Laura E. Gibbons

Background: Traumatic brain injury (TBI) is associated with increased dementia risk, yet its relationship to Alzheimer's disease (AD) neuropathology is unclear. Prior autopsy studies show inconsistent results, constrained by limited TBI ascertainment, semi-quantitative neuropathology methods, and selection bias. Objective: To examine whether TBI with loss of consciousness (TBI-LOC) is associated with quantitative measures of tau and amyloid-β ₄₂ (Aβ ₄₂ ) pathology in a community-based autopsy cohort. Methods: The analytic sample included 810 Adult Changes in Thought study brain donors with baseline TBI-LOC ascertainment and quantitative neuropathology data, weighted to represent the full living cohort (n = 5763). Modified Poisson regression estimated rate ratios (RRs) and 95% confidence intervals (CIs) for associations of TBI-LOC with percent-positive AT8 tau immunoreactivity and soluble Aβ ₄₂ (GuHCl and RIPA fractions) across brain regions. Models were adjusted for age at death, sex, education, and enrollment cohort; sensitivity analyses included unweighted and quantile models. Results: Weighted models showed lower frontal tau (RR = 0.50, p = 0.047) and lower soluble Aβ ₄₂ in temporal and occipital cortices (p = 0.019–0.037) among donors with baseline TBI-LOC. In unweighted sensitivity analyses, lower temporal RIPA Aβ ₄₂ remained significant (p < 0.001), and select inverse associations were observed in duration-stratified analyses, particularly in small >1 h LOC subgroups. Quantile analyses of pathology burden similarly suggest reduced parietal Aβ ₄₂ (p = 0.02–0.04); effects were small and driven by sparse subgroups. Conclusions: TBI-LOC was not associated with greater tau or amyloid burden, and inverse associations likely reflect data sparsity rather than biological protection. These findings suggest that links between TBI and late-life cognitive decline may involve non-AD pathological processes.

Background: Others have examined heterogeneity in Alzheimer's disease (AD); however, few have used longitudinal data while accounting for variation in disease stage. We used latent classes to model heterogeneity in the trajectories of three cognitive domains (memory, language, and executive functioning) starting at AD dementia diagnosis. Objective: Our aim was to describe the patterns of heterogeneity in cognitive decline across cognitive domains during the course of AD and to contextualize our findings by assessing associations with demographic factors and neuropathological measures. Methods: We used cognitive data from the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study in a multi-dimensional joint latent class mixed model, which allowed us to estimate cognitive trajectories that varied across cognitive domains and latent classes. We accounted for the uncertainty in latent class assignment and corrected for multiple hypotheses when assessing the association of the latent classes with demographic and neuropathological variables. Results: We identified five latent classes differentiated by level of impairment (high to low) and rate of decline (slow to fast). Within each latent class, the pattern of decline did not differ substantially across cognitive domains. Classes were associated with APOE genotype, sex, race, education, and neuritic plaque and neurofibrillary tangle burden. Conclusions: Our results highlight global differences in the level of cognitive impairment at diagnosis and the rate of decline rather than differences between domains of cognition. Examination of patterns in the global rate of cognitive decline may improve understanding of heterogeneity in AD.

INTRODUCTION: Early‐onset Alzheimer's disease dementia (EOAD) is characterized by more pronounced cognitive decline than late‐onset AD dementia (LOAD). Characteristic performance in spoken language remains undefined. METHOD: A cross‐sectional analysis of 1189 people with EOAD and 4646 with LOAD from the National Alzheimer's Coordinating Center (NACC) was conducted. RESULT: Based on data from their first NACC visit with AD, there was considerable heterogeneity in language performance across people with EOAD and LOAD. The distribution of naming ability was similar across these groups. On average, people with LOAD performed better than those with EOAD in category fluency, letter fluency, and spoken lexical retrieval, and had lower Clinical Dementia Rating (CDR) Language scores, although there was considerable overlap in the distributions for participants with EOAD and those with LOAD. DISCUSSION: At diagnosis, the language profiles of EOAD and LOAD are distinct. There is substantial variability in both groups in multiple aspects of language. Highlights: Early‐onset Alzheimer's disease (EOAD) is associated with significantly poorer category and phonemic fluency and global spoken lexical retrieval compared to late‐onset Alzheimer's disease (LOAD) at time of diagnosis. Participants with EOAD dementia show greater severity and variability in clinician‐rated language functioning, as measured by Clinical Dementia Rating (CDR) Language scores. No significant group differences were observed in confrontation naming performance between EOAD and LOAD dementia. Findings support that there are distinct profiles of language performance in EOAD and LOAD at time of dementia diagnosis.

BACKGROUND Early-onset Alzheimer’s disease dementia (EOAD) is characterized by more pronounced cognitive decline than late-onset AD dementia (LOAD). Characteristic performance in spoken language remains undefined. METHOD A cross-sectional analysis of 1,189 people with EOAD and 4,646 with LOAD from the National Alzheimer’s Coordinating Center (NACC). RESULT Based on data from their first NACC visit with AD, there was considerable heterogeneity in language performance across people with EOAD and LOAD. The distribution of naming ability was similar across these groups. On average, people with LOAD had better performance than people with EOAD for category fluency, letter fluency, and spoken lexical retrieval, and had lower Clinical Dementia Rating (CDR®) language scores, though there was considerable overlap in all of the distributions for people with EOAD and people with LOAD. DISCUSSION At diagnosis, EOAD and LOAD language profiles are distinct. There is substantial variability in both groups in multiple aspects of language.

Background: The Adult Changes in Thought (ACT) study is a cohort of Kaiser Permanente Washington members ages 65+ that began in 1994. Objective: We wanted to know how well ACT participants represented all older adults in the region, and how well ACT findings on eye disease and its relationship with Alzheimer’s disease generalized to all older adults in the Seattle Metropolitan Region. Methods: We used participation weights derived from pooling ACT and Behavioral Risk Factor Surveillance System (BRFSS) data to estimate prevalences of common eye diseases and their associations with Alzheimer’s disease incidence. Cox proportional hazards models accounted for age, education, smoking, sex, and APOE genotype. Confidence intervals for weighted analyses were bootstrapped to account for error in estimating the weights. Results: ACT participants were fairly similar to older adults in the region. The largest differences were more self-reported current cholesterol medication use in BRFSS and higher proportions with low education in ACT. Incorporating the weights had little impact on prevalence estimates for age-related macular degeneration or glaucoma. Weighted estimates were slightly higher for diabetic retinopathy (weighted 5.7% (95% Confidence Interval 4.3, 7.1); unweighted 4.1% (3.6, 4.6)) and cataract history (weighted 51.8% (49.6, 54.3); unweighted 48.6% (47.3, 49.9)). The weighted hazard ratio for recent diabetic retinopathy diagnosis and Alzheimer’s disease was 1.84 (0.34, 4.29), versus 1.32 (0.87, 2.00) in unweighted ACT. Conclusions: Most, but not all, associations were similar after participation weighting. Even in community-based cohorts, extending inferences to broader populations may benefit from evaluation with participation weights.

Background: Many people with clinically diagnosed Alzheimer’s disease (AD) dementia during life show multiple comorbid neuropathologies at autopsy. We sought to develop and evaluate a composite brain pathology score (BPS) score in the Adult Changes in Thought (ACT) study.Method: We chose nine standard neuropathological variables to derive the BPS: Thal phase, Braak stage, CERAD score, cerebral amyloid angiopathy (CAA) score, presence of Lewy Body disease, presence of hippocampal sclerosis, total microinfarcts, LATE stage, and presence of arteriolosclerosis. We used confirmatory factor analyses (CFA) to derive a composite score for BPS. We compared BPS to the AD Neuropathologic Change (ADNC) score.We performed non‐nested modeling to compare the association of each score (BPS vs ADNC) using the last cognitive score (memory, executive function, language, and visuospatial ability) prior to death, adjusting for age at death and sex. Non‐nested models were compared with the Adjusted‐R2, the Davidson‐MacKinnon J‐test, and the Cox–Pesaran test. We focused on people whose last cognitive data were≤2 years prior to death. We compared associations of ADNC and BPS with last known clinical diagnosis (no dementia vs. any dementia), adjusting for age at death and sex by considering area under receiver operator characteristic (ROC) curves.Result: Sample size was 886 with mean age of death was 89 and 57% were female. A bifactor model fit the best (Figure 1) with residual correlations for Thal phase and CERAD score, and for LATE stage and presence of hippocampal sclerosis. The BPS explained more of the variance for each of the cognitive scores (Table 1) and was superior and statistically significant compared to the ADNC score in comparisons of non‐nested models (Table 2). The BPS was also more strongly associated (Odds Ratio = 3.2) with dementia diagnosis than the ADNC score (Odds Ratio = 2.0). The area under the ROC curve for ADNC score was 0.74, while it was 0.78 for BPS score. The difference between the areas under ROC curves was statistically significant (p‐value < 0.0001).Conclusion: We demonstrate an approach to developing a composite brain pathology score which incorporates multiple forms of pathology. Future efforts will be focused on co‐calibrating and harmonizing BPS in other autopsy cohorts.

Background: More than 75 common variant loci account for only a portion of the heritability for Alzheimer’s disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD-related endophenotypes.Methods: We conducted genome-wide scans for cognitive domain performance using harmonized and co-calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community-based (FHS, ACT, and ROSMAP) and clinic-based (ADRCs and ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP × age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP’s main effect and interaction with age. Results across datasets were combined using inverse-variance meta-analysis. Genome-wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software.Results: Individual domain and pleiotropy analyses revealed genome-wide significant (GWS) associations with five established loci for AD and AD-related disorders (BIN1,CR1,GRN,MS4A6A, andAPOE) and eight novel loci.ULK2was associated with executive function in the community-based cohorts (rs157405,P = 2.19 × 10^–9). GWS associations for language were identified withCDK14in the clinic-based cohorts (rs705353,P = 1.73 × 10^–8) andLINC02712in the total sample (rs145012974,P = 3.66 × 10^–8).GRN(rs5848,P = 4.21 × 10^–8) andPURG(rs117523305,P = 1.73 × 10^–8) were associated with memory in the total and community-based cohorts, respectively. GWS pleiotropy was observed for language and memory withLOC107984373(rs73005629,P = 3.12 × 10^–8) in the clinic-based cohorts, and withNCALD(rs56162098,P = 1.23 × 10^–9) andPTPRD(rs145989094,P = 8.34 × 10^–9) in the community-based cohorts. GWS pleiotropy was also found for executive function and memory withOSGIN1(rs12447050,P = 4.09 × 10^–8) andPTPRD(rs145989094,P = 3.85 × 10^–8) in the community-based cohorts. Functional studies have previously linked AD toULK2,NCALD, andPTPRD.Conclusion: Our results provide some insight into biological pathways underlying processes leading to domain-specific cognitive impairment and AD, as well as a conduit toward a syndrome-specific precision medicine approach to AD. Increasing the number of participants with harmonized cognitive domain scores will enhance the discovery of additional genetic factors of cognitive decline leading to AD and related dementias.

Telephone-administered cognitive assessments are a cost-effective and sometimes necessary alternative to face-to-face assessments. There is limited information in large studies concerning mode effects, or differences in cognition attributable to the assessment method, as a potential measurement threat. We evaluated mode effects on cognitive scores using a population-based sample of community-living older adults. We used data from participants aged 65–79 in the 2014 Health and Retirement Study for whom the interview mode was randomized (n = 6,825). We assessed mode differences in test means, whether mode modifies associations of cognition with criterion variables, and formal measurement invariance testing. Relative to face-to-face assessment, telephone assessment was associated with higher scores for memory and calculation (0.06 to 0.013 standard deviations [SD]) and lower scores for nonmemory items (−0.09 to −0.01 SD). Cognition was significantly differentially related to instrumental activities of daily living difficulty depending on assessment mode. Measurement invariance testing identified evidence of mode differences in certain tests as a function of mode: adjusting for underlying cognition, the largest mode differences in memory and attention: immediate noun recall, delayed word recall, and serial-7s scores were higher given telephone administration. Differences by mode of administration are apparent in cognitive measurement in older adults, albeit to a small degree in our study, and most pronounced for tests of memory and attention. The importance of accounting for mode differences ultimately depends on one’s research question and study sample: not all associations may be affected by mode differences, and such modification may only be apparent among those with lower cognitive functioning.

As the number of U.S. veterans over age 65 has increased, interest in whether military service affects late-life health outcomes has grown. Whether military employment is associated with increased risk of cognitive decline and dementia remains unclear. We used data from 4,370 participants of the longitudinal Adult Changes in Thought (ACT) cohort study, enrolled at age 65 or older, to examine whether military employment was associated with greater cognitive decline or higher risk of incident dementia in late life. We classified persons as having military employment if their first or second-longest occupation was with the military. Cognitive status was assessed at each biennial Adult Changes in Thought study visit using the Cognitive Abilities Screening Instrument, scored using item response theory (CASI-IRT). Participants meeting screening criteria were referred for dementia ascertainment involving clinical examination and additional cognitive testing. Primary analyses were adjusted for sociodemographic characteristics and APOE genotype. Secondary analyses additionally adjusted for indicators of early-life socioeconomic status and considered effect modification by age, gender, and prior traumatic brain injury with loss of consciousness TBI with LOC. Overall, 6% of participants had military employment; of these, 76% were males. Military employment was not significantly associated with cognitive change (difference in modeled 10-year cognitive change in CASI-IRT scores in SD units (95% confidence interval [CI]): −0.042 (−0.19, 0.11), risk of dementia (hazard ratio [HR] [95% CI]: 0.92 [0.71, 1.18]), or risk of Alzheimer’s disease dementia (HR [95% CI]: 0.93 [0.70, 1.23]). These results were robust to additional adjustment and sensitivity analyses. There was no evidence of effect modification by age, gender, or traumatic brain injury with loss of consciousness. Among members of the Adult Changes in Thought cohort, military employment was not associated with increased risk of cognitive decline or dementia. Nevertheless, military veterans face the same high risks for cognitive decline and dementia as other aging adults.

Background: Diabetes is a risk factor for Alzheimer’s disease and related dementias (ADRD). Epidemiologic evidence shows an association between diabetes medications and ADRD risk; cell and mouse models show diabetes medication association with AD-related neuropathologic change (ADNC). Objective: This hypothesis-generating analysis aimed to describe autopsy-measured ADNC for individuals who used diabetes medications. Methods: Descriptive analysis of ADNC for Adult Changes in Thought (ACT) Study autopsy cohort who used diabetes medications, including sulfonylureas, insulin, and biguanides; total N = 118. ADNC included amyloid plaque distribution (Thal phasing), neurofibrillary tangle (NFT) distribution (Braak stage), and cortical neuritic plaque density (CERAD score). We also examined quantitative measures of ADNC using the means of standardized Histelide measures of cortical PHF-tau and Aβ1–42. Adjusted analyses control for age at death, sex, education, APOE genotype, and diabetes complication severity index. Results: Adjusted analyses showed no significant association between any drug class and traditional neuropathologic measures compared to nonusers of that class. In adjusted Histelide analyses, any insulin use was associated with lower mean levels of Aβ1–42 (–0.57 (CI: –1.12, –0.02)) compared to nonusers. Five years of sulfonylureas and of biguanides use was associated with lower levels of Aβ1–42 compared to nonusers (–0.15 (CI: –0.28, –0.02), –0.31 (CI: –0.54, –0.07), respectively). Conclusion: Some evidence exists that diabetes medications are associated with lower levels of Aβ1–42, but not traditional measures of neuropathology. Future studies are needed in larger samples to build understanding of the mechanisms between diabetes, its medications, and ADRD, and to potentially repurpose existing medications for prevention or delay of ADRD.