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Background: Subjective cognitive decline (SCD) may provide an early indicator of evolving neurodegenerative disease. Dyadic SCD patterns, or understanding the self/patient's in relation to an informant/loved one's endorsement of SCD, may more accurately reflect underlying Alzheimer's disease (AD) pathology in particular. We related dyadic discrepancies in SCD to markers of core AD pathology, including amyloid‐β42 (Aβ42) and phosphorylated tau (p‐tau). Method: Vanderbilt Memory and Aging Project participants free of clinical dementia [n = 150, 72±7years, 37% mild cognitive impairment (MCI)] and their informants completed the Everyday Cognition questionnaire. Dyadic discrepancy (self‐reported score minus informant‐reported score) was calculated. Positive scores indicate self>informant SCD and negative scores indicate informant>self SCD. Participants also underwent fasting lumbar puncture to obtain cerebrospinal fluid (CSF) for quantification of Aβ42 and p‐tau. Linear mixed‐effects regression models related dyadic score to individual CSF biomarkers adjusting for age, sex, self‐reported race/ethnicity, cognitive status, apolipoprotein E‐ε4 status (positive, negative), and depression symptoms (Geriatric Depression Scale) with false discovery rate (FDR) corrections for multiple comparisons. Models were repeated with a diagnosis x biomarker interaction. Result: SCD discrepancy in the negative direction (informant>self‐SCD) was associated with higher CSF p‐tau (β = ‐0.64, pFDR<0.001). Cognitive status modified the association between discrepancy score and Aβ42 (β = 10.81, pFDR = 0.02). Stratified analyses by cognitive status revealed that MCI participants with negative discrepancies (informant>self‐SCD) had lower Aβ42 levels (β = 5.592, pFDR = 0.02), indicating more cerebral amyloid deposition. The opposite pattern was observed in cognitively unimpaired participants, though findings did not survive FDR correction (β = 1.16, p = 0.03, pFDR = 0.24). Additionally, in MCI participants, negative SCD discrepancy was associated with higher p‐tau levels (β = ‐0.7223, pFDR = 0.02). All significant results survived outlier exclusion. See Figure for details. Conclusion: Dyadic SCD discrepancy correlates with AD biomarkers differently in preclinical and prodromal states. In MCI, greater informant‐SCD related to more amyloid and p‐tau deposition, likely due to patient anosognosia and increasing functional changes noted by others. Conversely, in an earlier, preclinical stage before the onset of overt problems, more self‐SCD appears indicative of greater amyloid pathology. Results are consistent with the purported pathological cascade of AD and highlight the relevance of considering dyadic SCD to inform underlying disease. [ABSTRACT FROM AUTHOR]

Background: Cerebral small vessel disease (SVD) is the most common pathology to co‐occur with Alzheimer's disease but pathophysiologic mechanisms leading to SVD are poorly understood. The arterial spin‐labeling (ASL) spatial coefficient of variation (sCoV), a proxy marker of arterial transit time (ATT), may better reflect SVD‐related hemodynamic disturbances than ASL‐derived cerebral blood flow (CBF). We investigated whether grey matter CBF and grey matter sCoV each related to neuroimaging markers of SVD, including white matter hyperintensities (WMHs), basal ganglia enlarged perivascular spaces (ePVS), cerebral microbleeds (CMBs), and lacunes. Methods: Vanderbilt Memory and Aging Project participants free of clinical dementia and stroke at study entry (n = 312, 73±7 years, 39% mild cognitive impairment, 41% female) underwent multimodal 3T brain magnetic resonance imaging to quantify ASL parameters and SVD burden. Pseudo‐continuous ASL assessed CBF in total grey matter. Grey matter sCoV was calculated as σ(CBFGrey Matter)/μ(CBFGrey Matter). WMHs and ePVS volumes were quantified using automated methods and ePVS volumes were standardized to basal ganglia volume. CMBs and lacune counts were quantified by an expert rater. Ordinary least squares regression models cross‐sectionally related grey matter CBF and sCoV individually to log‐transformed burden of each SVD marker. Models were adjusted for age, sex, race/ethnicity, education, cognitive status, Framingham Stroke Risk Profile (minus age), intracranial volume, grey matter volume, and apolipoprotein E‐ε4 status. Results: Grey matter CBF was unrelated to all SVD outcomes (p‐values>0.25). Higher grey matter sCoV was associated with greater WMHs (β = 2.1, p = 0.001), ePVS (β = 0.004, p = 0.0003), and lacunar infarcts (β = 1.4, p = 0.0006) but not CMBs (β = 1.0, p = 0.06). Conclusions: Our findings align with previous results showing that grey matter sCoV is a valuable marker of SVD. In contrast to previous work, we found an association between higher grey matter sCoV and higher basal ganglia ePVS burden. Potentially, our use of volumetric ePVS quantification rather than qualitative ePVS burden increased our ability to detect this association. As sCoV is a proxy marker of ATT, future work should consider quantifying sCoV or ATT in addition to CBF to better characterize SVD‐related hemodynamic disturbances. Funding: R01‐AG034962, K24‐AG046373, F31‐AG079640, P20‐AG068082 [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is associated with widespread reductions in cerebral blood flow (CBF), but the precise link between AD pathology and CBF is unclear. Hypoperfusion is a late‐stage event associated with tau, but not amyloid, pathology. We assessed whether baseline levels of cerebrospinal fluid (CSF)‐measured core AD pathology [β‐amyloid42 (Aβ42), phosphorylated tau (p‐tau)] related to CBF changes over a 7‐year period and if associations differed by baseline cognitive status. Methods: Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke at enrollment [n = 153, 72±6 years, 37% mild cognitive impairment (MCI), 33% female] underwent lumbar puncture to obtain CSF at study entry and serial multimodal 3T brain magnetic resonance imaging over a 7‐year follow‐up period (mean = 5.4 years). Enzyme‐linked immunosorbent assays quantified CSF Aβ42 and p‐tau181. Pseudo‐continuous arterial spin‐labeling captured CBF in total and lobar grey matter regions of interest (ROI). Linear mixed‐effects models related biomarker x time to longitudinal CBF variables adjusting for baseline age and cognitive status, sex, race/ethnicity, education, Framingham Stroke Risk Profile (minus age), ROI volume, APOE‐ε4 status, and time. Models were repeated testing a cognitive status x biomarker x time interaction term. Results: In main effect models, neither CSF Aβ42 (p‐values>0.31) nor p‐tau (p‐values>0.28) related to CBF outcomes. Aβ42 did not interact with cognitive status on CBF outcomes (p‐values>0.37), but p‐tau interacted with baseline cognitive status on longitudinal frontal, temporal, parietal, occipital, and total grey matter CBF trajectories (p‐values<0.005). Among cognitively unimpaired participants, higher p‐tau was associated with slower reductions in frontal (β = 0.01, p = 0.03), parietal (β = 0.01, p = 0.04), occipital (β = 0.01, p = 0.02), and total grey matter CBF (β = 0.01, p = 0.04). Among individuals with MCI, higher p‐tau was associated with faster reductions in frontal (β = ‐0.03, p = 0.008), temporal (β = ‐0.02, p = 0.01), parietal (β = ‐0.04, p = 0.002), occipital (β = ‐0.03, p = 0.0004), and total grey matter CBF (β = ‐0.03, p = 0.005). Conclusions: Results linking CSF p‐tau to CBF decline in MCI support the theory that grey matter hypoperfusion is a later‐stage event tied to neurofibrillary tangle pathology. Associations between higher p‐tau and slower rates of CBF decline among cognitively unimpaired individuals warrants further investigation. Funding: R01‐AG034962, K24‐AG046373, F31‐AG079640, T32‐AG058524, P20‐AG068082 [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) platelet‐derived growth factor receptor‐β (PDGFR‐β) is an emerging biomarker hypothesized to reflect pericyte damage. CSF PDGFR‐β levels are increased in Alzheimer's disease (AD), but it is unknown if pericyte injury contributes to cerebrovascular changes common in AD. We examined if PDGFR‐β relates to changes in cerebral blood flow (CBF) and white matter injury in older adults. Method: Vanderbilt Memory and Aging Project participants (n = 152, baseline age 73±7 years, 43% mild cognitive impairment [MCI]) underwent baseline lumbar puncture and serial brain MRI over a 7‐year (5.5±2.3) follow‐up period. CSF PDGFR‐β concentrated was measured by immunoassay. MRI included pseudo‐continuous arterial spin‐labeling to quantify CBF, T2‐FLAIR to quantify white matter hyperintensities (WMHs), and diffusion tensor imaging (DTI) to quantify white matter microstructural integrity. Ordinary least squares regression and linear mixed‐effects models related baseline CSF PDGFR‐β to baseline and longitudinal whole brain and regional CBF, WMH, and DTI metrics, adjusting for baseline demographic variables, modified Framingham Stroke Risk Profile, cognitive status, apolipoprotein‐ε4 status, and regional tissue volume. Longitudinal models adjusted for follow‐up time. Follow‐up models tested a CSF PDGFR‐β x cognitive status interaction. Result: In main models, higher CSF PDGFR‐β levels were cross‐sectionally associated with lower mean diffusivity (indicating better microstructural integrity) in white matter tracts in the frontal, temporal, parietal, and occipital lobes (p‐values<0.03) but were unrelated to WMHs (p‐values>0.18). Models investigating associations with longitudinal white matter variables were null (p‐values>0.35). CSF PDGFR‐β cross‐sectionally interacted with diagnosis on temporal lobe CBF, such that higher CSF PDGFR‐β related to higher CBF in MCI participants (p = 0.01). In longitudinal models, baseline CSF PDGFR‐β interacted with cognitive status on whole brain and occipital lobe CBF (p‐values<0.04). Stratified models showed higher baseline CSF PDGFR‐β related slower reductions in longitudinal CBF in whole brain (p = 0.02), frontal (p = 0.04), temporal (p = 0.02), parietal (p = 0.01), and occipital lobes (p = 0.008) in cognitively unimpaired participants only. Conclusion: Among older adults, higher CSF PDGFR‐β levels are associated with better white matter integrity at study entry and predict slower reductions in longitudinal CBF among cognitively unimpaired individuals. Results suggest that higher PDGFR‐β levels may reflect subclinical vascular remodeling that provides protection to future cerebrovascular compromise. [ABSTRACT FROM AUTHOR]

Background: Blood‐brain barrier (BBB) permeability is associated with Alzheimer's disease (AD) and neurodegeneration. Cerebrospinal fluid (CSF)/plasma albumin ratio (QAlb) is a biomarker commonly used to approximate BBB and blood‐CSF barrier (BCSFB) integrity. While sex‐based differences in AD risk are well‐established, limited work has evaluated these differences with QAlb and neurodegeneration and neuropsychological outcomes. Here, we examine if sex modifies the association of QAlb with neuropsychological and structural neuroimaging markers of neurodegeneration in community‐dwelling older adults. Method: Vanderbilt Memory and Aging Project participants (n = 152, 72±7 years, 33% female) completed a fasting blood draw, lumbar puncture, neuropsychological assessment, and multimodal 3T brain magnetic resonance imaging (MRI) to capture grey matter volumes and white matter hyperintensities (WMHs). Ordinary least squares regressions cross‐sectionally related sex to QAlb. Follow‐up models tested a sex x QAlbinteraction with neuropsychological and MRI outcomes. Models adjusted for age, sex, race/ethnicity, education, cognitive status, Framingham Stroke Risk Profile score (minus age), apolipoprotein (APOE)‐e4 status, and (for MRI outcomes) intracranial volume. Result: Female sex was associated with lower QAlb (p<0.001). However, sex did not interact with QAlb on any neuropsychological (p‐values>0.7) or neuroimaging outcomes (p‐values>0.2). Models stratified by sex were also null for neuropsychological (p‐values>0.93) and neuroimaging outcomes (p‐values>0.11). Conclusion: Elevated QAlb is believed to reflect disrupted brain‐barrier integrity such that blood‐based albumin (which lacks an active transport mechanism across the BBB) can enter the brain parenchyma and travel to the CSF. We found that female sex is associated with lower QAlb levels but does not interact with early cognitive or neuroimaging markers of AD‐associated neurodegeneration. The strong association between female sex and higher brain‐barrier integrity highlights the importance of considering sex differences when applying QAlb in clinical and research settings. Funding: R01‐AG034962, K24‐AG046373, T32‐AG058524, P20‐AG068082 [ABSTRACT FROM AUTHOR]

Background: Women have a higher prevalence of Alzheimer's disease (AD), but the underlying reason remains unknown. White matter damage is common in AD and partially attributed to inflammation. Animal models suggest that neuroinflammation with advanced age may differ between sexes, so we assessed whether sex modified associations between neuroinflammation assessed with cerebrospinal fluid (CSF) chitinase 3‐like 1 protein (YKL‐40) and white matter damage in older adults. Method: Vanderbilt Memory and Aging Project participants (n = 152, baseline age 73±7 years, 33% female) underwent lumbar puncture at study entry and brain magnetic resonance imaging (MRI) serially over a 7‐year period (mean follow‐up = 5.5 years). CSF YKL‐40 was quantified using an enzyme‐linked immunosorbent assay. MRI T2‐FLAIR was used to quantify total and lobar white matter hyperintensities (WMHs) at each timepoint. Ordinary least squares regression and linear mixed‐effects models related baseline CSF YKL‐40 to baseline and longitudinal WMHs, adjusting for baseline age, sex, race/ethnicity, education, modified Framingham Stroke Risk Profile, cognitive status, apolipoprotein‐e4 status, and intracranial volume. Longitudinal models adjusted for follow‐up time. Models were repeated with a sex interaction. Result: In main models, CSF‐YKL‐40 was cross‐sectionally unrelated to total and all lobar WMHs (p‐values>0.20) or longitudinal WMH progression (p‐values>0.06). However, CSF YKL‐40 cross‐sectionally interacted with sex on total, frontal, and parietal lobe WMHs (p‐values<0.05). In stratified models, higher CSF YKL‐40 levels related to greater WMH burden in the frontal (b = 0.005, p = 0.04), parietal (b = 0.005, p = 0.02), temporal (b = 0.003, p = 0.01), and occipital lobes (b = 0.003, p = 0.02) in females only. In longitudinal models, CSF YKL‐40 interacted with sex on temporal lobe WMH progression (p = 0.01), such that higher CSF YKL‐40 at study entry was associated with progression of temporal lobe WMHs over time in females only (b = 0.002, p = 0.003). Conclusion: Higher levels of neuroinflammation, reflected by higher levels of CSF YKL‐40, are associated with greater WMHs cross‐sectionally and progression over time in females only. Longitudinally, this effect is specific to the temporal lobe, where AD neuropathology originates. Neuroinflammation may be a key, sex‐specific etiology of temporal lobe white matter damage in females. Additional research is needed to characterize the role of this damage in cognitive decline. Funding: IIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373, P20‐AG068082 [ABSTRACT FROM AUTHOR]

Background: Living in a socioeconomically disadvantaged neighborhood has a negative impact on health outcomes, including increased risk for Alzheimer's disease (AD). The biological mechanisms underlying this risk are poorly understood. We examined how neighborhood disadvantage relates to core AD pathology, neurodegeneration, and inflammatory biomarkers in community‐dwelling older adults Method: Vanderbilt Memory and Aging Project participants (n = 327, 73±8 years, 41% female) underwent fasting blood and cerebrospinal fluid (CSF) acquisition serially over a 9‐year follow‐up period (mean follow‐up = 5.8 years). Area Deprivation Index (ADI), representing neighborhood disadvantage, was quantified at baseline based on 17 components [e.g., housing, income, education, and household characteristics (Kind & Buckingham, 2018)]. Ordinary least squares regressions cross‐sectionally related ADI to plasma and CSF biomarkers adjusting for age, sex, race/ethnicity, education, modified Framingham Stroke Risk Profile score, apolipoprotein E‐e4 status, and cognitive status. Linear mixed‐effects regression models related baseline ADI to longitudinal biomarkers with identical baseline covariates plus follow‐up time. Outcomes included CSF chitinase‐3‐like protein 1 (YKL‐40), CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2), CSF amyloid‐b40 (Ab40), CSF amyloid‐b42 (Ab42), CSF Ab40/Ab42 ratio, CSF tau, CSF phosphorylated tau (ptau), plasma high sensitivity C‐reactive protein (CRP), and plasma and CSF neurofilament light chain (NfL). Result: On average, the sample was from relatively less disadvantaged neighborhoods (ADI national decile = 35.4±25.0, range = 1‐98). Greater neighborhood disadvantage at study entry was cross‐sectionally associated with elevated CSF YKL‐40 (β = ‐0.733, p = 0.003), sTREM2 (β = 19.74, p = 0.04), Aβ40 (β = 35.96, p = 0.01), tau (β = 2.31, p = 0.02), and ptau (β = 0.33, p = 0.03). Greater neighborhood disadvantage at study entry related to longitudinal increases in CRP (β = 0.012, p<0.001) and decreases in plasma NfL (β = ‐0.025, p = 0.04) over the follow‐up period. Conclusion: Among community‐dwelling older adults, greater neighborhood disadvantage was associated with elevated inflammatory and AD CSF biomarkers cross‐sectionally, and longitudinal increases in a non‐specific inflammatory blood biomarker. Collectively, findings suggest that neighborhood disadvantage confers immediate risk for systemic neuroinflammation and AD and future risk for non‐specific inflammation, providing valuable evidence of a sociobiological mechanism underlying health disparities in aging adults based on geographic location. Funding. R01‐AG034962, K24‐AG046373, T32‐AG058524, P20‐AG068082 [ABSTRACT FROM AUTHOR]

Background: Plasma phosphorylated tau (p‐tau)231 is an emerging blood‐based biomarker that has shown great promise for early identification of individuals at risk of Alzheimer's disease (AD). However, it is unclear if this biomarker is sufficient as a standalone test or if diagnostic classification improves when simultaneously considering other plasma biomarkers. We investigated various plasma biomarkers, individually and in combination, in relation to cerebrospinal fluid (CSF) amyloid positivity. Method: Vanderbilt Memory and Aging Project participants free of clinical dementia and stroke (n = 155, 72±6 years, 33% female) underwent fasting lumbar puncture and blood draw. CSF β‐amyloid42 (Aβ42) and β‐amyloid40 (Ab40) and plasma p‐tau231, glial fibrillary acidic protein (GFAP), Aβ42, Aβ40, and neurofilament light chain (NfL) were analyzed in batch. The Aβ42/40 ratio was used for all analyses and CSF amyloid positivity was defined as Aβ42/40 ratio <0.072. Logistic regression models related each biomarker to amyloid positivity, adjusting for age, sex, race/ethnicity, apolipoprotein E‐ε4 status, and cognitive status. Subsequent models included p‐tau231 as the predictor in a base model with other biomarkers being added individually and then in combination with other biomarkers to the base model. Models were compared using likelihood ratio test (LRTest) and Akaike Information Criterion (AIC) values. Result: In single predictor models, p‐tau231 (C‐index = 0.87, p = 0.005) and GFAP (C‐index = 0.87, p = 0.01) were associated with amyloid positivity, while other biomarkers were not (p‐values>0.35). In models including p‐tau231 and various biomarker combinations, p‐tau231 remained significant in each model (p‐values<0.02). In comparison to the base model with p‐tau231 only, models adding GFAP (AIC = 143.8, LRTest p = 0.008), GFAP and NfL (AIC = 145.5, LRTest p = 0.02), and GFAP and Aβ42/40 (AIC = 145.8, LRTest p = 0.03) improved prediction of amyloid positivity. The model including plasma p‐tau231 and GFAP was the best fitting model (C‐index = 0.89). Conclusion: In this sample of community‐dwelling older adults free of clinical dementia, we found plasma p‐tau231 and GFAP were associated with amyloid positivity. Models including both p‐tau231 and GFAP performed best, and adding additional plasma biomarkers to this combination did not produce a better fitting model. Taken together, these findings highlight the utility of plasma p‐tau231 for screening for amyloid status and suggest that including plasma GFAP will improve discriminative accuracy. [ABSTRACT FROM AUTHOR]

Background: Recent technological advances have enabled large‐scale proteomic profiling of plasma and especially in studies of Alzheimer's disease. However, studies that have comprehensively examined longitudinal cognitive decline as an outcome from plasma protein levels prior to the onset of clinical dementia are limited. This project aimed to identify plasma proteins predictive of cognitive decline across a robust neuropsychological protocol over a 7‐year follow‐up period. Methods: Vanderbilt Memory and Aging Project participants (n = 333, 73±7 years, 41% female) free of clinical dementia at study entry underwent fasting blood draw and comprehensive serial neuropsychological assessment over a 7‐year period (mean follow‐up = 5.8 years). Plasma samples were subjected to multiplex liquid chromatography tandem mass spectrometry analysis to quantify cross‐sectional protein abundances for each participant at study entry. Normalization of proteomic data adjusted for batch effects, high levels of missingness, and log2 transformation. Linear mixed‐effects regressions related protein levels to longitudinal neuropsychological outcomes, adjusting for age, sex, race/ethnicity, education, baseline cognitive status, apolipoprotein E ε4 status, and follow‐up time. False discovery rate correction was applied to the a priori significance threshold. Results: Initial proteomics analyses yielded 3,784 proteins, of which 686 were used as analytical predictors following quality control, post‐acquisition filtering, and data normalization. Regression analyses resulted in 86 proteins which predicted longitudinal decline in global cognition, as assessed by the Montreal Cognitive Assessment. In analyses with individual neuropsychological domains as outcomes, 144 proteins predicted longitudinal decline in at least one neuropsychological domain [episodic memory (40 proteins), language (72 proteins), information processing speed (99 proteins), executive function (22 proteins), visuospatial skills (55 proteins)]. There was a smaller number of proteins (i.e., five) that were predictive of longitudinal cognitive decline across all domains. Conclusion: We conducted large‐scale proteomics analyses and identified 144 plasma proteins at study entry among a cohort of older adults free of clinical dementia that predict subsequent decline in cognition over a 7‐year follow‐up period. Five of these proteins were predictive of decline across all domains suggesting these proteins may represent biological pathways that adversely affect brain health with increasing age. Replication is needed to validate identified proteins as potential biomarkers of cognitive decline. [ABSTRACT FROM AUTHOR]

Background: Von Willebrand Factor (VWF), a multimeric glycoprotein involved in hemostasis, and ADAMTS13, a metalloproteinase that cleaves VWF, are associated with dementia risk. In in vitro studies endothelial cells expressing apolipoprotein E (APOE)‐ε4 overexpress VWF but no clinical studies have investigated interactions between VWF or ADAMTS13 with APOE‐ε4 status in predicting brain health. We assessed whether VWF and ADAMTS13 levels predict longitudinal cognitive decline and atrophy, especially in APOE‐ε4 carriers. Methods: Vanderbilt Memory and Aging Project participants (n = 333, 73±7 years, 41% female) underwent blood draw, neuropsychological assessment, and brain magnetic resonance imaging (MRI) serially over a 7‐year period. Plasma abundance measures of VWF and ADAMTS13 at baseline were quantified using mass spectrometry. Linear mixed‐effects regressions related protein levels to longitudinal neuropsychological and brain MRI outcomes (including grey matter volume and an Alzheimer's disease (AD) neuroimaging signature), adjusting for age, sex, race/ethnicity, education, modified Framingham Stroke Risk Profile score, cognitive status, intracranial volume, APOE‐ε4 status, and follow‐up time. Models were repeated with an APOE‐ε4 interaction. Results: Lower baseline ADAMTS13 levels related to greater longitudinal decline in language, episodic memory, information processing speed, executive function, and visuospatial skills (p‐values<0.02) as well as temporal lobe, occipital lobe, and hippocampal atrophy (p‐values<0.02). APOE‐ε4 interacted with ADAMTS13, such that among APOE‐ε4 carriers, lower baseline ADAMTS13 related to greater decline in naming (p‐values< = 0.002), information processing speed (p = 0.006), executive function (p = 0.001), and visuospatial skills performances (p = 0.001) as well as greater occipital lobe atrophy (p = 0.002) and AD imaging signature thinning (p = 0.02). All results survive false discovery rate correction. By contrast, VWF did not relate to any outcomes (p‐values>0.08). Conclusion: Lower ADAMTS13 levels related to greater cognitive decline and neurodegeneration over a 7‐year follow‐up period, with effects driven by APOE‐ε4 carriers. VWF was unrelated to outcomes, potentially suggesting that ADAMTS13 relates to brain health independent of its role cleaving in VWF. While VWF is the only known substrate of ADAMTS13, ADAMTS13 may be involved in diverse biologic processes (e.g., inflammation, angiogenesis). Replication is needed to fully elucidate the role of VWF. Additional research is also needed to characterize mechanisms underlying interactions between ADAMTS13 and APOE‐ε4 in predicting brain health. [ABSTRACT FROM AUTHOR]

Background: Reduced cerebral blood flow (CBF) is a risk factor for white matter damage. Apolipoprotein E (APOE) e4, a genetic risk factor for Alzheimer's disease and vascular health modifier, is associated with lower CBF. However, it remains unknown if lower CBF is associated with more severe white matter damage among APOE‐e4 carriers. We examine whether associations among regional CBF, cerebrovascular reactivity (CVR), and white matter integrity are modified by APOE‐e4 status in older adults. Method: Vanderbilt Memory and Aging Project participants (n = 313, 73±7 years) underwent 3T brain MRI. Resting grey matter CBF and CVR (CBF response to hypercapnic stimulus, ΔCBF/100*ΔCO2) were quantified in regions of interest from pseudo‐continuous arterial spin labeling (ASL). Fractional anisotropy (FA) was quantified from diffusion tensor imaging in tracts of interest derived from tractography templates. Linear regressions related regional CBF and CVR to tract‐specific FA, adjusting for demographic and vascular variables, regional tissue volume, cognitive status, and APOE‐e4 status. Follow‐up models tested an APOE‐ε4 status x ASL variable interaction term. Result: In main models, lower temporal lobe CBF was associated with lower FA in the occipital lobe, suggesting compromised white matter integrity (p = 0.02). Lower CBF and higher CVR in the occipital lobe were associated with compromised lower FA in all lobes (all p‐values<0.04). Temporal lobe CBF and CVR interacted with APOE‐e4 status, such that lower temporal lobe CBF related to lower FA in the frontal lobe (p = 0.01) and higher temporal lobe CVR related to lower FA in the frontal (p = 0.001) and temporal (p = 0.007) lobes among APOE‐e4 carriers only. Frontal lobe CVR interacted with APOE‐e4 status, such that higher CVR related to lower FA in the frontal (p<0.001) and temporal lobes (p = 0.008) in APOE‐e4 carriers only. Conclusion: Among older adults, APOE‐e4 modifies associations between cerebral hemodynamics and white matter integrity, such that reduced CBF and greater CVR in the temporal lobe are associated with greater white matter damage in APOE‐e4 carriers. APOE‐e4 carriers may be more susceptible to changes in temporal lobe hemodynamics, and vascular changes in the temporal lobe may have a stronger impact on brain health outcomes for carriers compared to non‐carriers. [ABSTRACT FROM AUTHOR]