Alzheimer's disease and related dementias (AD/ADRD) are modulated by gene-environment (GxE) interactions across the lifespan. Variants of specific genes increase AD risk and synergize with exposures to environmental toxicants ("expo-some"), including neurotoxic metals and metalloids such as lead (Pb), cadmium (Cd), and arsenic (As). These neurotoxicants enter the body (via drinking water, contaminated food, and airborne particulates), transit in blood, cross the blood-brain barrier, and distribute in brain where the retained toxicant disrupts central nervous system development, structure, and function. Chronic exposure to these ubiquitous toxicants is common in disadvantaged communities, raising concerns about health risk disparities linked to geographic, socioeconomic, and racial demographics. While Pb, Cd, and As are established human neurotoxicants with suspected linkage to AD/ADRDs, the mechanisms underpinning AD/ ADRD-related GxE interactions specific to metal-metalloid toxicant exposures are largely unknown and potentially modifiable. Preclinical models and resources are needed to facilitate research into the underlying mechanisms by which AD genetics and exposome affect brain health, aging, and AD/ ADRD pathobiology.

Although the younger age of first exposure (AFE) to American football has not been associated with neurodegenerative pathology, AFE has been associated with clinical symptoms. However, the literature is mixed. We examined the association between AFE to football and clinical outcomes before and after age 60 at death, to isolate the potential role of decreased neuropathological resilience in older age. This study included 677 deceased male football players who donated their brains to the Understanding Neurologic Injury and Traumatic Encephalopathy Brain Bank. Informants completed modified scales assessing cognition, function, behavior, and neuropsychiatric features with dementia adjudicated through consensus conferences. Regressions tested the association between AFE and dementia, chronic traumatic encephalopathy (CTE) pathology, and each scale, adjusted for multiple testing. Analyses were stratified by age 60, adjusting for age at death, duration of play, and neuropathology. Most donors (mean age = 60.9, standard deviation = 19.8) played college or professional football (n = 509, 76%). CTE was the most prevalent neuropathology (n = 471, 70%). AFE was not associated with neurodegenerative disease pathology. Among those older than 60 at death, younger AFE was associated with cognitive composite score impairment (odds ratio: 0.897, 95% confidence interval [CI]: 0.814-0.988, p = 0.027) and worse cognitive (beta: 0.04, 95% CI: 0.01-0.069, p = 0.009), neurobehavioral (beta: 0.032, 95% CI: 0.002-0.062, p = 0.035), and neuropsychiatric (beta: 0.032, 95% CI: 0.00-0.064, p = 0.048) composite scores. Younger AFE was only associated with worse informant-reported clinical outcomes in older deceased football players, independent of neurodegeneration. Our findings offer a potential explanation for the mixed literature on AFE and clinical outcomes. The effects of AFE may only manifest in older adults when cognitive reserve is depleted, neuropathological resilience is reduced, or age-related vulnerabilities interact with prior head injury exposure, worsening clinical outcomes.

Interictal cerebral blood flow (CBF) may be useful for seizure focus localization. However, its accuracy is debatable. Studies suggested interictal hypoperfusion at the seizure focus, yet others suggested hyperperfusion. This study aims to investigate the patterns of interictal perfusion in epilepsy subjects compared to healthy controls using multiple labeling-delays arterial spin labeling MRI, and to explore the accuracy of perfusion estimation using single post-labeling delay arterial-spin labeling MRI by comparing it to multiple post-labeling delays arterial-spin labeling MRI. We analyzed CBF in 40 participants, 15 healthy (35.9 ± 9.5 years, 47% women) and 25 epilepsy (41.1 ± 10.5 years; 52% women). We acquired a multiple post-labeling delays arterial spin labeling MRI using Hadamard encoding, and structural MRI. Perfusion quantification was performed using in-house software and analyzed using surface-based method. Z-scores of CBF and its absolute value (|Z-score|) were calculated to evaluate abnormal perfusion. Brain perfusion showed interictal hypo- and/or hyper-perfusion in epilepsy compared to healthy participants involving focal to whole brain alterations. Epilepsy subjects had higher |Z-score| in most cortical regions compared to the healthy group. CBF generated from single post-labeling delay arterial-spin labeling MRI correlated with ones from multiple post-labeling delays in most cortical regions, yet the level of correlation was affected by regional arterial transit time and the labeling scheme. In regions with shorter arterial transit time, correlation peaked at shorter post-labeling delay (1300ms); whereas in regions with longer arterial transit time, correlation peaked at longer post-labeling delay (2250ms). Our findings suggest that the interictal CBF may fluctuate between hypo- and hyper-perfusion, and the involvement of brain regions may extend well beyond the seizure focus. Additionally, while single-post-labeling delay is efficient and clinically feasible, the accuracy of its assessment of perfusion depends on brain regions and the labeling scheme. We observed interictal hypo-/hyper-perfusion, possibly extending beyond the seizure focus. Caution is warranted when interpreting single-post-labeling-delay perfusion MRI in epilepsy, as its reliability varies by brain region and labeling scheme. Epilepsy subjects showed larger fluctuation of CBF, yet the fluctuation may happen in either direction: hypo- or hyper-perfusion. The extent of fluctuation can be focal, regional, hemispheric, or global. CBF derived from single-PLD MRI largely correlates with the ones derived from more reliable multi-PLD method. However, the level of correlation varies spatially (i.e., brain regions) and temporally (i.e., different labeling and post-labeling schemes), and may be explained by regional variability of arterial transit times.

Traumatic brain injury (TBI) is a risk factor for the earlier onset of Alzheimer's disease (AD), and the more severe the injury, the greater the risk of developing AD. Given the prevalence of AD in modern society, the possibility that TBI may predispose individuals to develop AD has significant social and economic implications. Therefore, it is important to understand how TBI triggers accelerated AD progression. In this study, we explored how neurotrauma accelerates hippocampal degeneration in a transgenic mouse model of AD using high-resolution ex vivo diffusion-MRI. Unanesthetized 3xTg-AD mice ( n  = 4) were pretreated with a non-sedating dose of the analgesic buprenorphine and then subjected to left-lateral closed-head impact injury (Figure 1) at 10-12 weeks of age. At 6-months post-TBI, the mice were sacrificed via transcardial perfusion. The harvested brains were submerged in 10% formalin for 24 hours and then stored in Gadavist-doped PBS (1:400 dilution) until MRI. MRI data were acquired using a 9.4T Bruker scanner and a cryoprobe. Key parameters were TR=300ms, TE=27.7ms, b=3000 (48 directions), and 5000s/mm 2 (80 directions), FOV=14.30x10.66x7.02mm 3 , Matrix=220x164x108, resolution=65mm 3 . Diffusion MRI was analyzed in DSI Studio and NODDI toolbox. T1-weighted (T1W) images (resolution=32.5 µm 3 ) were also acquired (FLASH) for structural reference. Age-, gender-matched 3xTg-AD mice ( n  = 4) without TBI were used as controls. Figure 2 shows a representative T1W image and corresponding diffusion-derived hippocampal maps from a TBI mouse. Compared to the contralateral side, the ipsilateral radiatum of CA1 and CA3 showed decreased quantitative anisotropy (QA) values and increased orientation dispersion index (ODI), the ipsilateral stratum pyramidale showed decreased QA and axial diffusivity (AxD), and the ipsilateral alveus showed decreased AxD. Statistical analysis revealed that the average fractional anisotropy (FA) values in radiatum were lower (CA3, significant; CA1, trend) in the ipsilateral hippocampus compared to the contralateral side of TBI mice or the bilateral sides of control mice (Figure 3). Our results demonstrate that the hippocampal CA1/CA3 subregions are more vulnerable to neurotrauma. This finding may help clarify the mechanisms underlying trauma-accelerated AD and suggest that advanced diffusion-MRI is a potential tool for the early diagnosis of trauma patients at risk of developing AD.

INTRODUCTION:This studyexamined the independent contribution of chronic traumatic encephalopathy (CTE) neuropathology to symptoms. METHODS:The sample included 614 brain donors with (n = 366) and without (n = 248) autopsy-confirmed CTE. Brain donors with other major neurodegenerative disease diagnoses were excluded. Informants completed cognitive and neuropsychiatric measures. Dementia was determined during diagnostic consensus conferences. RESULTS:CTE stage IV (of IV) was associated with 4.48 (95% confidence interval [CI] = 1.97-10.90) increased odds of having dementia. CTE stage III had an odds ratio of 2.12 (95% CI = 1.91-3.77). Higher CTE stage was associated with greater informant-reported cognitive symptoms (p < 0.01). There were no associations with mood/behavioral scales. DISCUSSION:CTE stage III/IV neuropathology was associated with dementia and cognitive symptoms: those with stage IV were 4.5 times more likely to have dementia than those without CTE. It is uncertain if low-stage CTE clinically manifests, and mood/behavioral symptoms likely have multifactorial causes and/or a fluctuating course. HIGHLIGHTS:Stage III and IV chronic traumatic encephalopathy (CTE) are independently associated with increased odds of having dementia. Higher CTE stage was associated with greater informant-reported cognitive symptoms. Stage I and II CTE were not associated with cognitive symptoms or dementia. CTE of any severity was not associated with informant-reported mood or behavioral symptoms.

There is growing interest in cognitive resilience to Alzheimer’s disease (AD), given limited success of therapies targeting hallmark proteins. Gene expression in the prefrontal cortex region obtained from brain donors in three cohorts was compared among pathological controls and pathological confirmed AD cases who met clinical criteria for AD (SymAD) or were cognitively normal (AsymAD) prior to death. Expression of genes that were differentially expressed at a transcriptome-wide significance level (TWS, P < 3.06 × 10⁻⁶) were tested for association with measures of performance in three cognitive domains and AD-related neuropathological traits. We also conducted gene network analyses seeded with nominally significant differentially expressed genes (DEGs, P < 0.05) to identify AD-related pathways. We identified 39 TWS DEGs distinguishing SymAD from AsymAD cases. Increased expression of two of the top-ranked DEGs, ADAMTS2 and PAFAH1B3, was associated with poorer memory, language and executive function performance and lower tau protein level and synaptic density. Increased expression of HMGN2 was associated with better memory performance. Pathway analyses showed that significant DEGs are involved in neuron projection, BDNF signaling and ciliopathy pathways. This study identified DEGs for cognitive resilience, revealing potential targets for delaying AD symptoms.

Importance:Accurate prediction of chronic traumatic encephalopathy (CTE) remains challenging in life. Objective:To assess the reliability and validity of the NINDS traumatic encephalopathy syndrome (TES) criteria to predict CTE pathology in life. Design:Clinicopathological Diagnostic/Prognostic Study. Setting:Six brain banks with varied recruitment criteria. Participants:Brain donors were selected across 6 brain banks (15+ donors each), 5 age groups spanning ages 20 to 80+ (25+ donors each) and 9 repetitive head impact (RHI)/traumatic brain injury (TBI) groups (15+ donors each): (1) college or professional American football; (2) less than college football; (3) college or professional contact sports, non-football; (4) less than college contact sports, non-football; (5) military combat, no contact sports; (6) military combat and contact sports; (7) concussion with loss of consciousness, no RHI; (8) moderate to severe TBI, no RHI; (9) no RHI/TBI. Exposures:Blinded to neuropathological information, clinicians reviewed prospective study and medical records and conducted informant interviews, and an expert panel adjudicated TES diagnoses, including provisional levels of certainty for CTE pathology (suggestive/possible/probable). TES diagnoses were a priori dichotomized: TES with possible/probable CTE (CTE pos/prob ) vs. no TES/TES with suggestive CTE (CTE sug ). Main Outcomes and Measures:Blinded to clinical information, neuropathologists applied NINDS/NIBIB CTE neuropathological criteria and staging (I-IV). CTE diagnoses were a priori dichotomized: stages II-IV vs. no CTE/stage I. Results:Among 193 brain donors [men:153 (79.3%), mean age:66.4 (SD:22.0)], 57 (29.5%) donors met clinical criteria for CTE pos/prob and 42 (21.8%) donors met neuropathological criteria for CTE stages II-IV. There was high agreement between panelists for CTE pos/prob vs. no TES/CTE sug (ICC:0.95, 95%CI:0.88-0.97). CTE pos/prob sensitivity, specificity, positive likelihood ratio (LR) and negative LR for CTE stages II-IV were: 0.77 (95%CI:0.64-0.89), 0.84 (95%CI:0.78-0.90), 4.8 (95%CI:3.02-7.61), 0.28 (95%CI:0.15-0.50); age≥50:0.90 (95%CI:0.80-1), 0.90 (95%CI:0.85-0.96), 9.2 (95%CI:4.9-17.27), 0.11 (95%CI:0.04-0.33). All younger false positives (age<50; n=13) had a mental health, substance use and/or pain disorder. All older false positives (age≥50; n=11) had non-CTE neurodegenerative and vascular pathologies. Among 10 false negatives, 8 had stage II CTE. Conclusions and Relevance:The NINDS TES criteria demonstrated good reliability, sensitivity and specificity, and provided moderate to large evidence to both rule out and rule in CTE pathology, particularly above age 50. Key Points:Question: What is the validity of the NINDS consensus diagnostic criteria for traumatic encephalopathy syndrome (TES) for predicting chronic traumatic encephalopathy (CTE) neuropathology?Findings: In this clinicopathological diagnostic/prognostic study that included brain donors from varied brain banks, head impact exposures and ages, TES criteria sensitivity, specificity, positive likelihood ratio (LR) and negative LR were 0.77, 0.84, 4.8 and 0.28 with improved performance above age≥50 (0.90, 0.90, 9.2, 0.11).Meaning: The NINDS TES criteria were sensitive and specific for CTE neuropathology across varied head impact exposures, particularly above age 50.

Background and Purpose Interictal cerebral blood flow (CBF) may be useful for seizure focus localization. However, its accuracy is debatable. Studies suggested interictal hypoperfusion at the seizure focus, yet others suggested hyperperfusion. This study aims to investigate the patterns of interictal perfusion in epilepsy subjects compared to healthy controls using multiple labeling-delays arterial spin labeling MRI, and to explore the accuracy of perfusion estimation using single post-labeling delay arterial-spin labeling MRI by comparing it to multiple post-labeling delays arterial-spin labeling MRI. Materials and Methods We analyzed CBF in 40 participants, 15 healthy (35.9 ± 9.5 years, 47% women) and 25 epilepsy (41.1 ± 10.5 years; 52% women). We acquired a multiple post-labeling delays arterial spin labeling MRI using Hadamard encoding, and structural MRI. Perfusion quantification was performed using in-house software and analyzed using surface-based method. Z-scores of CBF and its absolute value (|Z-score|) were calculated to evaluate abnormal perfusion. Results Brain perfusion showed interictal hypo- and/or hyper-perfusion in epilepsy compared to healthy participants involving focal to whole brain alterations. Epilepsy subjects had higher |Z-score| in most cortical regions compared to the healthy group. CBF generated from single post-labeling delay arterial-spin labeling MRI correlated with ones from multiple post-labeling delays in most cortical regions, yet the level of correlation was affected by regional arterial transit time and the labeling scheme. In regions with shorter arterial transit time, correlation peaked at shorter post-labeling delay (1300ms); whereas in regions with longer arterial transit time, correlation peaked at longer post-labeling delay (2250ms). Conclusions Our findings suggest that the interictal CBF may fluctuate between hypo- and hyper- perfusion, and the involvement of brain regions may extend well beyond the seizure focus. Additionally, while single-post-labeling delay is efficient and clinically feasible, the accuracy of its assessment of perfusion depends on brain regions and the labeling scheme.

Alzheimer’s disease (AD) and AD-related dementias (ADRD) are modulated by gene-environment (GxE) interactions across the lifespan. Variants of specific genes increase AD risk and synergize with lifetime exposure to environmental toxicants (“exposome”), including neurotoxic metals (lead, Pb; cadmium, Cd) and metalloid (As). These metal/metalloid toxicants readily enter the body (e.g., via contaminated drinking water), transit in blood, cross the blood-brain barrier (BBB), and distribute in the brain. Pb, Cd, and As are potent neurotoxicants and suspected modifiers of AD pathobiology. The mechanisms underpinning AD-related GxE interactions specific to Pb, Cd, As exposures are largely unknown and potentially modifiable. Hypothesis: Pb, Cd, As exposures alter expression of AD-linked genes and potentiate AD pathogenesis in a toxicant-specific, neurodevelopment-sensitive, biomarker-responsive, and age-dependent manner. We exposed mice expressing humanized AD gene variants (hAPOE, hMAPT, hAβ; NIA MODEL-AD) to Pb, Cd, As in drinking water at human-relevant toxicant levels (Pb: 200 ppm; Cd: 5, 50 ppm; As: 20 ppm) vs unspiked drinking water (control). Exposures were carried out for 30 days. Mice were sacrificed, blood collected by cardiac puncture, and cerebrovasculature cleared by transcardiac saline perfusion. Harvested brains were analyzed by ICP-MS solution analysis, high-resolution laser ablation metallomic imaging ICP-MS mapping), transcriptomics, biochemistry, other assays. MODEL-AD mice exposed to Pb, Cd, As in drinking water increased levels of metal/metalloid toxicant in blood and brain and altered expression of human AD genes in a toxicant-specific manner: decreased ↓ VGF (Pb, As), increased ↑ APP (Cd). Both ↓ VGF and ↑ APP are associated with increased AD risk. Pb distribution in brain showed striking regional variation. Significant associations (FDR<0.05; LOAD GO terms): Pb (600 genes): chaperone-dependent protein refolding (FDR = 0.02), glutamate signaling (FDR = 0.009), cognition (FDR = 0.003), synaptic transmission (FDR = 0.01); As (201 genes): synaptic plasticity (FDR = 0.02) and organization (FDR = 0.04), unfolded protein response (FDR = 0.008); Cd (348 genes): protein localization (FDR = 0.03), protein metabolism (FDR = 0.05), sensory perception (FDR = 0.001). No group differences noted in water intake or daily weight. MODEL-AD mice exposed to Pb, Cd, or As accumulate metal/metalloid toxicants in blood and brain and showed toxicant-specific alterations in AD-relevant gene expression and gene module profiles.

While linkage between Alzheimer's disease (AD)/AD-related dementias (ADRD) and lifetime exposure to environmental toxicants are known, the pathways and mechanisms underpinning them are poorly understood. Variants of specific genes increase AD risk and synergize with lifetime exposures to neurotoxic metals (lead, Pb; cadmium, Cd) and the metalloid (arsenic, As). These metal/metalloid toxicants enter the body (e.g. via contaminated drinking water or food), transit in blood, cross the blood-brain barrier (BBB), and distribute in the brain, disrupting neuronal function and modulating canonical AD pathways. Metal/metalloid neurotoxicants are suspected modifiers of AD pathobiology. Thus, we hypothesize that Pb, Cd, and As exposures alter the expression of AD-linked genes, potentiating AD pathogenesis in a toxicant-specific, neurodevelopment-sensitive, biomarker-responsive, and age-dependent manner. TOX-AD is a new NIA-funded consortium project (1U01AG088683) to evaluate this hypothesis and serve as an exposome resource for the AD/ADRD research community. MODEL-AD mice B6J.hAPO4.hAβ mice were exposed to Pb (200 ppm), Cd (5, 50 ppm), or As (20 ppm) in drinking water for 30 days vs. controls (unspiked water). B6.APPSwDI mice were also exposed to Pb (13.5, 27, 56 mg/kg) for 1 week to evaluate BBB integrity. Mice were euthanized, blood was collected by cardiac puncture, and tissues were cleared by transcardiac saline perfusion for further analysis. Animals exposed to environmental toxicants displayed no difference in water intake or daily intake. However, the animals increased levels of metal/metalloids in the blood and brain, altering gene expression associated with increased AD risk, such as ↑VGF (Pb, As) and ↓APP (Cd). B6.APPSwDI animals showed disruption in the BBB integrity, increased Aβ1-40/Aβ1-42 ratio, and Aβ deposition. Significant associations for late-onset AD gene ontology terms: Pb (600 genes): chaperone-dependent protein refolding (FDR=0.02), glutamate signaling (FDR=0.009), cognition (FDR=0.003), synaptic transmission (FDR=0.01); As (201 genes): synaptic plasticity (FDR=0.02) and organization (FDR=0.04), unfolded protein response (FDR=0.008); Cd (348 genes): protein localization (FDR=0.03), protein metabolism (FDR=0.05), sensory perception (FDR=0.001). MODEL-AD mice exposed to Pb, Cd, or As accumulate metal/metalloid toxicants in blood and region-specific accumulation in brain. Moreover, these exposures revealed toxicant-specific alterations in gene expression and gene module profiles relevant to AD pathobiology.

We previously discovered that Aβ accumulates in the lens of the eye in people with Alzheimer's Disease (AD) (Goldstein et al., 2003) and Down Syndrome (Moncaster et al., 2010). We also demonstrated Aβ in the Tg2576 APP Swedish mutation AD mouse model (Moncaster et al., 2022). Another protein that is involved in AD is Microtubule- Associated Protein Tau (MAPT). Tau is expressed in the brain and becomes hyperphosphorylated in AD eventually forming neurofibrillary tangles. Tau has previously been reported to be expressed in the mouse lens (Bai et al., 2007; Zhao et al., 2013) but the results vary depending on the mouse model and antibodies used. Here we investigated whether tau protein was expressed in non-transgenic mouse lenses and in a transgenic tau mutant (P301S) and whether there was a cataract phenotype. P301S tau mutant transgenic and non-transgenic mice were bred and maintained at Boston University. Breeder mice were purchased from The Jackson Laboratory, Bar Harbor, ME. Male and Female transgenic and non-transgenic mice were sacrificed throughout their lifespan at ages 3-12 months. Mice were perfused with phosphate buffered saline (PBS), lenses were isolated and then imaged under two different sources of light using a Nikon camera and a custom-adapted Zeiss stereophotomicroscope. Lenses were then snap frozen and analyzed by Western blotting using a panel of tau antibodies. Tissues from Tau knock-out (KO) mice were used as additional controls. P301S transgenic and non-transgenic mouse lenses all expressed tau during their lifespan when analyzed by Western blot. P301S transgenic lenses demonstrated an additional higher molecular weight band compared to the non-transgenic mice. No cataract phenotype was observed in transgenic or non-transgenic mouse lenses. There was no overt difference in lens phenotype between the P301S transgenic and non-transgenic mice. However, the banding pattern observed by Western blot for P301S transgenic mice compared to non-transgenic was different. Our data suggest the P301S tau mutation affects tau processing but does not result in a cataract phenotype. Based on our current and previous results, the data suggests that Aβ may play a more significant role than tau in lens pathology in AD.

We previously discovered that Aβ accumulates in the cortical/supranuclear region of the lens in people with Alzheimer’s Disease (AD) (Goldstein et al., 2003) and Down Syndrome (DS; (Moncaster et al., 2010). We also demonstrated Aβ in the Tg2576 APP Swedish mutation AD mouse model (Moncaster et al., 2022). Another protein that is involved in AD is Microtubule-Associated Protein Tau (MAPT). Tau is expressed in the brain and becomes hyperphosphorylated in AD eventually forming neurofibrillary tangles. Tau has previously been reported to be expressed in the mouse lens (Bai et al., 2007; Zhao et al., 2013) but the results vary depending on the mouse model and antibodies used. Here we investigated whether tau protein was expressed in non-transgenic mouse lenses and in a transgenic tau mutant (P301S) and whether there was a cataract phenotype. P301S tau mutant transgenic and non-transgenic mice were bred and maintained at Boston University. Breeder mice were purchased from The Jackson Laboratory, Bar Harbor, ME. Male and Female transgenic and non-transgenic mice were sacrificed throughout their lifespan at ages 3-12 months. Mice were perfused with phosphate buffered saline, lenses were isolated and then imaged under two different sources of light using a Nikon camera and a custom-adapted Zeiss stereophotomicroscope. Lenses were then snap frozen and analyzed by Western using a panel of tau antibodies. P301S transgenic and non-transgenic mouse lenses all expressed tau during their lifespan when analyzed by Western blot. P301S transgenic lenses demonstrated an additional higher molecular weight band compared to the non-transgenic mice. No cataract phenotype was observed in transgenic or non-transgenic mouse lenses. There was no overt difference in lens phenotype between the P301S transgenic and non-transgenic mice. However, the banding pattern observed by Western blot for P301S transgenic mice compared to non-transgenic was different. Our data suggest the P301S tau mutation affects tau processing but does not result in a cataract phenotype. Based on our current and previous results, the data suggests that Aβ may play a more significant role than tau in lens pathology in AD.

Chronic traumatic encephalopathy (CTE) is a progressive brain disease linked to repetitive head impacts (RHI), often incurred from contact sports, and can lead to dementia. Here, we investigated the association between RHI and white matter/vascular neuropathologies and their relative contribution to dementia status in deceased men 50 + years old with and without exposure to RHI from various types of contact and collision sports. Our sample included two RHI groups from the UNITE brain bank: (1) American Football players (RHI-AF, n = 79), and (2) non-AF contact and collision sport athletes (e.g., boxing, rugby; RHI-CCS, n = 49). Controls included similarly aged (± 5 years) male brain donors without RHI. A modified ischemic injury scale (mIIS) served as a global measure of white matter and vascular neuropathologies, encompassing nine subcomponents. Dementia was determined through diagnostic consensus conference based on interviews with families. Using linear regression models controlling for age at death, mIIS was different in RHI-AF versus non-RHI only (p = 0.036). Subsequent logistic regression of each mIIS subcomponent, controlling for age at death, demonstrated that worse white matter rarefaction (RHI-AF; Beta = 1.42, [95

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease caused by repetitive head impacts (RHI). However, individuals with similar RHI exposure can show differing pathology, suggesting a role for genetic variation. A common Transmembrane Protein 106B ( TMEM106B ) risk variant is associated with greater CTE severity, though its mechanism remains unclear. To determine whether TMEM106B alters the inflammatory response to pathology in CTE, we examined associations between microglia, via immunohistochemistry, and inflammatory cytokines, via immunoassay, in brain donors with CTE with and without the risk genotype ( rs3173615) . We analyzed 323 RHI-exposed brain donors: 55 without pathology (controls) and 268 with CTE. Regression models tested associations between TMEM106B risk and CTE presence, CTE stage, TDP-43, and dementia in those < = 65 and > 65 years of age. Within a subset of 122 brain donors, we examined associations between microglia, cytokines, and pathology stratified by TMEM106B genotype. Among donors > 65 years old, the TMEM106B risk genotype was associated with increased CTE stage (OR = 2.748 [95% CI 1.183–6.383], p = 0.019), comparable to the effect of playing > 8 years of contact sports, and with greater odds of having TDP-43 inclusions (OR = 3.649 [95% CI 1.278–10.422], p = 0.016). In donors < = 65, TMEM106B risk was associated with higher odds of dementia (OR = 6.912 [95% CI 2.015–23.705], p = 0.002). TMEM106B gene variation had a significant effect on associations between inflammatory markers and CTE-related pathology. In the protective genotype, IL-8 and IL-6 demonstrated positive associations with CD68, TREM2, and tau pathology within the dorsolateral prefrontal cortex. In the risk genotype, IFN-γ, IL-4, TNF-α, TNF-β, and IL-10 demonstrated negative associations with TREM2 ( p ’s < 0.05), and TNF-α was negatively associated with cortical tau ( p = 0.003). These results suggest that the microglial production of TREM2-associated cytokines and their association with pathology is aberrant in the TMEM106B risk genotype in CTE. Overall, TMEM106B rs3173615 is associated with an increased risk of developing higher stage CTE and TDP-43 pathology, potentially via impaired microglial activation and aberrant cytokine production.

Background Sex differences have consistently been identified on autopsy, neuroimaging, and cerebrospinal fluid outcomes related to Alzheimer's disease (AD), but the exact mechanisms for these associations are unclear. Blood-based biomarkers are practical alternatives for the investigation of mechanisms of AD, in addition to accurate disease detection and monitoring. Objective The objective of this study was to examine sex differences across a panel of blood-based plasma biomarkers in participants with and without cognitive impairment due to AD. Methods Plasma samples were collected from 567 participants from across the AD diagnostic continuum (i.e., normal cognition (NC), mild cognitive impairment (MCI), and dementia) and analyzed for glial fibrillary acidic protein (GFAP), neurofilament light (NfL), phosphorylated tau at threonine 181 (p-tau 181 ), and total tau (t-tau). Baseline and longitudinal analyses evaluated for any significant associations between sex and AD-related plasma biomarkers. Results Females were found to have higher plasma GFAP compared to males at baseline regardless of cognitive diagnosis. Among those with AD dementia, females were also found to have higher NfL levels compared to males. Longitudinal analyses found that higher plasma NfL at baseline was associated with an increased risk of worsening AD dementia status only in females. No significant findings were observed for p-tau 181 or t-tau. Conclusions This study found significant sex differences in plasma biomarkers of GFAP and NfL. Further research is needed to better understand the underlying mechanisms mediating these differences.

BACKGROUND:Subjective cognitive complaints (SCCs) can be an early indicator of Alzheimer's disease and related dementias. SCCs have been shown to be common in people exposed repetitive head impacts (RHI), particularly male former professional American football players. This study characterized participant and informant-reported SCCs in terms of rate, concordance with standardized neuropsychological measures, and potential associated factors among participants with diverse sources/severity of RHI exposure. METHOD:The sample included participants with (n = 172) and without (n = 320) RHI from the Boston University Alzheimer's Disease Research Center Clinical Core. RHI status is based on the 2021 NINDS TES Research Diagnostic Criteria. The Cognitive Change Index (CCI) and BRIEF-A Meta-Cognition Index (MI) measured self and informant-reported SCCs. Participants completed neuropsychological assessments of memory (Craft Story 21 Recall, NAB List Learning Long Delay) and executive function (Trails B). Informants completed the Neuropsychiatric Inventory-Questionnaire (NPI-Q). ANCOVAs compared performance of RHI/non-RHI groups on the SCC measures. Pearson correlation examined agreement between participant/informant responses. Multivariable linear regression models tested associations between SCCs and neuropsychological tests and examined correlates of SCCs. All models controlled for age, sex, race, and education. p-values were false discovery rate adjusted. RESULT:Table 1 describes the sample. Compared to non-RHI, the RHI group was younger, likelier to be male, and likelier to have MCI. The RHI group had significantly higher MI (B=8.084, p = 0.006), informant MI (B=9.014, p = 0.006), CCI (B=5.986, p <0.001), and informant CCI scores (B=7.062, p <0.001. Self/informant CCI and MI scores were more correlated in the RHI (r = 0.592, 0.540, respectively) vs non-RHI group (r = 0.416, 0.373, respectively). Figure 1. Within the RHI group, there were associations between participant/informant SCCs and the objective measures (e.g., B=-0.086, padj<0.001 for CCI and NAB) (Table 2). We observed fewer, weaker associations between SCCs and neuropsychological measures in the non-RHI group. NPI-Q was a consistent correlate of self/informant SCCs. Demographics (e.g., self/informant race) were also associated but to a lesser extent. CONCLUSION:In RHI settings, SCCs might be more frequent and reflect cognitive function. High SCC rates are likely multifactorial, with influence from neuropsychiatric factors. Future research should examine longitudinal change in self/informant SCCs and correlation with disease biomarkers.

Late-onset Alzheimer’s disease (LOAD) is the leading cause of dementia and a major contributor to increased mortality. Recent human datasets have revealed many LOAD genetic risk factors that are correlated with the degree of AD burden. Further, the complexity and heterogeneity of LOAD appears to be promoted by interactions between genetics and environmental factors such as diet, sedentary behavior, and exposure to toxicants, like lead (Pb), cadmium (Cd), and arsenic (As). While the neurotoxicants-LOAD association is known, the molecular mechanisms modulated by these gene-environmental interactions are unknown. Here we test the hypothesis that heavy metal exposure induces cerebrovascular deficits, neuroinflammation, and brain biometal dyshomeostasis which exacerbate AD-associated brain pathologies in next-generation mouse models of LOAD. Examination of these gene-environmental (“exposome”) interactions provides essential insight into the heterogeneity observed in human disease and may uncover potentially modifiable mechanisms that mediate AD pathogenesis. Young and aged mice from novel polygenic strains expressing LOAD risk alleles ( APOE4, Trem2, APP, Mthfr, Abca7 ) were exposed to heavy metal toxicants in drinking water. Toxicants and endogenous biometals were assayed by ICP-mass spectrometry in the brain, blood, and urine. Transcriptional profiling of brains revealed specific changes in human-aligned, LOAD-related gene expression networks indicating mechanisms of disease progression. Neuropathology was evaluated with LOAD-relevant phenotypes, including amyloid burden, glial activity, and neuron loss. Neurotoxicants were detected in all tissue samples collected. Pb, Cd, and As accumulated in the brain and altered expression of LOAD-relevant genes in a toxicant-specific manner, including a decrease in Vgf and an increase in App . Reduced VGF expression has been observed and reported in all four independent AMP-AD studies and nominated as a key therapeutic target in each and APP encodes amyloid precursor protein (APP) from which the Aβ peptides are generated. Pb, Cd, and As exposure is common, especially in disadvantaged populations (urban, rural), raising concern about LOAD risk disparities, socioeconomic/racial inequities, and environmental justice. These experiments provide critical feedback related to the impact of the “exposome” in the aging, disease progression, and gene expression of novel preclinical LOAD models. Collectively these data suggest a direct effect of neurotoxicant exposure related to LOAD progression.

Age, genetics, and environmental exposure are among the primary risk factors for Alzheimer's Disease (AD) and related dementias (ADRDs) [1]. Exposure to environmental toxicants is disproportionately high in disadvantaged groups, making research on this topic both a medical and social justice concern. This study ( TOX-AD: 1U01AG088683) focuses on exposure to lead (Pb), cadmium (Cd), and arsenic (As), each listed among the WHO “Top 10” chemical toxicants of public health concern [2]. We hypothesize that these neurotoxicants alter the expression of AD-linked genes and potentiate AD pathobiology in a toxicant-specific, neurodevelopment-sensitive, biomarker-responsive, and age-dependent manner. In this project, we used laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) imaging to conduct multi-elemental brain mapping with ultra-trace elemental quantification and precise anatomical localization. We employed LA-ICP-MS imaging to investigate neurotoxicants' accumulation and regional distribution in mouse brains following chronic exposure to Pb, Cd, and As in drinking water. The study utilized MODEL-AD mice of both sexes to establish levels of metal/metalloid retention in the brain and blood after 30-day exposure to Pb (200 ppm), Cd (5 and 50 ppm), As (20 ppm), control (no added metal) in drinking water. Brains and blood were collected, frozen using liquid nitrogen, and stored at -80C. Tissue concentrations of exogenously administered neurotoxicants (Pb, Cd, As) and endogenous biometals (Zn, Cu, Fe) were evaluated by inductively coupled plasma mass spectrometry (ICP-MS) solution analysis and LA-ICP-MS imaging. ICP-MS results showed robust Pb, Cd, and As uptake in mouse brain and blood after 30-day exposure to epidemiologically relevant levels of each metal/metalloid in drinking water. We also demonstrated a strong correlation between brain and blood levels of As, Cd, and Pb. LA-ICP-MS mapping showed that neurotoxicants have non-homogeneous element-specific accumulation in different brain regions and subregions, including the hippocampus and cortex. MODEL-AD mice exposed to Pb, Cd, or As accumulate neurotoxicants in blood and brain that can be detected, imaged, and quantified by ICP-MS solution analysis and LA-ICP-MS imaging. References : [1] R.A. Armstrong, Risk factors for Alzheimer's disease. Folia Neuropathologica ., 2019 , 57 , 87–105. [2] World Health Organization. 10 chemicals of public health concern. 2020 .

BACKGROUND:Validity of the 2021 NINDS Traumatic Encephalopathy Syndrome (TES) criteria, proposed to diagnose chronic traumatic encephalopathy (CTE) in life, has not been assessed. METHODS:Brain donors were selected across 6 brain banks (15+ donors each), 9 repetitive head impact (RHI)/traumatic brain injury (TBI) groups (15+ donors each): college or professional American football; less than college football; college or professional contact sports, not football; less than college contact sports, not football; military combat, no contact sports; military combat and contact sports, concussion with loss of consciousness, no RHI; moderate to severe TBI, no RHI; no RHI/TBI; and 5 age groups (25+ donors each): 20-34; 35-49; 50-64; 65-79; 80+. Blinded to clinical information, neuropathologists applied NINDS/NIBIB CTE neuropathological criteria and staging (I-IV). Blinded to neuropathological information, clinicians interviewed informants and reviewed medical records, and an expert panel adjudicated TES diagnoses, including provisional levels of CTE certainty (suggestive/possible/probable). Clinical and neuropathological diagnoses were a priori dichotomized for primary and age-stratified analyses: TES with possible/probable CTE vs. no TES/TES with suggestive CTE; CTE stages II-IV vs. no CTE/stage I CTE. RESULTS:Among 193 brain donors [men: 153 (79.3%), mean age: 66.4 (SD:22.0), white race: 158 (81.9%)], 57 (29.5%) donors met clinical criteria for TES with possible/probable CTE and 42 (21.8%) donors met neuropathological criteria for CTE stages II-IV. Using neuropathological diagnosis as the gold-standard, TES criteria sensitivity, specificity, positive likelihood ratio (LR) and negative LR were overall: 0.79, 0.84, 4.9, 0.25; age 50: 0.93, 0.90, 9.6, 0.07; age <50: 0.42, 0.66, 1.22, 0.89. Twenty-four donors who met clinical but not neuropathological criteria (false-positives), had stage I CTE (5) or other pathologies including vascular disease (11), Alzheimer's disease (9), Lewy body disease (2), motor neuron disease (2) and limbic predominant age-related TDP43 encephalopathy (1). Nine donors who met neuropathological but not clinical criteria (false-negatives) had TES with suggestive CTE (3), another etiology fully explain the syndrome (4), insufficient RHI exposure (1) or inconclusive course (1). CONCLUSION:The 2021 TES criteria were sensitive and specific for CTE pathology across a range of RHI/TBI exposures, particularly above age 50, raising optimism for use in clinical care.

V alidity of the 2021 NINDS Traumatic Encephalopathy Syndrome (TES) criteria, proposed to diagnose chronic traumatic encephalopathy (CTE) in life, has not been assessed. Brain donors were selected across 6 brain banks (15+ donors each), 9 repetitive head impact (RHI)/traumatic brain injury (TBI) groups (15+ donors each): college or professional American football; less than college football; college or professional contact sports, not football; less than college contact sports, not football; military combat, no contact sports; military combat and contact sports, concussion with loss of consciousness, no RHI; moderate to severe TBI, no RHI; no RHI/TBI; and 5 age groups (25+ donors each): 20-34; 35-49; 50-64; 65-79; 80+. Blinded to clinical information, neuropathologists applied NINDS/NIBIB CTE neuropathological criteria and staging (I-IV). Blinded to neuropathological information, clinicians interviewed informants and reviewed medical records, and an expert panel adjudicated TES diagnoses, including provisional levels of CTE certainty (suggestive/possible/probable). Clinical and neuropathological diagnoses were a priori dichotomized for primary and age-stratified analyses: TES with possible/probable CTE vs. no TES/TES with suggestive CTE; CTE stages II-IV vs. no CTE/stage I CTE. Among 193 brain donors [men: 153 (79.3%), mean age: 66.4 (SD:22.0), white race: 158 (81.9%)], 57 (29.5%) donors met clinical criteria for TES with possible/probable CTE and 42 (21.8%) donors met neuropathological criteria for CTE stages II-IV. Using neuropathological diagnosis as the gold-standard, TES criteria sensitivity, specificity, positive likelihood ratio (LR) and negative LR were overall: 0.79, 0.84, 4.9, 0.25; age 50: 0.93, 0.90, 9.6, 0.07; age <50: 0.42, 0.66, 1.22, 0.89. Twenty-four donors who met clinical but not neuropathological criteria (false-positives), had stage I CTE (5) or other pathologies including vascular disease (11), Alzheimer's disease (9), Lewy body disease (2), motor neuron disease (2) and limbic predominant age-related TDP43 encephalopathy (1). Nine donors who met neuropathological but not clinical criteria (false-negatives) had TES with suggestive CTE (3), another etiology fully explain the syndrome (4), insufficient RHI exposure (1) or inconclusive course (1). The 2021 TES criteria were sensitive and specific for CTE pathology across a range of RHI/TBI exposures, particularly above age 50, raising optimism for use in clinical care.