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Abstract INTRODUCTION We standardized positron emission tomography (PET) data across multiple cohorts and tracers to characterize the frequency of amyloid and tau PET severity along the clinical continuum. METHODS Clinical stage was defined using cohort‐specific criteria and included cognitively unimpaired (CU), mild cognitive impairment (MCI), and dementia. Amyloid severity was staged using Centiloids (CL). Tau severity was staged using a hierarchical Braak‐based schema. The cumulative probabilities of PET‐based stages were estimated using ordinal logistic regressions. RESULTS Among 10,396 individuals (mean [standard deviation] age: 71.9 [7.1] years), amyloid levels ≥ 25 CL increased with age among CU and MCI, while amyloid levels ≥ 100 CL were most common in dementia. In 3295 with tau PET, tau severity increased with amyloid and clinical stage and showed complex associations with age. Within each clinical stage, the full spectrum of amyloid and tau PET severity was observed. DISCUSSION PET‐based staging revealed heterogeneous amyloid and tau burden along the clinical continuum. Highlights PET‐based staging is feasible across multiple cohorts and PET tracers. There is heterogeneity in amyloid and tau severity across the clinical spectrum. The frequency of amyloid and tau PET severity increased with clinical severity. The likelihood of tau PET severity differed by age, amyloid, and clinical severity.

Abstract Background Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impacts (RHI). Autopsy studies show that RHI influences risk for other later‐life neuropathologies, particularly white matter and vascular injury. We have observed a unique pattern of white matter hyperintensities (WMH) on FLAIR MRI in people exposed to RHI (RHI‐WMH) characterized by small, discrete lesions near the depths of sulci (Figure 1a). The objective of this study was to characterize this pattern empirically in former American football players and to investigate neuropathology co‐localizing with the WMH. Method The sample included 164 male former football players ( n = 111 professional, n = 53 college) and 55 asymptomatic males without RHI from the DIAGNOSE CTE Project (Table 1). Visual ratings of WMH blind to the participant's RHI and clinical status were conducted to count lesions that were a.) within 1.0cm of the gray/white matter boundary, b.) as bright as the cortex, c.) spherical and d.) <1.0cm in size. ANCOVA compared groups on total number of WMH adjusted for age and vascular risk factors. We selected one individual (former professional player) with the typical RHI‐WMH pattern and who donated their brain for neuropathological examination. Guided by in vivo MRI, ex vivo MRI was done to locate the WMH near the depths of the sulci in the tissue. Tissue sections were tested for phosphorylated tau immunoreactivity and reactive astrocytes and microglia in areas surrounding the lesion seen on MRI. Result Number of RHI‐WMH was greater in football players compared to controls ( p = 0.007) (Figure 1b). Number of RHI‐WMH was greater in former professional players compared to controls ( p = 0.001) but not compared to the college players ( p = 0.983). In the neuropathology case study, we located the punctate RHI‐WMH on ex vivo MRI. Immunostaining revealed that the RHI‐WMH was adjacent to a sulcus with the pathognomonic CTE p ‐tau lesion and was characterized by myelin pallor, dense GFAP‐positive glial scarring, and increased total and activated microglia (Figure 2). Conclusion We provide empirical support for exposure to RHI as potentially leading to a unique pattern of WMH. Importantly, histopathological evidence showed that the RHI‐WMH co‐localized with RHI and CTE‐related neuropathologies at the depths of the sulci.

Abstract Background Exposure to repetitive head impacts (RHI) is associated with developing chronic traumatic encephalopathy (CTE) neuropathology. Cognitive and behavioral symptoms have been associated with CTE neuropathology, but efforts to define the specific clinical syndrome are ongoing. This study characterizes the current use of centrally acting medications (CAMs), chronic pain, and number of orthopedic surgeries in former American football players and evaluates for associations with cognitive and behavioral symptoms. Methods This study analyzed data from the DIAGNOSE CTE Research Project, which includes 120 former professional football players, 60 collegiate football players, and 56 asymptomatic men without history of RHI. Medical history was obtained by self‐report, and participants completed the Montreal Cognitive Assessment (MoCA), Brief Pain Inventory, Barratt Impulsiveness Scale‐11 (BIS‐11), BRIEF‐A Behavioral Regulation Index (BRI), Beck Depression Inventory‐II (BDI‐II), Beck Anxiety Index (BAI), and Brown‐Goodwin Lifetime History of Aggression adulthood score (BGLHA). Logistic regression assessed the association of CAMs, average pain score, and orthopedic surgeries on the cognitive impairment and neurobehavioral dysregulation components of the NINDS traumatic encephalopathy syndrome (TES) research criteria, in former American football players. Linear regression assessed the associations with MoCA and behavioral scales. Models were adjusted for age, education, race, and years of football played. Results Tables 1 and 2 describe the sample and CAM burden. More orthopedic surgeries, CAMs, and higher average pain were observed in former American football players. Number of CAMs was associated with neurobehavioral dysregulation (OR = 2.18), lower MoCA (β = ‐0.47), and higher BIS‐11 (β = 2.23), BDI‐II (β = 2.01), BRI (β = 3.71), BAI (β = 2.04), and BGLHA (β = 0.68) scores. Higher average pain was associated with neurobehavioral dysregulation (OR = 1.57) and higher BIS‐11 (β = 2.20), BDI‐II (β = 1.98), BRI (β = 2.20), BAI (β = 1.84), and BGLHA (β = 0.52) scores. No associations were observed with orthopedic surgeries. Conclusions In former American football players, the number of CAMs and higher average pain were associated with neurobehavioral dysregulation. No associations were observed with diagnosis of cognitive impairment by TES criteria, though the number of CAMs was associated with decreased MoCA.

Abstract Repetitive head impacts are common in contact and collision sports and are linked to structural brain changes and an elevated risk of neurodegenerative diseases such as Chronic Traumatic Encephalopathy. Identifying early in vivo structural markers remains challenging. Although diagnosis currently requires post-mortem confirmation, clinical symptoms, including cognitive impairment and behavioural changes, are reflected in the diagnosis of Traumatic Encephalopathy Syndrome. These symptoms align with dysfunction in key brain regions—amygdala, hippocampus and thalamus—which support memory, emotion and behaviour and commonly show tau pathology in Chronic Traumatic Encephalopathy. This study uses shape analysis to examine structural differences in these regions between former American football players and unexposed asymptomatic controls and evaluates the influence of age, head impact exposure and clinical diagnosis on brain structure. We analyzed brain morphology in former American football players (n = 163) and unexposed, asymptomatic controls (n = 53). Structural segmentation was performed with FreeSurfer 7.1, and the shape analysis pipeline was used to generate subregional reconstructions. Vertex-level morphometry, based on the logarithm of the Jacobian determinant and radial distance, quantified local surface area dilation and thickness. Group differences were examined with covariate-adjusted linear regression models contrasting football players and controls, as well as participants with and without a Traumatic Encephalopathy Syndrome diagnosis. Partial correlations examined the influence of age, age of first football exposure and cumulative head impact index metrics, including frequency, linear acceleration and rotational force. Models were adjusted accordingly for age, body mass index, education, race, imaging site, apolipoprotein ϵ4 status and total intracranial volume. Former football players exhibited bilateral surface area contractions in the hippocampus and amygdala, along with reduced amygdala thickness, compared to controls. Older age was associated with widespread surface contractions and thinning across all regions, except for preserved thickness in the left hippocampus. An earlier age of first exposure to football correlated with surface contractions in the thalamus and left hippocampus. Greater cumulative linear acceleration was linked to bilateral hippocampal surface contractions and reduced thickness in the left thalamus, while greater rotational force exposure was associated with hippocampal thinning. No significant structural differences were found between players with and without a diagnosis of Traumatic Encephalopathy Syndrome. These findings extend volume-based research by revealing localized alterations in surface area dilation and thickness and emphasize the roles of age and repetitive head impact exposure in long-term brain changes.

Abstract INTRODUCTION Few African American (AA) donors have been included in post mortem Alzheimer's disease (AD) studies compared to European‐ancestry (EA) individuals. METHODS We generated transcriptome‐wide bulk pre‐frontal cortex (PFC) gene expression data from 125 AA donors with neuropathologically determined AD and 82 AA controls. RESULTS Transcriptome‐wide significant differential expression was observed with 482 genes. The most significant, ADAMTS2 , showed 1.52 times higher expression in AD cases ( p = 2.96x10 −8 ). Comparison of findings with those from a recent gene expression study of EA brain donors revealed substantial concordance, including ADAMTS2 . Other associations not observed in EA results may be especially relevant to AD risk in the AA population. Examination of AA AD GWAS‐implicated variants identified several expression quantitative trait loci. CONCLUSION This first large‐scale AA brain AD gene expression study identified many differentially expressed genes, including ADAMTS2 , and supports gene expression as a molecular pathway underlying the impact of several AA AD risk variants. Highlights We performed the largest African American brain tissue Alzheimer's disease (AD) gene expression study. Expression differences for 482 genes, notably ADAMTS2 , were study‐wide significant. Many significant differentially expressed genes are involved in energy metabolism. Several previously known AD‐associated variants in African Americans are eQTLs. These results advance knowledge of the genetic basis of AD in the AA population.

Abstract Repetitive head impacts are associated with structural brain changes and an increased risk for chronic traumatic encephalopathy, a progressive neurodegenerative disease that can only be diagnosed after death. Chronic traumatic encephalopathy is defined by the abnormal accumulation of phosphorylated tau protein, particularly at the depths of the superior frontal sulci, suggesting that sulcal morphology may serve as a relevant structural biomarker. Contact sport athletes, such as former football players, are at elevated risk due to their prolonged exposure to repetitive head impacts. Cortical atrophy linked to underlying tau accumulation may result in shallower and wider sulci, potentially making sulcal morphology an imaging marker for identifying individuals at risk for this disease. This study investigated sulcal morphological differences in former football players and examined associations with age, football-related exposure, clinical diagnosis of traumatic encephalopathy syndrome, levels of certainty for chronic traumatic encephalopathy pathology, neuropsychological performance, and positron emission tomography imaging using flortaucipir. We analysed structural magnetic resonance imaging data from 169 male former football players (mean age 57.2 (8.2) years, range 45–74) and 54 age-matched, unexposed asymptomatic male controls (mean age 59.4 (8.5) years, range 45–74). Sulcal depth and width were quantified using the CalcSulc, focusing on two regions in each hemisphere commonly affected by chronic traumatic encephalopathy pathology: the superior frontal and occipitotemporal sulci. Generalized least squares models were used to assess group differences and interactions with age and football exposure variables, including age of first exposure, total years played, and cumulative head impact exposure. An analysis of covariance evaluated relationships between sulcal morphology, clinical measures, and flortaucipir uptake, adjusting for age, race, body mass index, education, imaging site, apolipoprotein E4 status, and total intracranial volume. Former football players demonstrated significantly shallower sulcal depth in the left superior frontal sulcus compared to unexposed controls. Earlier age of first exposure and longer football careers were associated with greater widening of the left occipitotemporal sulcus. Higher cumulative head impact exposure was linked to reduced sulcal depth in the left superior frontal region. However, sulcal morphology was not associated with clinical diagnosis, levels of certainty, neuropsychological test performance, or flortaucipir imaging. These findings suggest that sulcal morphology may reflect cumulative exposure to repetitive head impacts, particularly in brain regions vulnerable to chronic traumatic encephalopathy pathology. Future ante- and post-mortem validation studies are needed to determine whether sulcal morphology can serve as a reliable in vivo biomarker of risk.

Background: Cognitive change is an important factor in understanding dementia. Estimating effects of exposures on cognitive change requires choosing an analytical timescale, typically time on study or current age. There is limited consensus regarding timescale choice in epidemiologic cognitive aging research. Methods: Using a coordinated analytic approach in 10 cohorts of older adults, we evaluated whether estimated effects of two exposures on memory change differed depending on timescale (time on study or current age). We modeled effects of apolipoprotein-E (APOE) ε4 genotype (a time-invariant exposure) and diabetes (a potentially time-varying/acquired exposure evaluated at baseline) using mixed-effects models with linear and nonlinear time specifications for both timescales. Results: Among APOE ε4 carriers, model-estimated memory scores at baseline (time on study timescale) or at each cohort’s median baseline age (current age timescale) were lower, and the average rate of decline was faster than among APOE ε4 noncarriers. Model-estimated memory scores at baseline or at median baseline age were generally similar across baseline diabetes status, with variability across cohorts in the diabetes-memory change association. In some cohorts, trends in diabetes-memory change associations differed in direction across timescales. Conclusions: Timescale was largely inconsequential for estimated effects of APOE genotype, but yielded differences in estimated diabetes effects, raising questions about the appropriate scale. The current age scale may be problematic because diabetes was measured heterogeneously in age across individuals, a common issue in aging cohorts. Our work demonstrates approaches to evaluate alternative timescales, including in multicohort analyses, and highlights potential implications for estimated exposure effects on cognitive change.