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

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

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

Purpose. To characterize societal participation profiles after moderate-severe traumatic brain injury (TBI) along objective (Frequency) and subjective (Satisfaction, Importance, Enfranchisement) dimensions. Materials and Methods. We conducted secondary analyses of a TBI Model Systems sub-study (N = 408). Multiaxial assessment of participation included the Participation Assessment with Recombined Tools-Objective and -Subjective questionnaires (Participation Frequency and Importance/Satisfaction, respectively) and the Enfranchisement Scale. Participants provided responses via telephone interview 1–15 years post-injury. Multidimensional participation profiles (classes) were extracted using latent profile analysis. Results. A 4-class solution was identified as providing maximal statistical separation between profiles and being clinically meaningful based on profile demographic features. One profile group (48.5% of the sample) exhibited the "best" participation profile (High Frequency, Satisfaction, Importance, and Enfranchisement) and was also the most advantaged according to socioeconomic indicators. Other profile groups showed appreciable heterogeneity across participation dimensions. Age, race/ethnicity, education level, ability to drive, and urbanicity were features that varied between profiles. Conclusions. Societal participation is a critical, but inherently complex, TBI outcome that may not be adequately captured by a single index. Our data underscore the importance of a multidimensional approach to participation assessment and interpretation using profiles. The use of participation profiles may promote precision health interventions for community integration. Our study found unidimensional measures of societal participation in traumatic brain injury (TBI) populations that focus exclusively on frequency indicators may be overly simplistic and miss key subjective components of participation Taking a multidimensional perspective, we documented four meaningfully distinct participation subgroups (including both objective and subjective dimensions of societal participation) within the TBI rehabilitation population Multidimensional profiles of participation may be used to group individuals with TBI into target groups for intervention (e.g., deeper goal assessment for individuals who do not rate standard participation activities as important, but also do not participate and do not feel enfranchised). [ABSTRACT FROM AUTHOR]

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

For many years, experts have recognized the importance of studying traumatic brain injury (TBI) among active-duty service members and veterans. A majority of this research has been conducted in Veterans Administration (VA) or Department of Defense settings. However, far less is known about military personnel who seek their medical care outside these settings. Studies that have been conducted in civilian settings have either not enrolled active duty or veteran participants, or failed to measure military history, precluding study of TBI outcomes by military history. The purpose of the present study was to determine associations between military history and medical (prevalence of 25 comorbid health conditions), cognition (Brief Test of Adult Cognition by Telephone), and psychological health (Patient Health Questionnaire-9 [PHQ-9], Generalized Anxiety Disorder-7, suicidality [9th item from PHQ-9]) in the first 5 years after TBI. In this prospective study, we analyzed data from the TBI Model Systems National Database. Participants were 7797 individuals with TBI admitted to one of 21 civilian inpatient rehabilitation facilities from April 1, 2010, to November 19, 2020, and followed up to 5 years. We assessed the relationship between military history (any versus none, combat exposure, service era, and service duration) and TBI outcomes. We found specific medical conditions were significantly more prevalent 1 year post-TBI among individuals who had a history of combat deployment (lung disorders, post-traumatic stress disorder [PTSD], and sleep disorder), served in post-draft era (chronic pain, liver disease, arthritis), and served >4 years (high cholesterol, PTSD, sleep disorder). Individuals with military history without combat deployment had modestly more favorable cognition and psychological health in the first 5 years post-injury relative to those without military history. Our data suggest that individuals with TBI with military history are heterogeneous, with some favorable and other deleterious health outcomes, relative to their non-military counterparts, which may be driven by characteristics of service, including combat exposure and era of service. [ABSTRACT FROM AUTHOR]

Background: Prior studies into the association of head trauma with neuropathology have been limited by incomplete lifetime neurotrauma exposure characterization. Objective: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate associations between depression, anxiety, and cognitive impairment among individuals with complicated mild to severe traumatic brain injury (TBI) 1 year after injury. Setting: Multiple inpatient rehabilitation units across the United States. Participants: A total of 498 adults 16 years and older who completed inpatient rehabilitation for complicated mild to severe TBI. Design: Secondary analysis of a prospective, multicenter, cross-sectional observational cohort study. Main Measures: Assessments of depression (Traumatic Brain Injury Quality of Life [TBI-QOL] Depression) and anxiety (TBI-QOL Anxiety) as well as a telephone-based brief screening measure of cognitive functioning (Brief Test of Adult Cognition by Telephone [BTACT]). Results: We found an inverse relationship between self-reported depression symptoms and the BTACT Composite score (β = −0.18, P <.01) and anxiety symptoms and the BTACT Composite score (β = −0.20, P <.01). There was no evidence this relationship varied by injury severity. Exploratory analyses showed depression and anxiety were negatively correlated with both BTACT Executive Function factor score and BTACT Memory factor score. Conclusions: Both depression and anxiety have a small but significant negative association with cognitive performance in the context of complicated mild to severe TBI. These findings highlight the importance of considering depression and anxiety when interpreting TBI-related neuropsychological impairments, even among more severe TBI. [ABSTRACT FROM AUTHOR]

Objective: To describe the rates and causes of rehospitalization over a 10-year period following a moderate-severe traumatic brain injury (TBI) utilizing the Healthcare Cost and Utilization Project (HCUP) diagnostic coding scheme. Setting: TBI Model Systems centers. Participants: Individuals 16 years and older with a primary diagnosis of TBI. Design: Prospective cohort study. Main Measures: Rehospitalization (and reason for rehospitalization) as reported by participants or their proxies during follow-up telephone interviews at 1, 2, 5, and 10 years postinjury. Results: The greatest number of rehospitalizations occurred in the first year postinjury (23.4% of the sample), and the rates of rehospitalization remained stable (21.1%-20.9%) at 2 and 5 years postinjury and then decreased slightly (18.6%) at 10 years postinjury. Reasons for rehospitalization varied over time, but seizure was the most common reason at 1, 2, and 5 years postinjury. Other common reasons were related to need for procedures (eg, craniotomy or craniectomy) or medical comorbid conditions (eg, diseases of the heart, bacterial infections, or fractures). Multivariable logistic regression models showed that Functional Independence Measure (FIM) Motor score at time of discharge from inpatient rehabilitation was consistently associated with rehospitalization at all time points. Other factors associated with future rehospitalization over time included a history of rehospitalization, presence of seizures, need for craniotomy/craniectomy during acute hospitalization, as well as older age and greater physical and mental health comorbidities. Conclusion: Using diagnostic codes to characterize reasons for rehospitalization may facilitate identification of baseline (eg, FIM Motor score or craniotomy/craniectomy) and proximal (eg, seizures or prior rehospitalization) factors that are associated with rehospitalization. Information about reasons for rehospitalization can aid healthcare system planning. By identifying those recovering from TBI at a higher risk for rehospitalization, providing closer monitoring may help decrease the healthcare burden by preventing rehospitalization. [ABSTRACT FROM AUTHOR]

Persons with military involvement may be more likely to have Parkinson's disease (PD) risk factors. As PD is rare, case finding remains a challenge, contributing to our limited understanding of PD risk factors. Here, we explore the validity of case-finding strategies and whether military employment is associated with PD. We identified Adult Changes in Thought (ACT) study participants reporting military employment as their longest or second longest occupation. We used self-report and prescription fills to identify PD cases and validated this case-finding approach against medical record review. At enrollment, 6% of 5,125 eligible participants had military employment and 1.8% had prevalent PD; an additional 3.5% developed PD over follow-up (mean: 8.3 years). Sensitivity of our case-finding approach was higher for incident (80%) than prevalent cases (54%). Specificity was high (>97%) for both. Military employment was not associated with prevalent PD. Among nonsmokers, point estimates suggested an increased risk of incident PD with military employment, but the result was non-significant and based on a small number of cases. Self-report and prescription medications can accurately identify incident PD cases relative to the reference method of medical record review. We found no association between military employment and PD. [ABSTRACT FROM AUTHOR]