Background: Evidence from observational studies and short-duration randomized controlled trials (RCTs) suggests that equol, a gut-derived metabolite of soy isoflavone daidzein, may confer cognitive benefits through efficient blood-brain barrier permeability, high selective affinity to the estrogen receptor-beta, and anti-atherogenic properties. Only 20-30% of Westerners possess the ability to convert daidzein to equol as compared to 50-70% of East Asians. Cross-sectional studies conducted in Japan reported that equol producers exhibit fewer white matter lesions (WMLs) and better cognition. However, it is unclear whether equol or the equol producer phenotype as a surrogate for certain microbiome composition or both may protect against dementia. Objective: To delineate the effect of equol and equol producers by testing whether equol producers have fewer WMLs and better cognitive function than non-producers in an older population with very low soy consumption. Methods: The Arterial Stiffness, Equol, and Cognition (ACE) trial (NCT05741060) recruited dementia-free infrequent soy consumers aged 65-85 to test whether equol supplementation can slow the progression of arterial stiffness, WMLs, and cognitive impairment. This analysis included 362 ACE participants (mean age 72.0 ± 4.7 years; 52% female; 21% African American) who underwent brain magnetic resonance imaging (MRI) scans and NIH Toolbox Cognitive Battery assessments. Equol producer phenotype was defined as the urinary equol-to-daidzein ratio (log10 ≥ -1.75) after a three-day soy challenge. Associations of equol producer phenotype with WMLs normalized to total intracranial volume (WML%) and cognitive tests were assessed using gamma-distributed generalized linear regression and linear regression adjusting for demographics, APOE-e4 status, and cardiovascular risk factors. Results: 30% of the participants were equol producers (Table 1). There is no statistically significant difference in WML% (Table 2) or cognitive performance (Table 3) between equol producers and non-producers. Conclusions: Among infrequent soy consumers, equol producer phenotype is not associated with WMLs or cognitive performance. Without soy intake, equol producers do not show a similar cognitive advantage as observed in East Asians. The results suggest that equol is critical for the cognitive benefits.

Introduction Loneliness is increasingly recognized as a serious and pervasive psychosocial risk factor in late life and has been linked to heightened risks of cognitive decline, depression, and mortality (Hawkley and Cacioppo, 2022; Oken et al., 2024). In late-life brain health, loneliness may be particularly toxic, exerting physiological effects through heightened stress reactivity, systemic inflammation, and vascular dysfunction (Finley 2022; Xia et al. 2018). One neurological substrate of aging is the accumulation of white matter hyperintensities (WMH), brain lesions that act as indicators of cerebral small vessel diseases (Griffanti et al., 2021), and have been linked to cognitive impairments, ​mood disturbances, and​ decreased quality of life. While various psychosocial factors across the lifespan have been implicated in WMH burden, their relative contributions remain unclear in the geriatric population (Taylor et al., 2018). By focusing on loneliness, this study investigates its association with WMH volume to inform therapeutic strategies that target social well-being as a pathway to neurological health in aging populations. Methods We analyzed baseline data from older adults (n=98: median age = 72.4years, IQR, 69.4-76.3; 51% male, 49% female; Table 1), recruited from an ancillary cohort of the parent Arterial Stiffness, Cognition, and Equol trial. The sample was predominantly White (90%), with 10% African American. Educational levels were distributed into three groups: some college or less (22%), completed college (25%), and postgraduate (53%). Participants completed a comprehensive neuropsychological battery, and we employed the UCLA Loneliness Scale (UCLA-LS) as an index of loneliness level. WMH volume was quantified on the T2w FLAIR image using a 2D U-Net machine learning method developed in our lab (Li et al., 2023), normalized by intracranial volume, and log-transformed (nWMH). Linear regression models were used to examine associations between UCLA-LS and WMH burden. Model 1 included unadjusted associations, while Model 2 adjusted for age, sex, race, education, hypertension and diabetes status. Results In univariate analyses (Model 1, Table 2), higher loneliness was marginally associated with greater WMH burden (β = ​0.02, 95% CI [​0.00,0.04], p = 0.060). In fully adjusted analyses (Model 2, Table 2), higher loneliness was significantly associated with greater WMH burden (β = 0.02, 95% CI [0.00, 0.05], p = 0.030), indicating that loneliness was uniquely associated with greater WMH burden, independent of demographic and health characteristics. Sex, race, education, hypertension, and diabetes were not significant predictors, although males showed a marginal trend toward lower WMH burden compared with females (β = -0.39, 95% CI [–0.83, 0.06], p = 0.088). Conclusions In our analysis, loneliness was significantly associated with greater WMH burden, highlighting the potential importance of social and emotional well-being in brain aging. Although other measures were not significant, these results should be interpreted cautiously, given limited power. These results suggest that loneliness may represent a meaningful intervention target aiming at promoting brain health in aging populations. Given the cross-sectional design, causality cannot be inferred; future longitudinal and interventional studies are needed to determine whether reducing loneliness can mitigate WMH progression.

Background Sedentary behavior is common in older adulthood and is associated with poor health outcomes. Less is known about how sedentary behavior relates to cognition in older adulthood and how it relates to increased risk for cognitive decline associated with Alzheimer's disease (AD).Objective We sought to examine these associations in a large, population-based cohort of community-dwelling older adults residing in a Rust Belt region of the United States.Methods A subset of the population-based Monongahela-Youghiogheny Healthy Aging Team (MYHAT) participants (n = 193) completed 7 days of wrist-accelerometry following comprehensive neuropsychological assessment. Cross-sectional linear regression models related sedentary time to domains of cognition. Models were adjusted by age, sex, education, and APOE4 carrier status and moderate to vigorous physical activity (MVPA). The interaction between sedentary behavior and APOE4 genotype on cognition was also examined.Results Greater sedentary behavior was associated with worse executive function (beta = -0.06, p = 0.01) and memory (beta = -0.06, p = 0.05) performance. These results were attenuated when adjusting for MVPA. No significant interactions between sedentary time and APOE4 carrier status were observed, although estimation results applying the delta method on regression coefficients suggested the associations were stronger in APOE4 non-carriers when compared to APOE4 carriers.Conclusions Higher levels of sedentary behavior were associated with worse performance in cognitive domains implicated in AD. Public health initiatives and precision-based medicine approaches to reduce sedentary behavior in a population-based cohort of older adults may be important AD prevention measures. Results support the importance of reducing sedentary time.

INTRODUCTION:We evaluated the effects of astrogliosis on Alzheimer's disease (AD) pathology, co-pathology, and symptoms. METHODS:Cross-sectional data from 187 non-demented participants were processed to obtain measures of SMBT-1 standard uptake value ration (SUVR), plasma glial fibrillary acidic protein (GFAP), β-amyloid (Aβ), Centiloids (CL), tau (CenTauR), white matter hyperintensities (WMH), hippocampal volume (HV), and cognition. Linear regressions evaluated pairwise associations, linear regression interaction terms indicated moderating association, and causal mediation analysis evaluated mediating associations. RESULTS:Astrogliosis was associated with CL (p < 0.01), neurodegeneration (0.05 < p < 0.1), and global cognition (p < 0.01). Moderation analyses revealed SMBT-1 SUVR had an attenuating interaction with CL in respect to CenTauR (β = -0.13, p = 0.0006) and memory impairment (β = 0.064, p = 0.05). Plasma GFAP had an attenuating interaction with CL in respect to CenTauR (β = -0.19, p = 0.00001). DISCUSSION:Reactive astrogliosis is an early and important player in the AD development pathway by having an early attenuating effect against Aβ. More work is needed to further understand these complex associations.

Background: Skeletal muscle adiposity (i.e. myosteatosis) increases with age and is a risk factor for cardiometabolic diseases. Recent studies suggest that myosteatosis may play a role in cognitive functioning. Prospective studies in African ancestry populations are sparse, yet this population has higher risks of myosteatosis and Alzheimer’s disease and related dementias than Whites. Aim: To investigate the association between changes in myosteatosis over an 18-year follow-up period and cognitive functioning among middle-aged and older African Caribbean men. Method: Two hundred ninety-two (292) men participating in the Tobago Health Study were analyzed. Calf muscle density (MD) was measured at baseline, follow-up visit (FV) 1 (6.2±0.4 years after baseline), and FV2 (12.0±0.8 years after FV1) using peripheral quantitative computed tomography, where lower density reflects greater myosteatosis. Neurocognitive functioning was assessed using validated tests at FV2 across 6 domains (global cognition (MoCA), executive function (Trails B), psychomotor speed (Digit Symbol, Trails A), language (Animals&Vegetables), memory (Word List Recall), and visual-spatial skills (Benson Figure Copy)). Individual slopes of MD change over time from linear regression were used as predictors in linear and Poisson regression models to test the association between cognition and longitudinal changes in MD. Results: At FV2, men were 69.5 ± 5.8 years old, with high prevalences of obesity (23.2%), hypertension (82.0%), and diabetes (25.0%). MD decreased over the 18-year follow-up period (-0.17 ± 0.24 mg/cm3 per year). After adjusting for demographics, baseline MD, muscle area, comorbidities, lifestyle factors, and medication use, a 0.1 mg/cm3 per year faster decline in MD was associated with a 0.286-point lower MoCA score (p=0.03). Similarly, a 0.1 mg/cm3 per year faster decline in MD was associated with a 1.71 second slower psychomotor speed (p=0.032). Yearly decreases in MD were also associated with worse semantic verbal fluency (β: -1.73, p=0.02). Conclusion: Faster declines in muscle density are associated with poor domain-specific cognitive performance and may signal early cognitive impairment. Future research should include women and focus on mechanisms to understand the role of myosteatosis in cognitive impairment.

BackgroundPlasma biomarkers for Alzheimer's disease (AD) studies, but much remains unknown about the associations of plasma and PET biomarkers of amyloid-β (Aβ).ObjectiveTo determine the associations of plasma Aβ with PET Aβ accumulation and progression from PET A- to A + .MethodsWe evaluated PET A- participants with baseline plasma Aβ measurements and longitudinal indices of PET Aβ. Linear mixed effects models characterized the association of plasma biomarker outcomes with changes in PET Aβ values. Survival analysis evaluated the ability of baseline plasma biomarker A+/- status to differentiate trajectories of progression from PET A- to A + .ResultsLinear mixed effects models showed significant interactions between time and plasma Aβ42/40 with respect to longitudinal measures of PET Aβ burden. Survival analysis found that A status determined from plasma Aβ42/40 predicted distinct patterns of progression from PET A- to A + .ConclusionsThese models suggest that, in PET A- participants, baseline plasma Aβ42/40 can be used to predict both how much Aβ will accumulate over time and likelihood of becoming PET A + .

Blood-based biomarkers have expanded access to biologically supported diagnosis of Alzheimer's disease (AD), particularly through measurement of amyloid-beta (Aβ) and phosphorylated tau species1-3. Among these, plasma tau phosphorylated at threonine 217 (p-tau217) is currently the leading biomarker recommended by clinical guidelines4-6. However, circulating p-tau217 originates from both central nervous system (CNS) and peripheral tissues7, potentially limiting specificity, particularly in individuals with common age-related comorbidities8. Here we report a next-generation biomarker, brain-derived p-tau217%, which quantifies the proportion of circulating tau that is CNS-derived and phosphorylated at threonine 217. Across neuropathologically defined, Aβ- and tau-neuroimaging-characterized, and memory clinic cohorts, brain-derived p-tau217% consistently identified AD pathology and clinical AD with larger effect sizes, higher discriminative accuracy, and improved sensitivity and specificity, outperforming conventional non-CNS-selective plasma p-tau217, p-tau217/Aβ1-42 and p-tau217% alternatives as well as brain-derived-p-tau217 alone. Furthermore, the CNS-selective biomarker demonstrated more robust prediction of future clinical progression in individuals followed for up to two decades. Importantly, diagnostic performance remained high in older adults with diabetes and cardiovascular disease, populations in which standard p-tau217 showed reduced specificity. Moreover, superiority extended to comparisons against multiple CNS disease-related proteins in targeted proteomic analyses. These findings establish plasma brain-derived p-tau217% as a biologically grounded and clinically robust biomarker that advances molecular definition, detection, and prognosis of Alzheimer's disease.

Background:Plasma p-tau217 is a promising biomarker for detecting incipient AD pathology, but direct comparison of different p-tau217 assays in community-based cohorts are limited. Methods:We evaluated two cohorts from southwestern Pennsylvania, USA; the MYHAT-NI sub-study, which included two-year longitudinal follow-up neuroimaging assessments of Aβ, tau, and cortical thickness; and the Human Connectome Project/CoBRA, targeting a 50:50 split of self-identified Black and non-Hispanic White individuals. Plasma p-tau217 was measured using four different assays: Lumipulse, Johnson&Johnson, ALZpath, and NULISA. Aβ and tau pathologies were assessed with [11C]PiB PET and [18F]Flortaucipir PET, respectively. Clinical Dementia Rating (CDR) and Montreal Cognitive Assessment were used to assess cognitive performance. Results:We included 344 participants (MYHAT-NI: n=111, median age 76 [IQR: 72-80], 54% female; HCP/CoBRA: n=234, median age 62 [IQR: 52-70], 65% female). All four p-tau217 assays exhibited moderate to strong cross-platform correlations (Spearman correlations of 0.40 - 0.86), and statistically equivalent AUCs (of 0.84-0.90) for determining Aβ positivity. Conclusions:Our findings showed strong equivalent performances of plasma p-tau217 assays to identify amyloid positivity across two highly diverse cohorts of community-dwelling older adults.

BACKGROUND/OBJECTIVE:Loneliness has been linked with cognitive decline and dementia. Studies show relationships between loneliness and neurodegeneration, amyloid, and tau burden. We investigated whether loneliness relates to plasma biomarkers of neurodegenerative processes among cognitively normal or mildly impaired older adults at the population level. SETTING/PARTICIPANTS:A population-based cohort (n = 884) in southwestern Pennsylvania. MEASUREMENTS:Demographics; loneliness and social isolation composite scores, depression symptoms, Clinical Dementia Rating, plasma amyloid beta (Aβ) 42, Aβ40, p-tau181, p-tau217, NfL, GFAP. DESIGN:We examined the associations of loneliness with plasma biomarkers using regression analyses in both cross-sectional and longitudinal models. For cross-sectional analysis, we used data from 884 dementia-free participants at the closest wave to biomarker testing (within 180 days). For longitudinal analysis, we first derived loneliness trajectories from 514 participants with repeated annual loneliness measurements for up to 15 years prior to biomarker testing, then used these trajectories as predictors in regression models examining their associations with plasma biomarkers. RESULTS:Compared with the stable loneliness trajectory, the increasing loneliness trajectory showed nominally higher p-tau181 levels (β = 0.305 log-transformed, 95% CI: 0.022, 0.587; t_476 = 2.112; p = 0.035, uncorrected; multiple comparison-adjusted p = 0.211), adjusting for age, sex, education, social isolation, and depression symptoms. CONCLUSIONS:This exploratory analysis found a nominal association between increasing loneliness and p-tau181 that did not survive correction for multiple comparisons. Findings should be considered hypothesis-generating. If confirmed through replication in larger samples, associations between loneliness patterns and tau pathology could inform understanding of psychosocial contributions to neurodegeneration.

Background: Memory loss is a core feature of typical Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). Standard memory tests such as word lists assess verbal episodic memory with delayed recall and recognition. However, actual memory fidelity is likely variable, continuous, and has a subjective component. Objective: We investigated dual-processing models of episodic memory (recollection versus familiarity) using confidence ratings in a "judgment of knowing" paradigm (JOK). Methods: This paradigm was applied to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) memory test as part of neuropsychological evaluation at University of Pittsburgh Alzheimer's Disease Research Center (ADRC), to generate novel indices of memory function to improve sensitivity to early memory problems and provide a memory awareness metric. On recognition testing, participants rated how sure they were of their yes/no responses to each item. We derived novel variables related to memory and metacognition, including an Accuracy-Certainty Index and the Relative Certainty Index. Results: In this sample of 347 participants (185 with AD, 55 with MCI, 111 cognitively unimpaired), CERAD Delayed Recall was the best single variable for discriminating groups, although multiple certainty variables also discriminated groups well. Conclusions: The addition of certainty indices to a standard verbal memory task increased discriminative power between groups, particularly between cognitively normal controls and MCI or AD.

Differences in Alzheimer’s disease (AD) amyloid, tau, vascular, and neurodegeneration (ATV(N)) biomarkers by sex and racialized group have been reported, but little is known about the intersections of sex and racialization on these biomarkers. Participants in this cross-sectional analysis are from the Connectomics of Brain Aging study, a Human Connectome Project protocol evaluating brain structure and function in aging and AD. We measured A using global amyloid SUVR from 11 C-PiB PET, T using plasma p-tau 217, V using lobar unhealthy white matter connectivity (UWMC), a novel measure indicating the proportion of WM connections impacted by white matter hyperintensities (WMH), and N using cortical thickness from an AD-based meta-region of interest. We tested for intersectional effects of sex and racialized group on ATV(N) biomarkers in robust regressions by testing models with and without sex*racialized group interaction terms. The sample included N=202 participants with the following characteristics: age, 62 years; female sex, 67%; Black racialization, 50%; education, 14 years; APOE4+, 31%; cognitively impaired, 27%; Table 1. In robust regression models we found that women had significantly more amyloid and frontal UWMC, and less tau and parietal and occipital UWMC than men; participants racialized as Black had significantly more temporal lobe UWMC and significantly less occipital lobe UWMC, amyloid, tau, and cortical thickness than participants racialized as white (Table 2). Intersectional effects were found only for parietal lobe UWMC (p for interaction=0.03; Table 2), such that men racialized as Black had the greatest parietal UWMC, while men and women racialized as white did not vary in their parietal UWMC (Figure 1). Results with lobar WMH instead of UWMC were similar. Our results confirm ATV(N) biomarker differences by sex and racialized group. They suggest that men racialized as Black may be uniquely at risk for UWMC in the parietal lobe but found no intersectional effects on other biomarkers. Future work will investigate specific WM tracts involved in the parietal UWMC and associated risk factors such as structural and social determinants of health as well as cardiovascular risk factors and comorbidities.

Blood-based biomarkers offer a cost-effective and simple alternative for clinical use in the context of Alzheimer's disease (AD). It has already been shown that plasma phosphorylated tau at threonine 217 (p-tau217) is associated with amyloid (Aβ), neurofibrillary tau tangles, and cognitive decline. Longitudinal studies confirmed its ability to track AD progression. Therefore, the aim of this study is to evaluate the potential utility of changes in plasma p-tau217 as secondary outcome in clinical trials across the AD spectrum. We included 189 individuals with available plasma p-tau217 measurements at two time points (24 months follow-up) across two cohorts:[MYHAT-NI, population-based(USA): 51 Cognitively Unimpaired(CU); BICWALZS, memory clinic(South Korea): 135 Cognitively Impaired(CI) individuals], all with baseline Aβ-PET. Plasma p-tau217 was quantified using the ALZpath assay. We used linear regression to investigate p-tau217 association with cognitive decline. Effect size was determined by biomarker mean change divided by the standard deviation. We also estimated the sample size required to detect a 25% drug effect on p-tau217 reduction with 80% power at a significance level of 0.05. Baseline and longitudinal changes in p-tau217 were significantly associated with cognitive decline independently of Aβ status in both CU and CI individuals (Table 1). Functionally, individuals classified with mild dementia (CDR-SB>4.5) showed greater and pronounced annual changes in p-tau217 compared to the other groups (Figure 1A). Notably, Aβ+ individuals presented a higher effect size for p-tau217 changes in both CU(0.79) and CI(0.74) groups, compared to the whole population (Figure 2B). The sample size required for a clinical trial including of Aβ+ individuals were 1,276 for CU and 940 for the CI. Cost analysis revealed that in trials recruiting CU Aβ+ individuals targeting tau pathology using p-tau217 as a secondary outcome was 1.5, 3.7, and 3.9 times more cost-effective than 18 F-MK-6240 tau-PET, 18 F-Flortaucipir tau-PET, and p-tau181, respectively (Figure 2). Similarly, in trials with CI Aβ+ participants, p-tau217 was 1.5 times less expensive than [ 18 F]-MK-6240 tau-PET, and 3.7 times less than [ 18 F]-Flortaucipir tau-PET. Our results demonstrated that changes in plasma p-tau217 is associated with cognitive decline across the AD continuum. Furthermore, p-tau217 shows promise as a secondary outcome in AD clinical trials.

Background Extracranial carotid artery calcification (ECAC) is a known risk factor for the development of cardiovascular diseases (CVD) and has been associated with an increased risk of dementia and Alzheimer's disease. However, the relationship between ECAC and amyloid-β (Aβ) deposition in older adults has not been fully understood. Objective This study aims to determine the relationship between ECAC and Aβ deposition in very old adults. Methods 90 participants (87.2 ± 2.7 years old, 96% whites, 63% males) without dementia from an observational study were included in the cross-sectional analysis. Aβ deposition in the brain was assessed using the 11 C-labeled Pittsburgh compound-B positron emission tomography (PiB-PET) scans performed in 2009 and 2011. Carotid artery plaque and ECAC status were measured via high-resolution carotid ultrasonography in 2011. Results Among the participants, 82 (91%) had carotid plaques, and 46 (51%) were globally Aβ positive by PiB-PET. ECAC was less frequently observed in the Aβ positive group compared to the Aβ negative group (90% versus 81%, p = 0.3). The odds of Aβ positivity in those with ECAC were 62% lower than in those without ECAC. However, the association was not statistically significant (OR = 0.38, 95% CI: [0.08, 1.76 ], p = 0.2). Conclusions In the population whose average age is older than 85 without dementia, there is no statistically significant association between ECAC and Aβ deposition after adjusting for confounding factors. The relationship between ECAC and dementia in older adults warrants further analysis in a larger and more racially and ethnically diverse population.

Rest-activity rhythms (RAR) may serve as early indicators of cognitive decline, yet their associations with cognitive impairment and Alzheimer’s disease (AD) biomarkers remain unclear. Thus, our study aims to examine the associations between objectively measured rest-activity rhythms, diagnosis of mild cognitive impairment (MCI) and AD, and AD-related plasma biomarkers in older adults in the Connectomics in Brain Aging and Dementia study. A total of 180 participants (mean age=65.0y, 64.4%women, 55.56% Black) had valid 7-day wrist-worn accelerometer assessment and consensus cognitive diagnosis in 2016-2021. RAR measures were computed using nparACT R package including interdaily stability (IS), intradaily variability (IV), relative amplitude (RA), M10 (activity levels at the most active 10 hours), and L5 (activity levels at the least active 5 hours). Plasma biomarkers (Aβ42, Aβ40, phosphorylated tau [p-tau]181, p-tau217, p-tau231, glial fibrillary acidic protein [GFAP], and neurofilament light chain [NfL]) were measured. Logistic regression models showed that higher IS and higher M10 were associated with lower odds of MCI or dementia diagnosis (odds ratio [OR]=0.15, 95% confidence interval[CI]=0.03-0.82, p = 0.03; OR = 0.94, 95% CI = 0.90-0.98, p = 0.003, respectively) after adjusting for sociodemographic factors. No significant associations were found between RAR and Aβ or p-tau biomarkers. However, linear regression models showed that higher RA was significantly associated with lower GFAP levels (β=-164.3, p = 0.02). Findings suggest that more stable (IS) and robust (RA) rest-activity rhythms may serve as non-invasive markers of cognitive health in older adults. Circadian disruptions may be linked to neuroinflammatory processes more than amyloid or tau pathology, but warrant further investigations in longitudinal studies.

INTRODUCTION:Long-term brain health profiles following exposure to repetitive head impacts and/or concussions in contact sports are a public health focus and the subject of a national debate. The true prevalence rates of mild cognitive impairment (MCI) or neurobehavioural dysregulation are unknown in the nearly 20 000 current/living former professional football players. Here, we describe the procedures and methodology of the prevalence study of cognitive function in former professional football players from the Brain Health Initiative at the University of Pittsburgh. The objective is to define the prevalence of normal cognitive function versus neurodegeneration in former professional football players through clinical, neuroimaging and biomarker assessments. METHODS AND ANALYSIS:Participants include former professional football players aged 29-59 years at study onset who played a minimum of three professional football games in three professional seasons and non-exposed controls. Participants are recruited by two mechanisms, a random and non-random sample. The full study protocol includes a 3-4-day, multidomain assessment (eg, neurological, neurocognitive, psychiatric, sleep, vestibular, orthopaedic and cardiovascular) for neurodegenerative disease and overall health and function, including MRI, positron emission tomography scans, analysis of blood plasma and cerebrospinal fluid, neurocognitive assessments, applanation tonometry, overnight sleep study and informant interview. A multidisciplinary clinical panel conducts a blinded diagnostic consensus conference to adjudicate the presence of MCI and/or traumatic encephalopathy syndrome, which serve as the study's primary and secondary outcomes, respectively. Point prevalence of these for both the exposed and unexposed cohorts will be calculated as the primary statistical analysis. ETHICS AND DISSEMINATION:The University of Pittsburgh Institutional Review Board approved the study prior to recruiting human subjects (protocol numbers STUDY19010008: sIRB - Brain Health Initiative (Part 1) and STUDY19030211: sIRB - Brain Health Initiative (Part 2)). The results will be disseminated in peer-reviewed journals and as presentations at national and international scientific conferences.

Given the increasing usage of plasma biomarkers for Alzheimer’s disease (AD) studies, it is necessary to better understand relationships between plasma biomarker and PET and MR imaging outcomes, particularly within the AT(N) framework. We evaluated plasma samples from 233 subjects (age 74.05.9y) who underwent 3T MR and both [ 11 C]PiB and [ 18 F]flortaucipir (FTP) PET imaging. SUVR values were calculated for Global PiB, and Meta-Temporal FTP. An AD signature cortical thickness (CT) composite was derived from MR images using FreeSurfer 5.3, Blood samples were processed and sampled to obtain measures of plasma Aβ42, Aβ40, p-tau181, p-tau217, p-tau231 and neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Imaging outcomes were split into infra (-) and supra (+) threshold groups using 1.35 SUVR for Global PiB, 1.18 SUVR for Meta-Temporal FTP, and 2.7 mm for CT. Plasma Aβ was expressed as Aβ42/Aβ40 ratio while p-tau181, p-tau217, p-tau231, NfL, and GFAP were natural-log-transformed to normally distribute the data. Simple regression models between continuous variables of each imaging-derived measure and all plasma biomarkers were evaluated. Full group regression model R 2 and regional p-values are shown in Table 1, suprathreshold regressions are shown in Table 2. Full Global PiB was significantly associated with all plasma biomarkers while CT was associated with NfL, p-tau181, and p-tau231. Meta-Temporal FTP was associated with GFAP and p-tau217. Additionally, A+Global PiB was significantly associated with Aβ42/Aβ40, GFAP, and p-tau217; (N+) CT with NfL; and T+ Meta-Temporal FTP with p-tau181 and GFAP. The significant associations between suprathreshold imaging and plasma biomarkers suggests that, in A+, T+, or (N+) both capture abnormal AD pathophysiology. Further, the absence of an association in the infrathrehold cases supports that the suprathreshold associations are not artifactual. Future work will explore plasma thresholds and concordance between imaging and plasma AT(N).

INTRODUCTION:Most available phosphorylated tau (p-tau)217 immunoassays have similar performance. It is unclear if this is due to the use of the same antibody (the "ALZpath antibody"). We established and evaluated a novel p-tau217 assay that uses an alternative antibody and benchmarked the results against ALZpath-p-tau217. METHODS:After development and analytical validation of the University of Pittsburgh ("Pitt-p-tau217") method, clinical verification was performed in three independent cohorts (n = 363). RESULTS:Pitt-p-tau217 demonstrated high between-run stability, linearity, and specificity. Clinically, Pitt-p-tau217 differentiated neuropathologically confirmed PSEN1 mutation carriers from controls with area under the curve (AUC) = 0.94, and amyloid beta (Aβ) positron emission tomography (PET)-positive from Aβ PET-negative cognitively normal older adults with AUC up to 0.84, equivalent to ALZpath-p-tau217 results. Both Pitt-p-tau217 and ALZpath-p-tau217 were slightly elevated in tau PET-positive versus tau PET-negative participants. Between-assay correlations were up to 0.93. DISCUSSION:The new Pitt-p-tau217 assay exhibits high and reproducible classification accuracies for identifying individuals with biological evidence of Alzheimer's disease, equivalent to the widely used ALZpath-p-tau217. HIGHLIGHTS:We designed and developed an alternative assay to quantify plasma phosphorylated tau (p-tau)217, aiming to enhance accuracy and enable early detection of Alzheimer's disease (AD). Comprehensive analytical and clinical validation demonstrated that the new p-tau217 assay is a valuable and affordable resource for investigating AD pathophysiology. The new p-tau217 assay showed similar performance to the established ALZpath assay in staging and monitoring early AD.

Many complex traits and diseases show sex-specific biases in clinical presentation and prevalence. For instance, two-thirds of AD cases are female. Studies suggest that women might have higher cognitive reserve but steeper cognitive decline in older age. Cognitive traits have substantial genetic influence. Cognitive impairment could vary among sexes due to sex-specific genetic factors. To understand the sex-specific genetic architecture of cognitive decline, we performed genome-wide association study (GWAS) on sex-stratified data and assessed a SNP-sex interaction. We derived inter-individual specific slopes using linear mixed effect model adjusting for age, education, and sex across five cognitive domains (attention, memory, executive function, language, visuospatial function) and global cognitive function in 3021 older adults aged ≥65 years (females = 1545, males = 1476) belonging to three prospective cohorts: Gingko Evaluation of Memory (GEM), Monongahela-Youghiogheny Heathy Aging Team (MYHAT), and Monongahela Valley Independent Elders Survey (MoVIES). GWAS was conducted on each cognitive phenotype in each cohort adjusting for the first four genetic principal components. Gene-based analysis was also conducted to discover genes specific to biological sexes. We identified a novel genome-wide significant (GWS) intergenic locus for decline of memory in males near RPS23P3 on chromosome 4 (top SNP: rs6851574; MAF = 0.39; P male = 4.10E-08, b male = -0.19; P female = 6.13E-01, b female = -0.017; P interaction = 3.76E-04). This intergenic region has previously been associated with other cognitive related traits such as educational attainment, anatomical brain aging and brain shape. We also identified a subthreshold GWS locus for decline of executive function in females near NDUFA12 on chromosome 12 (top SNP: rs11107823; MAF = 0.12; P female = 9.35E-08, b female = 0.28; P male = 0.151, b male = -0.077; P interaction = 7.42E-06). NDUFA12 /rs11107823 is cis-eQTL for NDUFA12 , NTN4 and VETZ in blood and brain tissues. NDUFA12 codes for a gene involved in oxidative phosphorylation in mitochondria and was also found to be suggestively associated with decline of executive function in gene-based analysis in females (P = 1.40E-04). In this sex-stratified analysis of cognitive decline, we identified two novel loci affecting cognition. Our study illustrates that sex-aware genetic studies can help in the identification of novel genetic loci and enhance sex-specific understanding of cognitive aging.