Adult Changes In Thought Study Research Articles

Traffic-related air pollution and dementia incidence in the Adult Changes in Thought Study

BackgroundWhile epidemiologic evidence links higher levels of exposure to fine particulate matter (PM2.5) to decreased cognitive function, fewer studies have investigated links with traffic-related air pollution (TRAP), and none have examined ultrafine particles (UFP, ≤100 nm) and late-life dementia incidence. ObjectiveTo evaluate associations between TRAP exposures (UFP, black carbon [BC], and nitrogen dioxide [NO2]) and late-life dementia incidence. MethodsWe ascertained dementia incidence in the Seattle-based Adult Changes in Thought (ACT) prospective cohort study (beginning in 1994) and assessed ten-year average TRAP exposures for each participant based on prediction models derived from an extensive mobile monitoring campaign. We applied Cox proportional hazards models to investigate TRAP exposure and dementia incidence using age as the time axis and further adjusting for sex, self-reported race, calendar year, education, socioeconomic status, PM2.5, and APOE genotype. We ran sensitivity analyses where we did not adjust for PM2.5 and other sensitivity and secondary analyses where we adjusted for multiple pollutants, applied alternative exposure models (including total and size-specific UFP), modified the adjustment covariates, used calendar year as the time axis, assessed different exposure periods, dementia subtypes, and others. ResultsWe identified 1,041 incident all-cause dementia cases in 4,283 participants over 37,102 person-years of follow-up. We did not find evidence of a greater hazard of late-life dementia incidence with elevated levels of long-term TRAP exposures. The estimated hazard ratio of all-cause dementia was 0.98 (95 % CI: 0.92–1.05) for every 2000 pt/cm3 increment in UFP, 0.95 (0.89–1.01) for every 100 ng/m3 increment in BC, and 0.96 (0.91–1.02) for every 2 ppb increment in NO2. These findings were consistent across sensitivity and secondary analyses. DiscussionWe did not find evidence of a greater hazard of late-life dementia risk with elevated long-term TRAP exposures in this population-based prospective cohort study.

A genome‐wide association study of LATE‐NC (limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change) reveals a distinct genetic architecture

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is the third leading cause of late‐life dementia. However, its pathophysiology remains largely unknown, and the relationship of LATE‐NC with Alzheimer’s disease (AD) pathology and frontotemporal lobar degeneration‐TDP (FTLD‐TDP) remains unclear. To address this knowledge gap, we performed a genome‐wide association study (GWAS) of LATE‐NC.MethodDeceased participants of European ancestry from the Religious Orders Study, the Rush Memory and Aging Project (ROSMAP, n = 1,379), and the Adult Changes in Thought study (ACT, n = 459) were included in our study. The primary phenotypes were LATE‐NC burden (a multi‐regional semi‐quantitative TDP‐43 composite, continuous) in ROSMAP, and the presence/absence of LATE‐NC (binary) in ACT, assessed with post‐mortem TDP‐43 immunohistochemistry. Quantitative amyloid‐β (Aβ) and paired helical filament tau (PHFtau) burden were also examined in ROSMAP. GWAS was performed using linear (ROSMAP) or logistic (ACT) additive models. We controlled age, sex, genotyping platforms, and the first three genotype principal components. Sample size‐weighted GWAS meta‐analysis (total n = 1,838) was performed by combining p‐values considering the direction of the association. Confounding and moderating effects of AD pathology on LATE‐NC risk variants were examined in ROSMAP.ResultWe observed two genome‐wide significant risk loci (p<5.0×10−8) in APOE (ε4) and SHANK2 (s146617441G, allele frequency 0.021). In ROSMAP, APOE ε4 was associated with higher LATE‐NC burden after controlling for quantitative Aβ and PHFtau (beta = 0.27, p = 7.3×10−6), and the APOE ε4 – LATE‐NC association was present in the subgroup without detectable Aβ (n = 170, beta = 0.50, p = 0.025). rs146617441G was not directly associated with quantitative Aβ or tau. Instead, rs146617441G×Aβ interaction term was associated with higher LATE‐NC burden (beta = 0.25, p = 0.032), suggesting the synergy between Aβ‐dependent and LATE‐NC‐specific pathways in LATE‐NC pathogenesis. Three additional loci reached a pre‐specified suggestive p‐value threshold (p<1.0×10−6; CMTM7 [rs56284874G], RNF145 [rs111653954T], and CACNA2D3 [rs71303704C]). A previously reported FTLD‐TDP risk locus in TMEM106B (rs1990622A) showed a weaker positive association with LATE‐NC (meta‐analysis p = 9.6×10−4).ConclusionOur GWAS revealed LATE‐NC‐specific risk loci (SHANK2 and other suggestive loci). The unique genetic architecture of LATE‐NC further supports the distinction between LATE‐NC and FTLD‐TDP, and the AD‐independent effect of APOE ε4 on LATE‐NC highlights the pleiotropic role of APOE in neurodegeneration.

Association of Perceived Neighborhood Environments With Cognitive Function in Older Adults.

The current study examined the associations between perceptions of the social and physical neighborhood environments and cognitive function in older adults. This cross-sectional study analyzed 821 adults aged ≥65 years from the Adult Changes in Thought study. Perceived neighborhood attributes were measured by the Physical Activity Neighborhood Environment Scale. Cognitive function was assessed using the Cognitive Ability Screening Instrument. The associations were tested using multivariate linear regression. One point greater perceived access to public transit was associated with 0.56 points greater cognitive function score (95% confidence interval [CI] [0.25, 0.88]), and an additional one point of perceived sidewalk coverage was related to 0.22 points higher cognitive function score (95% CI [0.00, 0.45]) after controlling for sociodemographic factors. The perception of neighborhood attributes alongside physical infrastructure may play an important role in supporting older adults' cognitive function. [Journal of Gerontological Nursing, 49(8), 35-41.].

Large‐scale quantitative neuropathological analysis across the spectrum of Alzheimer’s disease neuropathologic change

AbstractBackgroundWhile traditional histologic neuropathological assessment of neurodegenerative disease has tremendous diagnostic value, insights into neurodegeneration’s pathophysiological underpinnings can be significantly enhanced with large‐scale quantitative analyses. As part of the Seattle Alzheimer’s Disease Brain Cell Atlas (SEA‐AD), we present a neuropathology dataset across 84 brains spanning the spectrum of AD neuropathologic change donated by UW Alzheimer’s Disease Research Center and Adult Changes in Thought study participants.MethodHuman brain tissue was collected at rapid autopsy (postmortem interval <12 hours). One hemisphere (randomly selected) was embedded in alginate for uniform coronal slicing (4mm), with alternating slabs fixed in 10% neutral buffered formalin or frozen in a dry ice isopentane slurry. Superior and Middle Temporal Gyrus (MTG) was sampled from fixed slabs and subjected to standard processing, embedding, sectioning (5µm), histochemical (H&E/Luxol fast blue), and immunohistochemical (duplex pTau and pTDP‐43, Aβ and Iba1, and monoplex GFAP, a‐synuclein, and NeuN) labeling. HALO image analysis software (Indica Labs, Albuquerque NM) was used to define and quantify relevant cellular and pathological features within each cortical layer (Figures 1‐3).Result84 individuals were included in these analyses (Table 1).While quantitative metrics of pTau and Aβ aligned with traditional neuropathological measures, they showed substantial variability within discrete diagnostic stages (Figure 4). These findings were robust to quantification (discrete count vs. total area stained) and normalization (total nuclei vs. total area analyzed) methods, and highlight the importance of deploying highly quantitative, continuous measures of pathology in the study of neurodegeneration. This unique resource provides spatially preserved measures of pathologic burden across the spectrum of AD with potential for correlative analysis across pathologies, clinical and biomarker parameters, and omics applications to better support the identification of vulnerable cell types in early stages of AD progression, the principal goal of SEA‐AD.ConclusionHere we present a large‐scale quantitative neuropathology dataset, which enables analysis of pathological proteins and cell types at unprecedented scale and accuracy. Little is known about the interactions of AD‐relevant cell types with pathologic peptides across disease progression. The presented analyses exemplify the potential of this unique publicly‐accessible resource to identify and quantify novel disease‐relevant relationships.

Association of Traumatic Brain Injury with Late Life Neuropathological Outcomes in a Community-Based Cohort.

Prior studies into the association of head trauma with neuropathology have been limited by incomplete lifetime neurotrauma exposure characterization. To investigate the neuropathological sequelae of traumatic brain injury (TBI) in an autopsy sample using three sources of TBI ascertainment, weighting findings to reflect associations in the larger, community-based cohort. Self-reported head trauma with loss of consciousness (LOC) exposure was collected in biennial clinic visits from 780 older adults from the Adult Changes in Thought study who later died and donated their brain for research. Self-report data were supplemented with medical record abstraction, and, for 244 people, structured interviews on lifetime head trauma. Neuropathology outcomes included Braak stage, CERAD neuritic plaque density, Lewy body distribution, vascular pathology, hippocampal sclerosis, and cerebral/cortical atrophy. Exposures were TBI with or without LOC. Modified Poisson regressions adjusting for age, sex, education, and APOE ɛ4 genotype were weighted back to the full cohort of 5,546 participants. TBI with LOC was associated with the presence of cerebral cortical atrophy (Relative Risk 1.22, 95% CI 1.02, 1.42). None of the other outcomes was associated with TBI with or without LOC. TBI with LOC was associated with increased risk of cerebral cortical atrophy. Despite our enhanced TBI ascertainment, we found no association with the Alzheimer's disease-related neuropathologic outcomes among people who survived to at least age 65 without dementia. This suggests the pathophysiological processes underlying post-traumatic neurodegeneration are distinct from the hallmark pathologies of Alzheimer's disease.

Expanding the ethnographic toolkit: Using medical documents to include kinless older adults living with dementia in qualitative research

Ethnographic research with cognitively impaired older adults can be challenging, in part because cognitive impairment raises questions about the ability to provide informed consent. Relying on proxy consent is a commonly used strategy, but often excludes people with dementia who lack close kin (de Medeiros, Girling, & Berlinger, 2022). In this paper, we describe how we have analyzed existing research data from a well-established and ongoing prospective cohort study, the Adult Changes in Thought Study, along with unstructured text from the medical records of participants who had no living spouse or adult children when they developed dementia, as a way of studying the circumstances, life trajectories, caregiving resources, and care needs of this vulnerable and difficult-to-research group. In this article, we detail this methodology, exploring what can and cannot be gleaned from it, what the ethical implications may be, and how and whether this type of research can be considered ethnographic. In conclusion, we argue that collaborative interdisciplinary research using existing, longitudinal research data and text from medical records deserves to be considered as a potentially useful addition to the ethnographic toolkit. We anticipate that this is a methodology that could be applied more broadly, and paired with more traditional ethnographic methods, might be one way to make research with this population more inclusive.

Cognitive domain harmonization and cocalibration in studies of older adults.

Studies use different instruments to measure cognitirating cognitive tests permit direct comparisons of individuals across studies and pooling data for joint analyses. We began our legacy item bank with data from the Adult Changes in Thought study (n = 5,546), the Alzheimer's Disease Neuroimaging Initiative (n = 3,016), the Rush Memory and Aging Project (n = 2,163), and the Religious on such as the Mini-Mental State Examination, the Alzheimer's Disease Assessment Scale-Cognitive Subscale, the Wechsler Memory Scale, and the Boston Naming Test. CocalibOrders Study (n = 1,456). Our workflow begins with categorizing items administered in each study as indicators of memory, executive functioning, language, visuospatial functioning, or none of these domains. We use confirmatory factor analysis models with data from the most recent visit on the pooled sample across these four studies for cocalibration and derive item parameters for all items. Using these item parameters, we then estimate factor scores along with corresponding standard errors for each domain for each study. We added additional studies to our pipeline as available and focused on thorough consideration of candidate anchor items with identical content and administration methods across studies. Prestatistical harmonization steps such qualitative and quantitative assessment of granular cognitive items and evaluating factor structure are important steps when trying to cocalibrate cognitive scores across studies. We have cocalibrated cognitive data and derived scores for four domains for 76,723 individuals across 10 studies. We have implemented a large-scale effort to harmonize and cocalibrate cognitive domain scores across multiple studies of cognitive aging. Scores on the same metric facilitate meta-analyses of cognitive outcomes across studies or the joint analysis of individual data across studies. Our systematic approach allows for cocalibration of additional studies as they become available and our growing item bank enables robust investigation of cognition in the context of aging and dementia. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Analysis of the 24-h activity cycle: An illustration examining the association with cognitive function in the Adult Changes in Thought study.

The 24-h activity cycle (24HAC) is a new paradigm for studying activity behaviors in relation to health outcomes. This approach inherently captures the interrelatedness of the daily time spent in physical activity (PA), sedentary behavior (SB), and sleep. We describe three popular approaches for modeling outcome associations with the 24HAC exposure. We apply these approaches to assess an association with a cognitive outcome in a cohort of older adults, discuss statistical challenges, and provide guidance on interpretation and selecting an appropriate approach. We compare the use of the isotemporal substitution model (ISM), compositional data analysis (CoDA), and latent profile analysis (LPA) to analyze 24HAC. We illustrate each method by exploring cross-sectional associations with cognition in 1,034 older adults (Mean age = 77; Age range = 65-100; 55.8% female; 90% White) who were part of the Adult Changes in Thought (ACT) Activity Monitoring (ACT-AM) sub-study. PA and SB were assessed with thigh-worn activPAL accelerometers for 7-days. For each method, we fit a multivariable regression model to examine the cross-sectional association between the 24HAC and Cognitive Abilities Screening Instrument item response theory (CASI-IRT) score, adjusting for baseline characteristics. We highlight differences in assumptions and the scientific questions addressable by each approach. ISM is easiest to apply and interpret; however, the typical ISM assumes a linear association. CoDA uses an isometric log-ratio transformation to directly model the compositional exposure but can be more challenging to apply and interpret. LPA can serve as an exploratory analysis tool to classify individuals into groups with similar time-use patterns. Inference on associations of latent profiles with health outcomes need to account for the uncertainty of the LPA classifications, which is often ignored. Analyses using the three methods did not suggest that less time spent on SB and more in PA was associated with better cognitive function. The three standard analytical approaches for 24HAC each have advantages and limitations, and selection of the most appropriate method should be guided by the scientific questions of interest and applicability of each model's assumptions. Further research is needed into the health implications of the distinct 24HAC patterns identified in this cohort.

Harmonization of neuropathology measures and characterization of neuropathological burden across population‐based autopsy samples

AbstractBackgroundMost autopsy samples are based on clinical cohorts or case series; the distribution of neuropathologies may be biased in these samples compared to the general population. A small number of population‐based neuropathology cohorts address these concerns but are often limited by small sample sizes and restrictions to specific geographic locations or groups. Harmonization would allow comparisons across settings and increases in precision of estimates.MethodWe leveraged data from the Religious Orders Study and Memory and Aging Project (N=1882), the Adult Changes in Thought study (N=721), the Cognitive Function and Ageing Studies (N=444), and the Cambridge City over‐75s Cohort Study (N=241). First, we identified measures in common across cohorts or a subset of cohorts and documented protocol differences. We characterized distributions of pathologies by age group (80‐89 vs. 90+) and quantified correlations between pathologies using polychoric correlations. We described overlap between pathologies for five key measures (CERAD neuritic plaques, Braak stage, macro‐ and micro‐infarcts, and Lewy body disease).ResultWe harmonized measures of 10 pathologies available in at least 3/4 studies (7 across all studies). Distributions of Alzheimer’s disease (AD) pathologies (CERAD neuritic plaques, Braak stage) varied less across cohorts (Range [Severe CERAD]=33%); Range [Braak stage V‐VI]=22%) than distributions of vascular disease pathology such as atherosclerosis (Range [Moderate‐Severe Atherosclerosis]=51%). After meta‐analyzing correlations across studies, we found strong correlations between AD pathological features (r=0.70,p<0.001: Braak stage and CERAD neuritic plaque score) and moderate correlations between vascular features (e.g. r=0.34,p<0.001: macro‐ and micro‐infarcts). There was also evidence of small correlations between AD features and other neuropathology measures (r=0.21,p<0.001: CERAD neuritic plaque score and hippocampal sclerosis). Pooling data across cohorts, out of five key measures, 69% of the sample had two or more co‐occuring pathologies (2=39%, 3=23%, 4=6%, 5=1%).ConclusionHarmonization and data pooling was feasible across a range of measures; however, we found that measures of AD pathology appear more standardized. Higher variability in vascular measures may partly reflect a lack of standardized criteria for quantification. Strong correlations and frequent co‐occurrence between measures highlights the complexity and multi‐morbidity of the brain pathologies thought to underlie dementia in older adults.

Association Between Cataract Extraction and Development of Dementia

Visual function is important for older adults. Interventions to preserve vision, such as cataract extraction, may modify dementia risk. To determine whether cataract extraction is associated with reduced risk of dementia among older adults. This prospective, longitudinal cohort study analyzed data from the Adult Changes in Thought study, an ongoing, population-based cohort of randomly selected, cognitively normal members of Kaiser Permanente Washington. Study participants were 65 years of age or older and dementia free at enrollment and were followed up biennially until incident dementia (all-cause, Alzheimer disease, or Alzheimer disease and related dementia). Only participants who had a diagnosis of cataract or glaucoma before enrollment or during follow-up were included in the analyses (ie, a total of 3038 participants). Data used in the analyses were collected from 1994 through September 30, 2018, and all data were analyzed from April 6, 2019, to September 15, 2021. The primary exposure of interest was cataract extraction. Data on diagnosis of cataract or glaucoma and exposure to surgery were extracted from electronic medical records. Extensive lists of dementia-related risk factors and health-related variables were obtained from study visit data and electronic medical records. The primary outcome was dementia as defined by Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria. Multivariate Cox proportional hazards regression analyses were conducted with the primary outcome. To address potential healthy patient bias, weighted marginal structural models incorporating the probability of surgery were used and the association of dementia with glaucoma surgery, which does not restore vision, was evaluated. In total, 3038 participants were included (mean [SD] age at first cataract diagnosis, 74.4 (6.2) years; 1800 women (59%) and 1238 men (41%); and 2752 (91%) self-reported White race). Based on 23 554 person-years of follow-up, cataract extraction was associated with significantly reduced risk (hazard ratio, 0.71; 95% CI, 0.62-0.83; P < .001) of dementia compared with participants without surgery after controlling for years of education, self-reported White race, and smoking history and stratifying by apolipoprotein E genotype, sex, and age group at cataract diagnosis. Similar results were obtained in marginal structural models after adjusting for an extensive list of potential confounders. Glaucoma surgery did not have a significant association with dementia risk (hazard ratio, 1.08; 95% CI, 0.75-1.56; P = .68). Similar results were found with the development of Alzheimer disease dementia. This cohort study found that cataract extraction was significantly associated with lower risk of dementia development. If validated in future studies, cataract surgery may have clinical relevance in older adults at risk of developing dementia.

Very long term visit‐to‐visit blood pressure variability and the risk of dementia in the Adult Changes in Thought study

AbstractBackgroundHigh visit‐to‐visit blood pressure variability (BPV) is associated with an increased risk of cardiovascular disease. However, for incident dementia, conflicting results are reported. Our objective was to assess the association of very long‐term visit‐to‐visit BPV and the risk of all‐cause dementia in community‐dwelling individuals.MethodCommunity‐dwelling individuals aged 65 years or older and free from dementia were randomly sampled from 1994 onwards from Kaiser Permanente Washington (KPW), Seattle, USA, and included in the Adult Changes in Thought (ACT) study. After enrollment, participants were followed‐up biannually. We retrospectively collected yearly data on blood pressure measurements and medical history from the age of 50 up to recruitment into the ACT study, through KPW electronic databases. Visit‐to‐visit BPV was defined as coefficient of variation (SD/mean*100) calculated with systolic blood pressure measurements. Dementia was diagnosed by an expert panel based on DSM‐IV and NINCDS‐ADRDA criteria. We used Cox regression adjusted for sex, blood pressure trend, antihypertensive medication use and cardiovascular risk factors. Subgroup analyses were performed for midlife (50‐64) and later life (≥65).ResultWe included 1174 individuals with a median age of 78 years [IQR=72‐83] at inclusion in the ACT study. Systolic blood pressure measurements (mean=27.9, SD=8.5, range: 2‐50) were collected over 2 to 54 years (mean=31.8, SD=9.4), and 483 (41.1%) individuals developed dementia. There was no significant association between very long term visit‐to‐visit BPV (mean=12.15; SD=2.67) and incident all‐cause dementia (HR=0.98; 95%CI=0.94‐1.02). Competing risk of death analyses (combined outcome dementia/death) showed a dementia/mortality risk reduction of 4% per point visit‐to‐visit BPV increase (HR=0.96; 95%CI=0.94‐0.99). The associations were similar for visit‐to‐visit BPV in later life (dementia: HR=0.99; 95%CI=0.95‐1.02, dementia/death: HR=0.96; 95%CI=0.93‐0.99). Visit‐to‐visit BPV in midlife was not associated with incident dementia (dementia: HR=0.99; 95%CI=0.96‐1.02, dementia/death: HR=1.01; 95%CI=0.99‐1.02).ConclusionIn our sample, higher very long‐term visit‐to‐visit BPV is associated with lower incident all‐cause dementia risks. This association might be stronger in later life than in midlife.

Change in central nervous system-active medication use following fall-related injury in older adults.

Central nervous system (CNS)-active medication use is an important modifiable risk factor for falls in older adults. A fall-related injury should prompt providers to evaluate and reduce CNS-active medications to prevent recurrent falls. We evaluated change in CNS-active medications up to 12 months following a fall-related injury in community-dwelling older adults compared with a matched cohort without fall-related injury. Participants were from the Adult Changes in Thought study conducted at Kaiser Permanente Washington. Fall-related injury codes between 1994 and 2014 defined index encounters in participants with no evidence of such injuries in the preceding year. We matched each fall-related injury index encounter with up to five randomly selected clinical encounters from participants without injury. Using automated pharmacy data, we estimated the average change in CNS-active medication use at 3, 6, and 12 months post-index according to the presence or absence of CNS-active medication use before index. One thousand five hundred sixteen participants with fall-related injury index encounters (449 CNS-active users, 1067 nonusers) were matched to 7014 index encounters from people without fall-related injuries (1751 users, 5236 nonusers). Among CNS-active users at the index encounter, those with fall-related injury had an average decrease in standard daily doses (SDDs) at 12 months (-0.43; 95% CI: -0.63 to -0.23), and those without injury had a greater (p= 0.047) average decrease (-0.66; 95% CI: -0.78 to -0.55). Among nonusers at index, those with fall-related injury had a smaller increase than those without injury (+0.17, 95% CI: +0.13 to +0.21, vs. +0.24, 95% CI: +0.20 to +0.28, p= 0.005). The differences in CNS-active medication use change over 12 months between those with and without fall-related injury were small and unlikely to be clinically significant. These results suggest that fall risk-increasing drug use is not reduced following a fall-related injury, thus opportunities exist to reduce CNS-active medications, a potentially modifiable risk factor for falls.

Association of Performance on Dichotic Auditory Tests With Risk for Incident Dementia and Alzheimer Dementia

Age-related hearing difficulties can include problems with signal audibility and central auditory processing. Studies have demonstrated associations between audibility and dementia risk. To our knowledge, limited data exist to determine whether audibility, central processing, or both drive these associations. To determine the associations between signal sensitivity, central auditory processing, and dementia and Alzheimer dementia (AD) risk. This follow-up observational study of a sample from the prospective Adult Changes in Thought study of dementia risk was conducted at Kaiser Permanente Washington, a western Washington health care delivery system, and included 280 volunteer participants without dementia who were evaluated from October 2003 to February 2006 with follow-up through September 2018. Analyses began in 2019 and continued through 2021. Hearing tests included pure tone signal audibility, a monaural word recognition test, and 2 dichotic tests: the Dichotic Sentence Identification (DSI) test and the Dichotic Digits test (DDT). Cognition was assessed biennially with the Cognitive Abilities Screening Instrument (range, 1-100; higher scores are better), and scores of less than 86 prompted clinical and neuropsychological evaluations. All data were reviewed at multidisciplinary consensus conferences, and standardized criteria were used to define incident cases of dementia and probable or possible AD. Cox proportional hazard models were used to determine associations with hearing test performance. A total of 280 participants (177 women [63%]; mean [SD] age, 79.5 [5.2] years). As of September 2018, there were 2196 person-years of follow-up (mean, 7.8 years) and 89 incident cases of dementia (66 not previously analyzed), of which 84 (94.4%) were AD (63 not previously analyzed). Compared with people with DSI scores of more than 80, the dementia adjusted hazard ratio (aHR) for DSI scores of less than 50 was 4.18 (95% CI, 2.37-7.38; P < .001); for a DSI score of 50 to 80, it was 1.82 (95% CI, 1.10-3.04; P = .02). Compared with people with DDT scores of more than 80, the dementia aHR for DDT scores of less than 50 was 2.66 (95% CI, 1.31-5.42; P = .01); for a DDT score of 50 to 80, it was 2.40 (95% CI, 1.45-3.98; P = .001). The AD results were similar. Pure tone averages were weakly and insignificantly associated with dementia and AD, and associations were null when controlling for DSI scores. In this cohort study, abnormal central auditory processing as measured by dichotic tests was independently associated with dementia and AD risk.

Invited Perspective: Air Pollution and Dementia: Challenges and Opportunities.

Invited Perspective: Air Pollution and Dementia: Challenges and Opportunities.

Fine Particulate Matter and Dementia Incidence in the Adult Changes in Thought Study.

Background:Air pollution may be associated with elevated dementia risk. Prior research has limitations that may affect reliability, and no studies have evaluated this question in a population-based cohort of men and women in the United States.Objectives:We evaluated the association between time-varying, 10-y average fine particulate matter () exposure and hazard of all-cause dementia. An additional goal was to understand how to adequately control for age and calendar-time-related confounding through choice of the time axis and covariate adjustment.Methods:Using the Adult Changes in Thought (ACT) population-based prospective cohort study in Seattle, we linked spatiotemporal model-based exposures to participant addresses from 1978 to 2018. Dementia diagnoses were made using high-quality, standardized, consensus-based protocols at biennial follow-ups. We conducted multivariable Cox proportional hazards regression to evaluate the association between time-varying, 10-y average exposure and time to event in a model with age as the time axis, stratified by apolipoprotein E (APOE) genotype, and adjusted for sex, education, race, neighborhood median household income, and calendar time. Alternative models used calendar time as the time axis.Results:We report 1,136 cases of incident dementia among 4,166 individuals with nonmissing APOE status. Mean [mean ± standard deviation (SD)] 10-y average was . Each increase in the moving average of 10-y was associated with a 16% greater hazard of all-cause dementia [1.16 (95% confidence interval: 1.03, 1.31)]. Results using calendar time as the time axis were similar.Discussion:In this prospective cohort study with extensive exposure data and consensus-based outcome ascertainment, elevated long-term exposure to was associated with increased hazard of all-cause dementia. We found that optimal control of age and time confounding could be achieved through use of either age or calendar time as the time axis in our study. Our results strengthen evidence on the neurodegenerative effects of . https://doi.org/10.1289/EHP9018

Application of deep learning to understand resilience to Alzheimer's disease pathology.

People who have Alzheimer's disease neuropathologic change (ADNC) typically associated with dementia but not the associated cognitive decline can be considered to be “resilient” to the effects of ADNC. We have previously reported lower neocortical levels of hyperphosphorylated tau (pTau) and less limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) in the resilient participants compared to those with dementia and similar ADNC as determined by current NIA‐AA recommendations using traditional semi‐quantitative assessments of amyloid β and pathological tau burden. To better understand differences between AD‐dementia and resilient participants, we developed and applied a deep learning approach to analyze the neuropathology of 14 brain donors from the Adult Changes in Thought study, including seven stringently defined resilient participants and seven age‐matched AD‐dementia controls. We created two novel, fully automated deep learning algorithms to quantify the level of phosphorylated TDP‐43 (pTDP‐43) and pTau in whole slide imaging. The models performed better than traditional techniques for quantifying pTDP‐43 and pTau. The second model was able to segment lesions staining for pTau into neurofibrillary tangles (NFTs) and tau neurites (neuronal processes positive for pTau). Both groups had similar quantities of pTau localizing to neurites, but the pTau burden associated with NFTs in the resilient group was significantly lower compared to the group with dementia. These results validate use of deep learning approaches to quantify clinically relevant microscopic characteristics from neuropathology workups. These results also suggest that the burden of NFTs is more strongly associated with cognitive impairment than the more diffuse neuritic tau commonly seen with tangle pathology and suggest that additional factors may underlie resilience mechanisms defined by traditional means.

Modeling semi-competing risks data as a longitudinal bivariate process.

As individuals age, death is a competing risk for Alzheimer's disease (AD) but the reverse is not the case. As such, studies of AD can be placed within the semi-competing risks framework. Central to semi-competing risks, and in contrast to standard competing risks , is that one can learn about the dependence structure between the two events. To-date, however, most methods for semi-competing risks treat dependence as a nuisance and not a potential source of new clinical knowledge. We propose a novel regression-based framework that views the two time-to-event outcomes through the lens of a longitudinal bivariate process on a partition of the time scales of the two events. A key innovation of the framework is that dependence is represented in two distinct forms, local and global dependence, both of which have intuitive clinical interpretations. Estimation and inference are performed via penalized maximum likelihood, and can accommodate right censoring, left truncation, and time-varying covariates. An important consequence of the partitioning of the time scale is that an ambiguity regarding the specific form of the likelihood contribution may arise; a strategy for sensitivity analyses regarding this issue is described. The framework is then used to investigate the role of gender and having ≥1 apolipoprotein E (APOE) ε4 allele on the joint risk of AD and death using data from the Adult Changes in Thoughtstudy.

Incident Dementia, Glycated Hemoglobin (HbA1c) Levels, and Potentially Preventable Hospitalizations in People Aged 65 and Older With Diabetes.

This study was aimed to determine whether incident dementia and HbA1c levels are associated with increased rates of potentially preventable hospitalizations (PPHs) in persons with diabetes. A total of 565 adults aged 65+ ever treated for diabetes were enrolled from Adult Changes in Thought study. PPHs were from principal discharge diagnoses and included diabetes PPH (dPPH), respiratory PPH (rPPH), urinovolemic PPH (uPPH), cardiovascular PPH, and other PPH. Poisson generalized estimating equations estimated rate ratios (RRs) and 95% confidence intervals (CIs) for the associations between dementia or HbA1c measures and rate of PPHs. A total of 562 individuals contributed 3 602 dementia-free years, and 132 individuals contributed 511 dementia follow-up years. One hundred twenty-eight (23%) dementia-free individuals had 210 PPH admissions and a crude rate of 58 per 1 000 person-years, while 55 (42%) individuals with dementia had 93 PPH admissions and a crude rate of 182 per 1 000 person-years. The adjusted RR (95% CI) comparing rates between dementia and dementia-free groups were 2.27 (1.60, 3.21) for overall PPH; 5.90 (2.70, 12.88) for dPPH; 5.17 (2.49, 10.73) for uPPH; and 2.01 (1.06, 3.83) for rPPH. Compared with HbA1c of 7%-8% and adjusted for dementia, the RR (95% CI) for overall PPH was 1.43 (1.00, 2.06) for >8% HbA1c and 1.18 (0.85, 1.65) for <7% HbA1c. The uPPH RR was also increased, comparing >8% and <7% HbA1c levels. Incident dementia is associated with higher rates of PPHs among people with diabetes, especially PPHs due to diabetes, urinary tract infection (UTI), and dehydration. Potential evidence suggested that HbA1c levels of >8% versus lower levels are associated with higher rates of overall PPHs and UTI- and dehydration-related PPHs.

Community-Dwelling Older Adults and Physical Activity Recommendations: Patterns of Aerobic, Strengthening, and Balance Activities.

Though it is known that most older adults do not meet the recommended physical activity (PA) guidelines, little is known regarding their participation in balance activities or the full guidelines. Therefore, we sought to describe PA patterns among 1,352 community-dwelling older adult participants of the Adult Changes in Thought study, a longitudinal cohort study exploring dementia-related risk factors. We used a modified version of the Community Healthy Activities Model Program for Seniors questionnaire to explore PA performed and classify participants as meeting or not meeting the full guidelines or any component of the guidelines. Logistic regression was used to identify factors associated with meeting PA guidelines. Despite performing 10hr of weekly PA, only 11% of participants met the full guidelines. Older age, greater body mass index, needing assistance with instrumental daily activities, and heart disease were associated with decreased odds of meeting PA guidelines. These results can guide interventions that address PA among older adults.

Association of remote traumatic brain injury and military employment with late-life trajectories of depressive symptom severity

BackgroundTraumatic brain injury (TBI) and military service are common lifetime exposures among current older adults that may affect late-life mental health. The objective of the present study was to evaluate the association between TBI with loss of consciousness (LOC) and military employment and late-life depressive symptom severity trajectory. Methods1445 males and 2096 females adults at least 65 years old without dementia or recent TBI were enrolled and followed biennially for up to 10 years in the Adult Changes in Thought study from Kaiser Permanente Washington in Seattle, Washington. ResultsUsing group-based trajectory modeling, we documented four distinct depressive symptom severity trajectories that followed a similar course in males and females (Minimal, Decreasing, Increasing, and Persistent). In multinomial regression analyses, TBI with LOC in males was associated with greater likelihood of Persistent versus Minimal depressive symptom severity compared to individuals without TBI (OR = 1.51, 95% CI: 1.01, 2.27; p=0.046). Males reporting past military employment had greater likelihood of Decreasing versus Minimal depressive symptom severity compared to individuals without past military employment (OR = 1.54, 95% CI: 1.03, 2.31; p=0.035). There was no association between TBI or military employment and depression trajectories in females, and no evidence of effect modification by age or between exposures. LimitationsLifetime history of TBI was ascertained retrospectively and may be subject to recall bias. Also, past military employment does not presuppose combat exposure. ConclusionsRemote TBI and past military employment are relevant to late-life trajectories of depressive symptom severity in dementia-free older males.