture/gait; postural instability. Αdjusted Cox proportional hazards models featuring sex by motor sign interactions were estimated. Throughout the average follow-up of 3.7 ± 3.1 years, among 4623 individuals with MCI, 2211 progressed to dementia (66 of whom converted to DLB). Masked facies [HR = 4.21 (1.74-10.18)], resting tremor [HR = 4.71 (1.44-15.40)], and bradykinesia [HR = 3.43 (1.82-6.45)] exclusively increased the risk of DLB. The HR of DLB was approximately 15 times greater in women compared to men with masked facies. Impaired posture-gait (approximately 10 times) and resting tremor (approximately 8.5 times) exhibited a similar trend (prominent risk-conferring properties in women compared to men) but failed to achieve statistical significance. Rigidity and hypophonia elevated the risk of other dementia entities, as well. The remaining motor features were not related to incident dementia of any type. Specific motor signs may herald DLB among individuals with MCI. Different associations may exist between masked facies, impaired posture-gait, resting tremor, and incident DLB in men versus women.

Depression Symptoms Moderate Associations between Daily Functioning and Neuropsychological Performance in Mexican American Adults.

The influence of depression on the relationship between cognition and daily living in aging Mexican American adults requires further investigation, given projected trends in general growth as well as prevalence of depression and Alzheimer's disease and related dementias (ADRD) in this population. In the present study, we examined the extent to which depression (assessed using the Geriatric Depression Scale - 15 item version) moderated the association between reported daily functioning (assessed using the Functional Activities Questionnaire [FAQ]) and objective neuropsychological performance in aging Mexican American adults in the National Alzheimer's Coordinating Center cohort. Worse reported daily functioning (higher FAQ scores) was associated with worse memory and language performance among participants without elevated depression symptoms (ps < .05), but no associations were observed among those with elevated symptoms (ps > .05). Moreover, depression did not moderate associations of reported daily functioning with performance in attention and working memory or executive functioning and processing speed (ps > .05). Aging Mexican American adults with elevated depression symptoms may have subjective informant reports of daily functioning that are discrepant from their objective performance on formal tests of memory and language. Within the context of neuropsychological evaluations for ADRD, failure to adequately assess mood to inform the nature of cognitive and/or functional changes could result in misdiagnosis and lead to delayed, premature, and/or improper intervention with this population.

Examining the Measurement Equivalence of Alzheimer Disease Research Centers' Neuropsychological Test Battery (Version 3) Between Singapore and US Samples.

Standardization of neuropsychological tests is crucial for consistency in cognitive assessment, as well as for validity and comparability of results across different populations. We examined the applicability and measurement equivalence of the Alzheimer Disease Research Centers' Neuropsychological Test Battery (version 3) (ADRC-NTB3) in Singapore. The ADRC-NTB3 was administered to 978 older persons with normal cognition in Singapore. To provide comparison between Singapore and US samples, a US sample with similar profile was retrieved from the National Alzheimer Coordinating Center (NACC) database. Scores were compared with 1853 participants with similar profile from the United States. Score-difference between the populations was computed using multiple linear regression (adjusted for covariates), with equivalent score considered present when 90% CI of the score-difference fell within the predefined margin of equivalence. Tasks assessing for memory, processing speed, and executive functioning showed equivalence in scores between US and Singapore samples (adjusted-score difference=-0.94 to 0.09). Singapore sample performed marginally better on the visuospatial task (adjusted-score difference=0.50), but poorer on the language task (adjusted-score difference=-3.22). Nonequivalence of visuospatial and language tasks, which may increase potential misinterpretation of cognitive profiles and misdiagnosis, are related to educational and cultural differences. This highlights the need for different normative data for more accurate diagnostic accuracy as well as research priorities.

Dementia risk scores, apolipoprotein E, and risk of Alzheimer's disease: One size does not fit all.

Evaluating the generalizability of dementia risk scores, primarily developed in non-Latinx White (NLW) participants, and interactions with genetic risk factors in diverse populations is crucial for addressing health disparities. We analyzed the association of the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) and modified CAIDE (mCAIDE) scores with dementia risk using logistic regression models stratified by race/ethnicity in National Alzheimer's Coordinating Center (NACC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), and assessed their interaction with apolipoprotein E (APOE). Higher CAIDE scores were associated with an increased risk of dementia in Asian, Latinx, and NLW participants but not in Black participants. In contrast, higher mCAIDE scores were also associated with an increased risk of dementia in Black participants. Unfavorable mCAIDE risk profiles exacerbated the apolipoprotein E*ε4 (APOE*ε4) risk effect and attenuated the APOE*ε2 protective effect. Our findings underscore the importance of evaluating the validity of dementia risk scores in diverse populations for their use in personalized medicine approaches to promote brain health. Dementia risk scores demonstrate race/ethnic-specific effects on dementia risk. Unfavorable modifiable risk profiles moderate the effect of APOE on dementia risk. Dementia risk scores need to be validated in diverse populations.

Amyloid-β predominant Alzheimer's disease neuropathologic change.

Different subsets of Alzheimer's disease neuropathologic change (ADNC), including the intriguing set of individuals with severe/widespread Aβ plaques but no/mild tau tangles (Aβ-predominant ADNC, or AP-ADNC), may have distinct genetic and clinical features. Analyzing National Alzheimer's Coordinating Center data, we stratified 1,187 participants into AP-ADNC (n = 95), low Braak primary age related tauopathy (PART; n = 185), typical-ADNC (n = 832), and high-Braak PART (n = 75). AP-ADNC differed in some clinical features and genetic polymorphisms in the APOE, SNX1, WNT3/MAPT, and IGH genes. We conclude that AP-ADNC differs from classical ADNC with implications for in vivo studies.

Referral Sources Across Racial and Ethnic Groups at Alzheimer's Disease Research Centers.

Despite the need to increase engagement of underrepresented groups (URG) in Alzheimer's disease and related dementias (ADRD) studies, enrollment remains low. Compare referral sources across racial and ethnic groups among participants enrolled in ADRC studies. Data for this cross-sectional secondary analysis were extracted from the National Alzheimer's Coordinating Center Uniform Data Set. We performed mixed effects logistic regression models using generalized estimating equations for professional referral versus non-professional referral by racial and ethnic group, adjusted for age, gender, education, visit year, and Clinical Dementia Rating scale (CDR) with a random effect for study site. Included in the analysis were 48,330 participants across 46 ADRCs (mean [SD] age, 71.3 [10.5] years; 20,767 female [57%]; 4,138 Hispanic [8.6%]; 1,392 non-Hispanic Asian [2.9%]; 6,766 non-Hispanic Black [14%] individuals; and 676 individuals [1.4%] of other races. Non-Hispanic Black and Asian participants had lower odds of being referred by a professional contact compared to non-Hispanic White participants (Black: adjusted OR = 0.61, 95% CI = 0.44-0.86, p = 0.005; Asian: adjusted OR = 0.65, 95% CI, p = 0.004). In participants who had completed an MRI, there was no significant difference in referral source across ethnic and racial groups. Further studies are needed to better understand the systemic and structural factors that contribute to differences in referral sources and disparities in recruitment of URG into ADRD studies.

GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia.

Genome-wide association studies (GWAS) have identified >80 Alzheimer's disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from the following three sources: the National Alzheimer's Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the Adult Changes in Thought study (n = 7,804 total autopsied participants). We identified eight independent significantly associated loci, of which four were new (COL4A1, PIK3R5, LZTS1 and APOC2). Separately testing known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false-discovery rate adjustment. Genetic colocalization analyses identified pleiotropic effects and quantitative trait loci. Methylation in the cerebral cortex at two sites near APOC2 was associated with cerebral amyloid angiopathy. Studies that include neuropathology endophenotypes are an important step in understanding the mechanisms underlying genetic ADRD risk.

Evaluating the updated LATE-NC staging criteria using data from NACC.

Limbic-predominant age-related TAR DNA-binding protein of 43kDa encephalopathy neuropathologic change (LATE-NC) staging criteria were updated in 2023. We evaluated this updated staging using National Alzheimer's Coordinating Center data. We examined associations of LATE-NC stages with cognition and other neuropathologic changes (NCs), and with cognition while accounting for other NCs, using multilevel regression models. Of 1352 participants, 502 (37%) had LATE-NC (23% stage 1a, 6% stage 1b, 58% stage 2, 13% stage 3). LATE-NC stages were associated with cognition, hippocampal sclerosis of aging (HS-A), Alzheimer's disease NC (ADNC), Lewy bodies (LBs), and hippocampal atrophy. While stage 1b was associated with cognition and HS-A consistent with other stages, it was not associated with ADNC or LBs. All LATE-NC stages remained significantly associated with worse cognition when accounting for other NCs. The updated LATE-NC staging criteria capture variations in early TDP-43 pathology spread which are consequential for cognition and associations with other NCs. We applied the updated limbic-predominant age-related TAR DNA-binding protein of 43kDa encephalopathy neuropathologic change (LATE-NC) staging criteria to data from the National Alzheimer's Coordinating Center. LATE-NC stage 1b was identified in 22% of participants with stage 1. In contrast to other LATE-NC stages, stage 1b was not associated with Alzheimer's disease neuropathologic change (ADNC) or Lewy bodies. Stages 1a and 1b were significantly associated with dementia and memory impairment. Stages 1b+ were more strongly tied to dementia than all other neuropathologic changes except high likelihood ADNC.

The Alzheimer's Disease Neuroimaging Initiative Neuropathology Core: An update.

Biomarkers for Alzheimer's disease neuropathologic change (ADNC) have been instrumental in developing effective disease-modifying therapeutics. However, to prevent/treat dementia effectively, we require biomarkers for non-AD neuropathologies; for this, neuropathologic examinations and annotated tissue samples are essential. We conducted clinicopathologic correlation for the first 100 Alzheimer's Disease Neuroimaging Initiative (ADNI) Neuropathology Core (NPC) cases. Clinical syndromes in this cohort showed 95% sensitivity and 79% specificity for predicting high/intermediate ADNC, a 21% false positive rate, and a ∼44% false negative rate. In addition, 60% with high/intermediate ADNC harbored additional potentially dementing co-pathologies. These results suggest that clinical presentation imperfectly predicts ADNC and that accurate prediction of high/intermediate ADNC does not exclude co-pathology that may modify presentation, biomarkers, and therapeutic responses. Therefore, new biomarkers are needed for non-AD neuropathologies. The ADNI NPC supports this mission with well-characterized tissue samples (available through ADNI and the National Institute on Aging) and "gold-standard" diagnostic information (soon to include digital histology). The Alzheimer's Disease Neuroimaging Initiative (ADNI) Neuropathology Core (NPC) brain donation cohort now exceeds 200 cases. ADNI NPC data in National Alzheimer's Coordinating Center format are available through the Laboratory of Neuro Imaging. Digitized slide files from the ADNI NPC will be available in 2025. Requests for ADNI brain tissue samples can be submitted online for ADNI/National Institute on Aging evaluation. Clinical diagnoses of Alzheimer's disease (AD)/AD and related dementias (ADRD) do not always predict post mortem neuropathology. Neuropathology is essential for the development of novel AD/ADRD biomarkers.

Sex Differences in Cortical Thickness and Neuropsychiatric Symptom Burden Based on APOE4 Homozygosity in Alzheimer's Disease.

Sex differences in patterns of cortical thickness and neuropsychiatric symptom (NPS) burden were examined among individuals with Alzheimer's disease (AD) and two copies (homozygote carriers) of the e4 allele of the apolipoprotein gene (APOE). A total of 752 participants with a clinical etiologic diagnosis of AD were selected from the National Alzheimer's Coordinating Center (NACC) database. Bayesian multilevel regression was used to examine both the within- and between-sex differences in gray-matter cortical thickness and total NPS burden associated with APOE homozygosity. Female homozygote carriers displayed a high probability of having reduced cortical thickness primarily in medial-lateral temporal regions and a greater burden of NPS, relative to both non-homozygous females and homozygous males. These findings support the notion that APOE4 status affects cortical thickness and symptom burden in men and women with AD differentially, with females showing more pronounced effects in brain areas known to be vulnerable in early AD. Future investigations should attempt to elucidate the proposed pattern of decline longitudinally.

Co-Occurring Mental and Physical Health Conditions Among Older Adults With and Without Post-traumatic Stress Disorder: A Case Control Study.

Rates of post-traumatic stress disorder (PTSD) among older adults range from 0.4%-4.5%. Research examining PTSD in adults has demonstrated numerous associations between physical and mental health conditions; however, these are less well characterized in older adults. The current study aimed to identify base rates of such conditions among older adults with and without a history of PTSD. In a case control design using the National Alzheimer's Coordinating Center Uniform Data Set, adults 65 years or older from the United States who endorsed either the presence or absence of PTSD were matched by age to assess between-group differences (N = 472; 236 pairs). We examined differences across self-reported sociodemographics and physical health, mental health, and substance use histories. More participants with a history of PTSD identified as Hispanic, non-white, non-married, and functionally independent. Compared to individuals without a history of PTSD, significantly more individuals with a history of PTSD had histories of depression, anxiety, substance abuse, Parkinson's disease, seizures, insomnia, and TBI. Among participants without PTSD history, only 14.7% reported a history of TBI, compared to 41.1% of individuals with PTSD history. Findings showed expected trends toward worse physical and mental health among older adults with self-reported PTSD. There was a striking difference in the frequency of TBI history between participants with and without PTSD. These findings underscore a need to assess for PTSD among older adults, particularly those reporting a history of TBI.

Association of Seizure Control With Cognition in People With Normal Cognition and Mild Cognitive Impairment.

Seizures are common in dementia and associated with accelerated cognitive decline. However, the impact of active vs remote seizures on cognition remains understudied. This study aimed to investigate the impact of active vs remote seizures on cognition in people with normal cognition and mild cognitive impairment (MCI). This longitudinal, multicenter cohort is based on National Alzheimer's Coordinating Center data of participants recruited from 39 Alzheimer's Disease Centers in the United States from September 2005 to December 2021. All participants with normal cognition and MCI and at least 2 visits were included. Primary outcome, that is, cognitive decline, was determined using Clinical Dementia Rating (CDR) from (1) normal-to-impaired (CDR ≥0.5) and (2) MCI-to-dementia (CDR ≥1) groups. The effect of active seizures (over the preceding 12 months), remote seizures (previous seizures but none over the preceding 12 months), and no seizures (controls) on cognition was assessed. Subgroups of chronic seizures at enrollment and new-onset seizures were further analyzed. Cox regression models assessed the risk of all-cause MCI and/or dementia. All models were adjusted for age, sex, education, race, hypertension, and diabetes. Of the 13,726 participants with normal cognition at enrollment (9,002 [66%] female; median age 71 years), 118 had active seizures and 226 had remote seizures. Of the 11,372 participants with MCI at enrollment (5,605 [49%] female; median age 73 years), 197 had active seizures and 226 had remote seizures. Active seizures were associated with 2.1 times higher risk of cognitive impairment (adjusted hazard ratio [aHR] 2.13, 95% CI 1.60-2.84, p < 0.001) in cognitively healthy adults (median years to decline: active seizures = ∼1, remote seizures = ∼3, no seizures = ∼3) and 1.6 times higher risk of dementia (aHR 1.58, 95% CI 1.24-2.01, p < 0.001) in those with MCI (median years to decline: active seizures = ∼1, remote seizures = ∼2, controls = ∼2). This risk was not observed with remote seizures. In this study, active seizures but not remote seizures were associated with earlier cognitive decline in both cognitively normal adults and those with MCI, independent of other dementia risk factors. Therefore, early identification and management of seizures may present a path to mitigation of cognitive decline in the aging epileptic population. A limitation is that causality cannot be confirmed in our observational longitudinal study.

The effect of study partner characteristics on the reporting of neuropsychiatric symptoms across the neurocognitive spectrum.

We explored the influence of study partner (SP) characteristics on SP-reported neuropsychiatric symptoms (NPS) presence across the neurocognitive spectrum and on the prognostic utility of mild behavioral impairment (MBI). We performed cross-sectional (n = 26,748) and longitudinal (n = 12,794) analyses using participant-SP dyad data from the National Alzheimer's Coordinating Center. Participants were cognitively normal (CN; n = 11,951) or had mild cognitive impairment (MCI; n = 5686) or dementia (n = 9111). SPs rated NPS using the Neuropsychiatric Inventory Questionnaire. We used multivariable logistic regression to model the association between SP characteristics (age, sex, and relationship to participant [spouse, child, and other]) and NPS status (outcome). Cox regressions assessed SP characteristics as moderators of MBI associations with incident dementia or as predictors of incident dementia in MBI + participants only. Among CN persons, younger, female, and spouse SPs reported NPS more frequently. In MCI, younger SPs and those who were spouses or children of participants reported higher NPS odds. For dementia participants, NPS odds were higher in female and spouse SPs. MBI associations with incident dementia were slightly weaker when SPs were older but did not depend on SP sex or relationship to participant. Among MBI + participants with spouse or child SPs, hazard for dementia was higher when compared to MBI + participants with other SPs. SP age, sex, and relationship to participant influence NPS reporting across the neurocognitive spectrum, with potential implications for MBI prognosis. Considering SP characteristics may enhance the accuracy of NPS assessments, which may facilitate therapy planning and prognosis.

Coping patterns associations with cognitive function in older adults.

Cognitive function may contribute to variability in older adults' ability to cope with chronic stress; however, limited research has evaluated this relationship. This study investigated the relationship between theoretically derived coping domains and cognitive function in 165 middle-to-older adults during the Omicron stage of COVID-19. Participants completed a clinical interview and self-report measures of health. The National Alzheimer's Coordinating Center Uniform Data Set neuropsychological battery was used to evaluate memory, language, executive function/speed, and working memory. Structural equation modeling evaluated the underlying factor structure of the Brief COPE adapted for COVID-19. The data supported the proposed second-order Approach factor comprised of Problem-Solving and Emotion Regulation (ER) strategies and a first-order Avoidance factor. Higher Avoidance was associated with greater depression symptoms, lower income and worse memory, executive function, working memory, and verbal fluency performance. Higher Problem-Solving was associated with better verbal fluency performance. ER strategies were not significantly associated with cognitive function. The use of Problem-Solving was not associated with less Avoidance. Greater use of Problem-Solving, ER, and Avoidance were all associated with higher levels of stress. Post-hoc analyses found that higher Acceptance was the only coping strategy associated with less stress. These findings demonstrate that older adults with worse cognitive function were more likely to use Avoidance during the pandemic, which could result in prolonged stress and adverse health consequences. Future research is warranted to investigate whether acceptance-based interventions reduce the avoidance and impact of stress on health in vulnerable older adults.

Association of education attainment, smoking status, and alcohol use disorder with dementia risk in older adults: a longitudinal observational study

BackgroundPrevious research on the risk of dementia associated with education attainment, smoking status, and alcohol use disorder (AUD) has yielded inconsistent results, indicating potential heterogeneous treatment effects (HTEs) of these factors on dementia risk. Thus, this study aimed to identify the important variables that may contribute to HTEs of these factors in older adults.MethodsUsing 2005–2021 data from the National Alzheimer’s Coordinating Center (NACC), we included older adults (≥ 65 years) with normal cognition at the first visit. The exposure of interest included college education or above, current smoking, and AUD and the outcome was all-cause dementia. We applied doubly robust learning to estimate risk differences (RD) and 95% confidence intervals (CI) between exposed and unexposed groups in the overall cohort and subgroups identified through a decision tree model.ResultsOf 10,062 participants included, 929 developed all-cause dementia over a median 4.4-year follow-up. College education or above was associated with a lower risk of all-cause dementia in the overall population (RD, -1.5%; 95%CI, -2.8 to -0.3), especially among the subpopulations without hypertension, regardless of the APOE4 status. Current smoking was not related to increased dementia risk overall (2.8%; -1.5 to 7.2) but was significantly associated with increased dementia risk among men with (21.1%, 3.1 to 39.1) and without (8.4%, 0.9 to 15.8) cerebrovascular disease. AUD was not related to increased dementia risk overall (2.0%; -7.7 to 11.7) but was significantly associated with increased dementia risk among men with neuropsychiatric disorders (31.5%; 7.4 to 55.7).ConclusionsOur studies identified important factors contributing to HTEs of education, smoking, and AUD on risk of all-cause dementia, suggesting an individualized approach is needed to address dementia disparities.

Comparison of Explainable AI Models for MRI-based Alzheimer's Disease Classification.

Deep learning models based on convolutional neural networks (CNNs) have been used to classify Alzheimer's disease or infer dementia severity from 3D T1-weighted brain MRI scans. Here, we examine the value of adding occlusion sensitivity analysis (OSA) and gradient-weighted class activation mapping (Grad-CAM) to these models to make the results more interpretable. Much research in this area focuses on specific datasets such as the Alzheimer's Disease Neuroimaging Initiative (ADNI) or National Alzheimer's Coordinating Center (NACC), which assess people of North American, predominantly European ancestry, so we examine how well models trained on these data generalize to a new population dataset from India (NIMHANS cohort). We also evaluate the benefit of using a combined dataset to train the CNN models. Our experiments show feature localization consistent with knowledge of AD from other methods. OSA and Grad-CAM resolve features at different scales to help interpret diagnostic inferences made by CNNs.

A - 111 Neuropsychological Functioning in those with Chronic Traumatic Encephalopathy

Abstract Objective To differentiate neurocognitive performance between those with chronic traumatic encephalopathy neuropathologic change (CTE-NC) and matched CTE-negative individuals. Methods Data were obtained from the National Alzheimer’s Coordinating Center (NACC). Participants with mild cognitive impairment (MCI) or dementia and CTE-NC (n = 22) were matched approximately 1:3 to those with MCI/dementia but without CTE-NC (n = 64) on demographics (age of initial cognitive diagnosis, education, sex) and postmortem Alzheimer’s and Lewy body neuropathology. ANCOVAs (covarying for symptom duration and cognitive diagnosis) compared neurocognitive measures between groups (MMSE and neuropsychological battery composites of Attention, Executive Function, and Speed [AEFS], Memory, and Language). Results Participants were all male, 89.3% White, and averaged 16.3 years of education. They were, on average, 74.8 years of age (SD = 7.3) when diagnosed with MCI/dementia and had 4.2 years (SD = 4.2) of cognitive symptoms prior to MCI/dementia diagnosis. Rates of comorbid moderate/severe Alzheimer’s or Lewy body pathology were high (n = 13, 54%) in the CTE-NC group. At time of cognitive diagnosis, individuals with CTE-NC performed slightly better on the MMSE (F = 4.510, p = 0.037, CTE-NC+ M = 26.03 [1.05] vs. CTE-NC- M = 23.44 [0.58]). No differences in AEFS [F = 0.280, p = 0.599], Memory [F = 2.265, p = 0.137], or Language [F = 3.424, p = 0.069] were observed between groups. Conclusions Those with CTE-NC did not greatly differ in neuropsychological domains, but had relatively higher MMSE scores compared to those without CTE-NC. This is the largest clinicopathological investigation utilizing in-vivo neurocognitive data, though NACC lacks CTE-NC severity/distribution data for sensitivity analyses. Nonetheless, results have implications for CTE clinical criteria frameworks and larger clinicopathological studies are needed to determine if CTE-NC has distinct neurocognitive features.