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Plasma-to-autopsy studies are essential for validation of blood biomarkers and understanding their relation to Alzheimer’s disease (AD) pathology. Few such studies have been done on phosphorylated tau (p-tau) and those that exist have made limited or no comparison of the different p-tau variants. This study is the first to use immunoprecipitation mass spectrometry (IP-MS) to compare the accuracy of eight different plasma tau species in predicting autopsy-confirmed AD. The sample included 123 participants (AD = 69, non-AD = 54) from the Boston University Alzheimer’s disease Research Center who had an available ante-mortem plasma sample and donated their brain. Plasma samples proximate to death were analyzed by targeted IP-MS for six different tryptic phosphorylated (p-tau-181, 199, 202, 205, 217, 231), and two non-phosphorylated tau (195–205, 212–221) peptides. NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Binary logistic regressions tested the association between each plasma peptide and autopsy-confirmed AD status. Area under the receiver operating curve (AUC) statistics were generated using predicted probabilities from the logistic regression models. Odds Ratio (OR) was used to study associations between the different plasma tau species and CERAD and Braak classifications. All tau species were increased in AD compared to non-AD, but p-tau217, p-tau205 and p-tau231 showed the highest fold-changes. Plasma p-tau217 (AUC = 89.8), p-tau231 (AUC = 83.4), and p-tau205 (AUC = 81.3) all had excellent accuracy in discriminating AD from non-AD brain donors, even among those with CDR < 1). Furthermore, p-tau217, p-tau205 and p-tau231 showed the highest ORs with both CERAD (OR p-tau217  = 15.29, OR p-tau205  = 5.05 and OR p-tau231  = 3.86) and Braak staging (OR p-tau217  = 14.29, OR p-tau205  = 5.27 and OR p-tau231  = 4.02) but presented increased levels at different amyloid and tau stages determined by neuropathological examination. Our findings support plasma p-tau217 as the most promising p-tau species for detecting AD brain pathology. Plasma p-tau231 and p-tau205 may additionally function as markers for different stages of the disease.

Introduction This study examined plasma glial fibrillary acidic protein (GFAP) as a biomarker of cognitive impairment due to Alzheimer's disease (AD) with and against plasma neurofilament light chain (NfL), and phosphorylated tau (p‐tau)181+231. Methods Plasma samples were analyzed using Simoa platform for 567 participants spanning the AD continuum. Cognitive diagnosis, neuropsychological testing, and dementia severity were examined for cross‐sectional and longitudinal outcomes. Results Plasma GFAP discriminated AD dementia from normal cognition (adjusted mean difference = 0.90 standard deviation [SD]) and mild cognitive impairment (adjusted mean difference = 0.72 SD), and demonstrated superior discrimination compared to alternative plasma biomarkers. Higher GFAP was associated with worse dementia severity and worse performance on 11 of 12 neuropsychological tests. Longitudinally, GFAP predicted decline in memory, but did not predict conversion to mild cognitive impairment or dementia. Discussion Plasma GFAP was associated with clinical outcomes related to suspected AD and could be of assistance in a plasma biomarker panel to detect in vivo AD.

INTRODUCTION We examined the relationship between sedentary behavior (SB), moderate‐to‐vigorous physical activity (MVPA), and white matter hyperintensity (WMH) volumes, a common magnetic resonance imaging (MRI) marker associated with risk of neurodegenerative disease in middle‐aged to older adults. METHODS We used data from the UK Biobank (n = 14,415; 45 to 81 years) that included accelerometer‐derived measures of SB and MVPA, and WMH volumes from MRI. RESULTS Both MVPA and SB were associated with WMH volumes (βMVPA = −0.03 [−0.04, −0.01], p < 0.001; βSB = 0.02 [0.01, 0.03], p = 0.007). There was a significant interaction between SB and MVPA on WMH volumes (βSB×MVPA = −0.015 [−0.028, −0.001], pSB×MVPA = 0.03) where SB was positively associated with WMHs at low MVPA, and MVPA was negatively associated with WMHs at high SB. DISCUSSION While this study cannot establish causality, the results highlight the potential importance of considering both MVPA and SB in strategies aimed at reducing the accumulation of WMH volumes in middle‐aged to older adults. Highlights SB is associated with greater WMH volumes and MVPA is associated with lower WMH volumes. Relationships between SB and WMH are strongest at low levels of MVPA. Associations between MVPA and WMH are strongest at high levels of SB. Considering both SB and MVPA may be effective strategies for reducing WMHs

INTRODUCTION Vascular comorbidities are modifiable contributors to cognitive impairment and Alzheimer's disease (AD), yet brain health outcomes are rarely evaluated in cardiovascular patients. METHODS This study prospectively evaluated cognition and AD pathology in 162 community‐dwelling adults with asymptomatic cardiovascular disease who did not have a clinical diagnosis of dementia or cognitive impairment. RESULTS Twenty‐nine percent of the cohort had Montreal Cognitive Assessment (MoCA) scores indicative of cognitive impairment or dementia after adjusting for age, sex, and education based on National Alzheimer's Coordinating Center normative data. AD blood biomarker phosphorylated tau217 was elevated in 55% of the cohort, significantly associated with decreased MoCA scores (β = −1.46, 95% confidence interval [CI] −2.53 to −0.39, p < 0.01), and accurately differentiated cognitive impairment (area under the curve 0.94, 95% CI 0.88–0.99). DISCUSSION This level of undiagnosed cognitive impairment and AD pathology exceeds what would be expected in the general population and highlights a potential need for screening and future work to better identify treatment options. Highlights Brain health outcomes are rarely evaluated in vascular patients. One hundred sixty‐two adults with asymptomatic cardiovascular disease but without diagnoses of cognitive impairment or dementia were evaluated. Phosphorylated tau217 accurately differentiated cognitive impairment in patients with cardiovascular disease. High levels of cognitive impairment and Alzheimer's disease pathology are greatly underdiagnosed in the cardiovascular population.

Background Longitudinal studies exploring the associations of sedentary behavior (SB) in different contexts with brain structure remain limited. We aimed to examine the association of SB at leisure and work with the risk of dementia and brain structure in middle‐aged and older adults over a 22‐year follow‐up. Method We analyzed data from the Atherosclerosis Risk in Communities (ARIC) study. Participants were enrolled between 1987‐1989, with visit 5 between 2011‐2013. SB was measured as the frequency of watching television during leisure and sitting during work time over the 12 months prior to baseline (categorized as never/seldom, sometimes, often, or very often). We identified prevalent dementia cases based on NIA‐AA criteria using telephone interviews and medical record review. Brain structure was assessed during visit 5 using 3T MRI to quantify white matter hyperintensities (WMH) and regional cortical volumes estimated from Freesurfer. Poisson (dementia risk) and linear regression (brain structures) models were adjusted for sociodemographic, behavioral, and clinical variables in addition to total intracranial volume in structural analyses. Result Participants (N = 5,747; 57% women) had a mean age of 52 (SD: 5.2) years at baseline. Participants who reported watching TV very often had a higher risk of dementia compared to those who watched TV never or seldom (RR: 1.69; 95%CI: 1.16, 2.45). In contrast, sitting often during work was linked to a lower risk (RR: 0.75; 95%CI: 0.57, 0.98). Watching TV very often was also associated with reduced cortical volume in the frontal (beta: ‐0.18; 95%CI: ‐0.30, ‐0.05), occipital (beta: ‐0.15; 95%CI: ‐0,30, ‐0.00), deep gray matter (beta: ‐0.15; 95% CI: ‐0.29, ‐0.00), and Alzheimer's disease signature regions (parahippocampal, entorhinal, inferior parietal lobules, hippocampus, and precuneus) (beta: ‐0.18; 95%CI: ‐0.31, ‐0.05) (Figure 1 and 2). Sitting during work often was linked to larger frontal (beta: 0.12; 95%CI: 0.04, 0.20) and temporal (beta: 0.13; 95%CI: 0.04, 0.22) cortical volumes. Participants who reported watching TV very often had increased WMH volumes (beta: 0.34; 95% CI: 0.13, 0.54) (Figure 2). Conclusion The association of SB with the risk of dementia and brain structure is dependent of the cognitive demands involved in the behavior.

INTRODUCTION Longitudinal studies linking sedentary behavior (SB) in different contexts to brain structure and white matter hyperintensity (WMH) volume remain limited. METHODS We analyzed data from the Atherosclerosis Risk in Communities (ARIC) study (n = 1,712). Self‐reported SB was assessed at visit 1 (1987–1989), with neuroimaging (3T magnetic resonance imaging [MRI]) at visit 5 (2011–2013). Participants were non‐demented adults (57% women; 53[5.2] years) who reported frequency of TV watching and occupational sitting. Outcomes included cortical, subcortical, and Alzheimer's disease–signature regions (ADSR), and total WMH brain volumes. RESULTS Frequent TV watching was associated with increased WMH volume and reduced frontal, occipital, and ADSR volumes. Sitting during work, which is more cognitively active, was linked to lower WMH and larger frontal (males only), occipital, and parietal volumes. Results remained consistent when adjusted for physical activity. DISCUSSION SB is associated with structural brain and WMH volumes. Cognitively active SB may preserve brain structure and cerebrovascular health. Highlights Sedentary behavior (SB) is associated with structural differences in brain regions vulnerable to Alzheimer's disease, distinct from physical activity. The associations between SB and cortical, subcortical, and white matter hyperintensity (WMH) volumes were context‐dependent (e.g., TV watching vs. occupational sitting) and sex‐specific. High frequency of TV watching was associated with higher WMH volume and, among males, with reduced cortical and subcortical volumes in regions involved in cognition and emotional processing. Occasional sitting during work showed an inverse association with cortical volumes. Sitting during work was linked to greater volume of frontal cortices only in males.

INTRODUCTION Poor sleep has been associated with elevated dementia risk, potentially related to its cerebrovascular consequences, measured by cerebral white matter hyperintensity (WMH) volume. METHODS We examined self‐reported sleep behaviors and prospective magnetic resonance imaging (MRI) WMH volume, measured 8.8 ± 1.7 (mean ± SD) years later, in 23,377 healthy UK Biobank participants. Each sleep behavior was adjusted for demographic, imaging, and clinical covariates (Model 1), as well as vascular health and lifestyle factors (Model 2), and significant sleep behaviors were then mutually adjusted. RESULTS In Model 1, all poor sleep behaviors were associated with greater WMH volume. In Model 2, only sleep duration outside 7–9 h (β = 0.015, false discovery rate [FDR]p = 0.014), increased daytime napping (β = 0.018, FDRp = 0.008), and greater sleeplessness (β = 0.015, FDRp = 0.014) were associated with greater WMH volume, with each behavior demonstrating distinct contributions (0.004 ≤ FDRp’s ≤ 0.025). DISCUSSION Self‐reported sleep behaviors were prospectively associated with greater WMH volume, suggesting a potential sleep‐related pathway influencing vascular brain health and dementia risk. Highlights Indicators of poor sleep are linked to greater WMH volume among healthy adults Sleep duration, napping, and sleeplessness impact brain aging beyond vascular risk Sleep may have a unique role in vascular brain health and dementia risk

INTRODUCTION Asymptomatic extracranial carotid atherosclerotic disease (aECAD) has been associated with Alzheimer's disease (AD), but the earliest cognitive deficits in this hallmark vascular population are largely unknown. METHODS A total of 182 participants 50–85 years of age with ≥2 vascular comorbidities with/without aECAD were evaluated prospectively using a neurocognitive battery and compared to vascular comorbidities, percent stenosis, apolipoprotein E (APOE) ε4 status, and plasma phosphorylated tau (p‐tau217). Dementia, stroke < 6 months, and neurological disorders were exclusionary. RESULTS aECAD was associated with significantly worse scores in processing speed (β = −0.19, p = 0.004) and executive function (β = −0.20, p = 0.009) domains after controlling for age, sex, education, race, and ethnicity. From these, a carotid cognitive index was created, which correlated with p‐tau217 (β = −0.29, p < 0.001), accounting for demographics, vascular comorbidities, white matter lesions, and APOE ε4 status. DISCUSSION These data identify specific cognitive deficits associated with carotid stenosis and build further impetus to understand how vascular‐related cognitive deficits contrast and complement the classic memory deficits of AD.

Objective:Blood-based biomarkers represent a scalable and accessible approach for the detection and monitoring of Alzheimer’s disease (AD). Plasma phosphorylated tau (p-tau) and neurofilament light (NfL) are validated biomarkers for the detection of tau and neurodegenerative brain changes in AD, respectively. There is now emphasis to expand beyond these markers to detect and provide insight into the pathophysiological processes of AD. To this end, a reactive astrocytic marker, namely plasma glial fibrillary acidic protein (GFAP), has been of interest. Yet, little is known about the relationship between plasma GFAP and AD. Here, we examined the association between plasma GFAP, diagnostic status, and neuropsychological test performance. Diagnostic accuracy of plasma GFAP was compared with plasma measures of p-tau181 and NfL.Participants and Methods:This sample included 567 participants from the Boston University (BU) Alzheimer’s Disease Research Center (ADRC) Longitudinal Clinical Core Registry, including individuals with normal cognition (n=234), mild cognitive impairment (MCI) (n=180), and AD dementia (n=153). The sample included all participants who had a blood draw. Participants completed a comprehensive neuropsychological battery (sample sizes across tests varied due to missingness). Diagnoses were adjudicated during multidisciplinary diagnostic consensus conferences. Plasma samples were analyzed using the Simoa platform. Binary logistic regression analyses tested the association between GFAP levels and diagnostic status (i.e., cognitively impaired due to AD versus unimpaired), controlling for age, sex, race, education, and APOE e4 status. Area under the curve (AUC) statistics from receiver operating characteristics (ROC) using predicted probabilities from binary logistic regression examined the ability of plasma GFAP to discriminate diagnostic groups compared with plasma p-tau181 and NfL. Linear regression models tested the association between plasma GFAP and neuropsychological test performance, accounting for the above covariates.Results:The mean (SD) age of the sample was 74.34 (7.54), 319 (56.3%) were female, 75 (13.2%) were Black, and 223 (39.3%) were APOE e4 carriers. Higher GFAP concentrations were associated with increased odds for having cognitive impairment (GFAP z-score transformed: OR=2.233, 95% CI [1.609, 3.099], p<0.001; non-z-transformed: OR=1.004, 95% CI [1.002, 1.006], p<0.001). ROC analyses, comprising of GFAP and the above covariates, showed plasma GFAP discriminated the cognitively impaired from unimpaired (AUC=0.75) and was similar, but slightly superior, to plasma p-tau181 (AUC=0.74) and plasma NfL (AUC=0.74). A joint panel of the plasma markers had greatest discrimination accuracy (AUC=0.76). Linear regression analyses showed that higher GFAP levels were associated with worse performance on neuropsychological tests assessing global cognition, attention, executive functioning, episodic memory, and language abilities (ps<0.001) as well as higher CDR Sum of Boxes (p<0.001).Conclusions:Higher plasma GFAP levels differentiated participants with cognitive impairment from those with normal cognition and were associated with worse performance on all neuropsychological tests assessed. GFAP had similar accuracy in detecting those with cognitive impairment compared with p-tau181 and NfL, however, a panel of all three biomarkers was optimal. These results support the utility of plasma GFAP in AD detection and suggest the pathological processes it represents might play an integral role in the pathogenesis of AD.

Objective:Blood-based biomarkers offer a more feasible alternative to Alzheimer’s disease (AD) detection, management, and study of disease mechanisms than current in vivo measures. Given their novelty, these plasma biomarkers must be assessed against postmortem neuropathological outcomes for validation. Research has shown utility in plasma markers of the proposed AT(N) framework, however recent studies have stressed the importance of expanding this framework to include other pathways. There is promising data supporting the usefulness of plasma glial fibrillary acidic protein (GFAP) in AD, but GFAP-to-autopsy studies are limited. Here, we tested the association between plasma GFAP and AD-related neuropathological outcomes in participants from the Boston University (BU) Alzheimer’s Disease Research Center (ADRC).Participants and Methods:This sample included 45 participants from the BU ADRC who had a plasma sample within 5 years of death and donated their brain for neuropathological examination. Most recent plasma samples were analyzed using the Simoa platform. Neuropathological examinations followed the National Alzheimer’s Coordinating Center procedures and diagnostic criteria. The NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Measures of GFAP were log-transformed. Binary logistic regression analyses tested the association between GFAP and autopsy-confirmed AD status, as well as with semi-quantitative ratings of regional atrophy (none/mild versus moderate/severe) using binary logistic regression. Ordinal logistic regression analyses tested the association between plasma GFAP and Braak stage and CERAD neuritic plaque score. Area under the curve (AUC) statistics from receiver operating characteristics (ROC) using predicted probabilities from binary logistic regression examined the ability of plasma GFAP to discriminate autopsy-confirmed AD status. All analyses controlled for sex, age at death, years between last blood draw and death, and APOE e4 status.Results:Of the 45 brain donors, 29 (64.4%) had autopsy-confirmed AD. The mean (SD) age of the sample at the time of blood draw was 80.76 (8.58) and there were 2.80 (1.16) years between the last blood draw and death. The sample included 20 (44.4%) females, 41 (91.1%) were White, and 20 (44.4%) were APOE e4 carriers. Higher GFAP concentrations were associated with increased odds for having autopsy-confirmed AD (OR=14.12, 95% CI [2.00, 99.88], p=0.008). ROC analysis showed plasma GFAP accurately discriminated those with and without autopsy-confirmed AD on its own (AUC=0.75) and strengthened as the above covariates were added to the model (AUC=0.81). Increases in GFAP levels corresponded to increases in Braak stage (OR=2.39, 95% CI [0.71-4.07], p=0.005), but not CERAD ratings (OR=1.24, 95% CI [0.004, 2.49], p=0.051). Higher GFAP levels were associated with greater temporal lobe atrophy (OR=10.27, 95% CI [1.53,69.15], p=0.017), but this was not observed with any other regions.Conclusions:The current results show that antemortem plasma GFAP is associated with non-specific AD neuropathological changes at autopsy. Plasma GFAP could be a useful and practical biomarker for assisting in the detection of AD-related changes, as well as for study of disease mechanisms.