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Background: Modeling the dynamics of Alzheimer's disease (AD) biomarkers over the entire continuum of AD progression is important, yet challenging due to limited resources to collect longitudinal biomarkers from the aging population with fully observed clinical spectrum of AD. This study proposed and applied a synchronized sigmoidal mixed‐effects model to characterize dynamics of longitudinal memory performance using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The model leveraged time to AD onset as the time scale and additionally allowed inclusion of participants without AD onset, drastically expanding future applications. Method: ADNI participants with observed mild cognitive impairment (MCI) and/or AD onset (n = 312, mean (SD) baseline age 74.9 (6.44) years) were included (Table 1). A memory composite previously built in ADNI was leveraged for all analyses. A synchronized sigmoidal mixed‐effects model was constructed for dynamics of memory performance with parameters for initial memory level, magnitude of decline, and half‐life of decline. For participants with observed MCI but not AD onset, an additional parameter (t0) quantifying the time from MCI onset to AD was incorporated (Figure 1). We considered random effects for all parameters and allowed t0 to vary by age at MCI onset (nonlinearly), sex, apolipoprotein E (APOE)‐ε4 status and their interactions. Result: The mean initial harmonized memory score is 0.24 (95% CI: 0.17‐0.32). The mean decline in the harmonized memory score is 1.53 (95% CI: 1.43‐1.64). The mean time when the harmonized memory score declined by half is 0.57 years before AD onset (95% CI: 0.32‐0.82). Female is associated with faster progression from MCI onset to AD (p = 0.002). Age at MCI onset is nonlinearly associated with MCI‐to‐AD progression (p < 0.001) and APOE‐ε4 status interacts with age at MCI onset on MCI‐to‐AD progression (p = 0.002) (Figure 2). Conclusion: The proposed synchronized sigmoidal mixed effect model can be used to characterize dynamics of AD biomarkers relative to AD onset using participants with and without AD onset. A model to estimate duration of MCI‐to‐AD progression can be simultaneously included for synchronization purpose, which identified gender, age at MCI onset and APOE‐ε4 status as factors associated with MCI‐to‐AD progression. [ABSTRACT FROM AUTHOR]

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: 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: Stressful social environments exert a strong influence on unhealthy aging, both in greater magnitude and independent of individual socioeconomic and lifestyle factors. Neighborhood disadvantage specifically has been linked to accelerated biological aging, cognitive decline, and core Alzheimer's disease (AD) neuropathology, but little is known about whether neighborhood disadvantage contributes to cerebrovascular dysfunction commonly observed in aging and AD. We examine whether neighborhood disadvantage relates to changes in cerebrovascular outcomes over time, including blood‐brain barrier (BBB) integrity, cerebral blood flow (CBF), and small vessel disease (SVD) biomarkers. Methods: Vanderbilt Memory and Aging Project participants (n = 296, 73±7 years, 40% female) underwent fasting blood and cerebrospinal fluid (CSF) acquisition serially over a 9‐year follow‐up period (mean follow‐up = 5.5 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)]. BBB markers (MMP‐2, MMP‐3, MMP‐9, TIMP‐1, TIMP‐2, PDGFRβ) were quantified from CSF and CSF/plasma albumin ratio was quantified from both CSF and plasma. 3T multimodal MRI images were used to quantify grey matter CBF and SVD markers, including white matter hyperintensities (WMHs), perivascular spaces (PVS), and lacunes. Linear mixed effects regression models related time x ADI to longitudinal BBB, CBF, and SVD outcomes adjusting for age, sex, race/ethnicity, education, cognitive status, Framingham Stroke Risk Profile (minus age), apolipoprotein ε4 status, and follow‐up time. CBF models additionally adjusted for corresponding grey matter volume while SVD models adjusted for T1‐weighted intracranial volume. Results: Baseline ADI related to increased MMP‐9 (β = 0.03, p‐value = 0.01) and decreased PDGFRβ (β = ‐0.1407, p‐value<0.05) over time but unrelated to longitudinal changes in CBF (p‐values>0.35), SVD (p‐values>0.36), or other BBB outcomes (p‐values>0.07). Conclusions: Neighborhood socioeconomic disadvantage relates to changes in BBB integrity among older adults over time, particularly molecular markers of barrier disruption and pericyte damage. Findings support the hypothesis that adverse environmental conditions, including low quality housing and community‐wide resource constraints, may contribute to early‐stage cerebrovascular dysfunction beyond individual socioeconomic and lifestyle factors. Funding: HHMI James H. Gilliam Fellowship for Advanced Study; IIRG‐08‐88733; R01‐AG034962; R01‐AG056534; K24‐AG046373; P20‐AG068 [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: 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]

Introduction: Patterns of atrophy can distinguish normal cognition from Alzheimer's disease (AD), but neuropathological drivers of this pattern are unknown. This study examined associations between cerebrospinal fluid biomarkers of AD pathology, synaptic dysfunction, and neuroaxonal injury with two AD imaging signatures. Methods: Signatures were calculated using published guidelines. Linear regressions related each biomarker to both signatures, adjusting for demographic factors. Bootstrapped analyses tested if associations were stronger with one signature versus the other. Results: Increased phosphorylated tau (p‐tau), total tau, and neurofilament light (P‐values <.045) related to smaller signatures (indicating greater atrophy). Diagnosis and sex modified associations between p‐tau and neurogranin (P‐values<.05) and signatures, such that associations were stronger among participants with mild cognitive impairment and female participants. The strength of associations did not differ between signatures. Discussion: Increased evidence of neurodegeneration, axonopathy, and tau phosphorylation relate to greater AD‐related atrophy. Tau phosphorylation and synaptic dysfunction may be more prominent in AD‐affected regions in females. [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]

Background: Greater physical activity is known to be beneficial for healthier brain aging outcomes. However, less is known about how inactivity might influence the aging brain. Inactivity is highly prevalent in older adulthood and may be an important modifiable risk factor. We examined how inactivity relates to cognitive performance and structural imaging variables in community‐dwelling older adults, particularly among individuals at genetic risk for sporadic AD (i.e., apolipoprotein E (APOE)‐e4 carriers). Method: Vanderbilt Memory and Aging Project (n = 265, 74±8 years, 37% female) participants completed at least 7 days of wrist actigraphy, neuropsychological assessment, and 3T brain MRI. Actigraphy data was processed using the GGIR package. Linear regression analyses related average daily minutes spent in inactivity during wake periods to cognition and brain structure adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile score, APOE‐e4 status, cognitive status, actigraphy wear time, and intracranial volume (for MRI outcomes). Models were repeated testing interactions with APOE‐e4 status. Result: The total sample was inactive for 14±2 hours/day. More minutes of inactivity related to worse episodic memory performance (β = ‐0.001, p = 0.03), a smaller AD‐signature composite of cortical thickness (β = ‐0.0002, p = 0.008), and lower occipital lobe grey matter volume (β = ‐10.01, p = 0.01). Inactivity time interacted with APOE‐e4 status on naming (β = ‐0.01, p = 0.01) and visuospatial performances (β = ‐0.02, p = 0.04); total grey matter volume (β = ‐201.40, p<0.001); and frontal (β = ‐96.24, p = 0.001), temporal (β = ‐27.13, p = 0.03), and parietal lobe volumes (β = ‐54.72, p<0.001). In stratified models, more minutes of inactivity related to worse neuropsychological performance and smaller brain volumes among APOE‐e4 carriers. All stratified models in non‐carriers were null (p‐values>0.12). Conclusion: Among community‐dwelling older adults, more time spent inactive each day related to worse episodic memory performance and lower cortical thickness in regions susceptible to AD‐related neurodegeneration. Results were stronger among APOE‐e4 carriers. This study supports the importance of not just increasing physical activity but also reducing the time spent inactive each day, particularly among aging adults at genetic risk for AD. Funding: IIRG‐08‐88733, P20‐AG068082, R01‐AG034962, K24‐AG046373 [ABSTRACT FROM AUTHOR]

Background: Age‐associated remodeling of cerebral large arteries contributes to worse systemic and brain health in older adults. Vessel wall imaging (VWI) is a neuroimaging technique that offers the critical ability to quantify thickness and lumen diameter across arterial segments of the circle of Willis (CoW). Inflammation, a well‐known feature of aging, cerebrovascular disease, and Alzheimer's disease, may be a central driver of age‐related changes in CoW morphology. We investigate if fluid biomarkers of inflammation predict key features of intracranial arterial aging, including CoW thickening and dilatation over time. Methods: Vanderbilt Memory and Aging Project participants were studied (n=96, 73±7 years, 80% male, mean follow‐up=3.0 years). Baseline systemic inflammatory biomarkers (TNF‐α, IL‐6) were quantified from blood plasma samples. Baseline neuroinflammatory biomarkers (sTREM2, YKL‐40, MMP‐2, MMP‐3, MMP‐9) were quantified from cerebrospinal fluid samples. Intracranial artery lumen diameter and thickness were manually measured across the basilar artery (BA) and bilateral segments of the internal carotid artery (ICA), anterior cerebral artery (ACA), and middle cerebral artery (MCA) using serial VWI MRI. Linear mixed effects regressions related time x inflammatory biomarker (one predictor per model) to longitudinal VWI lumen diameter and thickness outcomes, adjusting for baseline age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive status, apolipoprotein ε4 status, T1‐weighted intracranial volume, and time. Results: Higher CSF sTREM2 levels related to faster luminal narrowing (right ACA, p‐value=0.001). Higher CSF YKL‐40 levels related to faster luminal narrowing (right ACA, p‐value=0.07). Lower CSF MMP‐2 levels related to faster wall thickening (left MCA, p‐value<0.05). Lower CSF MMP‐3 levels related to luminal narrowing, while higher CSF MMP‐3 levels related to luminal widening (left ICA, p‐value=0.05). TNF‐α, IL‐6, and MMP‐9 were unrelated to any VWI changes (p‐values>0.14). Conclusion: Results suggest neuroinflammatory biomarkers are largely related to longitudinal intracranial artery narrowing and thickening. However, additional associations between MMPs and luminal widening may reflect the mixed nature of MMP activity on cerebrovascular remodeling. Immune responses mediated by astroglial and microglial activity as well as MMPs may be key pathophysiological mechanisms underlying age‐related cerebral arterial remodeling. [ABSTRACT FROM AUTHOR]

Background: Enlarged perivascular spaces (ePVS) on magnetic resonance (MR) imaging are difficult to quantify due to their small size, diffuse distribution, and often, high prevalence. We present a method for automating ePVS volume quantification in the basal ganglia. Method: Vanderbilt Memory and Aging Project participants (n=327, 73±7, 41% female) underwent MR imaging and serial neuropsychological assessment. Fifty T1‐weighted MR scans were manually coded for basal ganglia ePVS and used to train and test a deep learning U‐net. The model was then used to segment 277 remaining scans. Dice similarity coefficient (DSC), volume Pearson correlation, and mean symmetric surface distance (MSSD) were used to compare ground‐truth segmentations to predicted segmentations. In head‐to‐head regressions using pseudo‐conditional R2, basal ganglia ePVS volume and count were compared to two existing ordinal scores (Patankar et al., 2005; Hansen et al., 2015) to assess which method best predicted longitudinal cognition. Models adjusted for demographic, genetic, and risk factors. Result: The basal ganglia deep learning model attained a mean DSC of 0.76 on testing images (n=10) with an ePVS volume correlation of 0.95 and MSSD of 1.16 mm. Next, to assess the utility of automated measures derived from the model, ePVS volume and count were compared to commonly used ordinal scores on cognitive trajectory over a mean follow‐up time of 5.2±1.7 years. All automated and ordinal ePVS predictors achieved comparable pseudo‐conditional R2 values (e.g., 0.893 to 0.894 for episodic memory, 0.829 to 0.831 for executive function) on the longitudinal cognitive outcomes. ePVS volume had the highest or identical to the highest pseudo‐conditional R2 value on four of seven outcomes, including episodic memory (0.894), information processing (0.559), executive function (0.831), and visuospatial skills (0.743). Conclusion: We present a deep learning model that reliably segments ePVS in the basal ganglia of T1‐weighted brain MR scans, creating regional volume measures of ePVS. Automated basal ganglia ePVS volume measures perform comparably to existing validated manual methods when predicting longitudinal cognition. Automated methods are less time‐consuming and produce a continuous measure, providing a more robust way to quantify longitudinal ePVS change. Funding: F31‐AG066358, IIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373, P20‐AG068082 [ABSTRACT FROM AUTHOR]

Background: The vascular endothelial growth factor (VEGF) family is involved in angiogenic signaling and has been implicated in Alzheimer's Disease (AD). Previous work from our team has found that higher transcript levels of VEGFB, PGF, FLT1, and FLT4 in the brain relate to worse cognitive performance and higher levels of AD neuropathology. This study explored whether comparable associations are observed when measuring mRNA in whole blood. Method: Transcriptomic, cognitive, and biomarker data were acquired from the Vanderbilt Memory & Aging Project. Participants (n=335) included older adults (age=72+/‐7.32) with normal cognition (n=203) or mild cognitive impairment (n=132). Expression of the ten genes in the VEGF family were quantified using RNA sequencing of blood. Outcomes included a composite measure of memory and cerebrospinal fluid (CSF) levels of β‐amyloid, total tau, and phosphorylated tau (ptau181). Linear regression models related VEGF family member expression to baseline cognitive performance and AD biomarkers. Linear mixed effects regression models assessed longitudinal change in cognition. All models covaried for age at baseline and sex. To aid in interpretation, Pearson correlations between blood and brain expression were calculated leveraging data from 137 participants from the Genotype Tissue Expression Project (GTexportal.org). Result: At baseline, higher levels of VEGFB mRNA were associated with better memory performance (Figure 1, β=0.47, p=0.008). In longitudinal analyses, higher baseline expression of PGF was associated with more rapid decline in memory (β= 0.02, p=0.04). No other significant associations were observed (p‐values>0.09). Among GTEx participants, higher expression of VEGFB in blood was correlated with lower expression in the brain (Figure 2, r=‐0.19, p=0.02). PGF correlations did not reach statistical significance (r=0.09, p=0.27). Conclusion: Higher PGF expression in blood relates to worse cognitive outcomes, consistent with previous findings in the brain. In contrast, higher levels of VEGFB in blood relates to better performance, opposite of the previously observed association in the brain. Notably, in GTEx we observed opposing correlations between blood levels of VEGFB and brain levels of VEGFB, suggesting that higher levels of VEGFB in the blood may indeed reflect lower levels in the brain. Our results highlight the potential of VEGFB and PGF as blood biomarkers in aging and AD. [ABSTRACT FROM AUTHOR]

Background: Growth‐associated protein 43 (GAP‐43) is a presynaptic protein involved in synaptic plasticity implicated in Alzheimer's disease (AD). This study investigates cerebrospinal fluid (CSF) levels of GAP‐43 in relation to AD fluid biomarkers and clinical outcomes. To determine how associations change across disease states, interactions with cognitive and amyloid status are examined. Method: Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n=153, 72±7 years, 37% mild cognitive impairment (MCI)) underwent fasting lumbar puncture, 3T brain MRI, neuropsychological assessment, and informant‐reported functional activities questionnaire (FAQ). CSF GAP‐43, b‐amyloid1‐42 (Ab1‐42), tau, and phosphorylated‐tau (p‐tau) were analyzed in batch. An AD‐signature imaging composite was calculated by summing cortical thickness measurements from brain regions commonly affected by AD (Schwarz et al., 2016). Linear mixed effects models cross‐sectionally related GAP‐43 to CSF AD biomarkers, structural neuroimaging, cognitive, and FAQ variables adjusting for baseline age, sex, education, race/ethnicity, apolipoprotein E (APOE)‐e4 status, modified Framingham Stroke Risk Profile, and cognitive status. Follow‐up models assessed GAP‐43 x cognitive status (normal cognition (NC), MCI) and GAP‐43 x amyloid positivity interactions on outcomes. Result: In main effect models, higher CSF GAP‐43 was associated with higher CSF tau (p<0.0001) and CSF p‐tau (p<0.0001); worse semantic fluency (p<0.02), visuospatial (p<0.007) and episodic memory performances (p=0.06); and worse FAQ scores (p=0.003). Remaining models were null (p‐values>0.23). GAP‐43 interacted with cognitive status on all CSF biomarkers, AD‐signature composite cortical thickness, visuospatial, executive functioning, and memory performances, and FAQ score (p‐values<0.06). CSF GAP‐43 interacted with amyloid positivity on CSF tau and CSF p‐tau, and memory composite score (p‐values<0.03). Stratified results suggested most associations were slightly stronger in participants with MCI (p‐values<0.02) versus NC and in amyloid positive (p‐values<0.02) versus negative participants. Conclusion: We found higher CSF GAP‐43 levels were associated with tau and p‐tau pathology, AD‐related neurodegeneration on MRI, and worse cognitive and functional scores. Results were more prominent in individuals at increased risk for AD‐type dementia (i.e., participants who were amyloid positive or have MCI). These findings extend prior work by highlighting the importance of synaptic dysfunction in the AD clinical syndrome. [ABSTRACT FROM AUTHOR]

Background: Oxygen extraction fraction (OEF), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2) are complexly interrelated. Low OEF and CMRO2 are promising early indicators of Alzheimer's disease (AD) pathophysiology. To better understand how alterations in cerebral oxygen utilization relate to abnormal brain aging, we investigated baseline oxygen metabolism variables (OEF, CBF, CMRO2) in relation to longitudinal cognition and brain structure, and if these associations were different among individuals at genetic risk for sporadic AD (i.e., apolipoprotein E (APOE)‐ε4 carriers). Methods: Vanderbilt Memory and Aging Project participants (n=244, 74±7 years, mean follow‐up=3.7 years) underwent serial neuropsychological testing and multimodal 3T brain MRI. We used T2‐relaxation‐under‐spin‐tagging to calculate OEF and pseudo‐continuous arterial spin‐labeling to assess grey matter CBF. CMRO2 was calculated as: CMRO2=OEF*CBF*arterial oxygen content. Linear mixed‐effects regression models related time x oxygen metabolism variable (one predictor per model) to longitudinal cognitive and brain MRI outcomes. Models were adjusted for baseline age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive status, intracranial volume (for MRI outcomes), APOE‐ε4 status, and time. Models were repeated testing anAPOE‐ε4 status x oxygen metabolism variable x time interaction term. Results: Lower baseline OEF was associated with faster hippocampal atrophy (p=0.02). Lower baseline CBF was associated with faster cortical thinning in regions susceptible to AD‐related neurodegeneration (p=0.008). Lower baseline CMRO2 was associated with faster language decline (p=0.01) and hippocampal atrophy (p=0.01) and inferior lateral ventricle volume increase (reflecting faster atrophy of adjacent tissue; p=0.02). OEF interacted with APOE‐ε4 status on executive function (p=0.002), language (p=0.006), and visuospatial performances (p=0.02), and inferior lateral ventricle volume (p=0.007). CBF interacted with APOE‐ε4 status on executive function performance (p=0.0003). CMRO2 interacted with APOE‐ε4 status on temporal lobe volume (p=0.03). In stratified models, lower baseline OEF and CMRO2 tended to relate to faster brain health decline among APOE‐ε4 carriers. Conclusions: Lower OEF, CBF, and CMRO2 are associated with worse brain health trajectories over a 4‐year follow‐up. Assessing oxygen metabolism variables in combination may provide more comprehensive insight into longitudinal brain aging and serve as an early biomarker of disease, particularly among older adults at genetic risk for AD. Funding: T32‐AG058524, IIRG‐08‐88733, R01‐AG034962, R01‐NS100980 [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) polygenic risk scores (PRS) are often derived from case/control GWAS, which are typically not sensitive to preclinical disease changes, limiting their clinical utility. To overcome this pitfall, we built and evaluated the performance of multiple PRS of AD‐related endophenotypes, including resilience to cognitive impairment in the presence of amyloid. Method: Four PRS were derived from GWAS of baseline memory, memory decline, cognitive resilience (Dumitrescu et al., 2021), and AD (Kunkle et al. 2019). PRS were built in an independent cohort that was free of dementia, the Vanderbilt Memory and Aging Project (N=255). We used linkage disequilibrium clumping on TOPMed‐imputed genotypes, and a threshold of P=0.01. We ran linear models with baseline memory score as the outcome, and baseline age, sex, and PRS as predictors. Linear mixed effects models, with identical predictors, were used when longitudinal memory was the outcome, letting individual slope and intercept vary. Finally, we tested a CSF Aβ42‐by‐PRS interaction term to assess if PRS modified associations between amyloid and cognition. Sensitivity analyses excluded APOE from PRS calculations. Result: As expected, the baseline memory PRS related to baseline memory (β=0.12, P=0.04), and the memory decline PRS related to longitudinal memory (β=0.04, P=0.001). Without APOE, the baseline memory PRS and the memory decline PRS results attenuated. The AD PRS related to both baseline memory (β=‐0.19, P=0.002) and longitudinal memory (β=‐0.03, P=0.01), but results attenuated without APOE. The resilience PRS did not have a main effect on baseline or longitudinal memory. However, interestingly, the resilience PRS interacted with CSF Aβ42 on baseline memory (β=‐0.001, P=0.02; Figure 1), whereby the resilience PRS related to memory among amyloid‐positive individuals (β=0.44, P=0.01) but not amyloid‐negative individuals (β=0.06, P=0.46). No other PRS was predictive of memory among amyloid‐positive individuals, and resilience PRS results remained consistent without APOE. Conclusion: Our results demonstrate that a resilience PRS appears to be predictive of individual cognitive performance downstream of amyloidosis. Future work is needed to replicate this finding, but our preliminary findings highlight the potential utility of resilience PRS for predicting individual risk for AD‐related cognitive impairment during the preclinical stages of disease. [ABSTRACT FROM AUTHOR]

Background: Age‐associated changes in intracranial large arteries, including hypertrophic and dilatative remodeling, contribute to worse systemic and brain health in older adults. Vessel wall imaging (VWI) is a novel neuroimaging technique that offers the critical ability to quantify thickness and lumen diameter across arterial segments of the circle of Willis (CoW). Research suggests inflammation, a well‐known feature of aging, cerebrovascular disease, and Alzheimer's disease, may be a central driver of age‐related changes in CoW morphology. We investigate if fluid biomarkers of inflammation predict key features of intracranial arterial aging, including CoW thickening and dilatation visible on VWI MRI. Methods: Vanderbilt Memory & Aging Project participants free of clinical stroke and dementia were studied (n=117, 74±7 years, 73% male). Systemic inflammatory biomarkers (TNF‐α, IL‐6) were quantified from blood plasma samples and neuroinflammatory biomarkers (sTREM2, YKL‐40) were quantified from cerebrospinal fluid samples. Intracranial artery lumen diameter and thickness were manually measured across the basilar artery (BA) and bilateral segments of the internal carotid artery (ICA), anterior cerebral artery (ACA), and middle cerebral artery (MCA) using VWI MRI. Linear regressions related each inflammatory biomarker to intracranial artery lumen diameter and thickness in separate cross‐sectional models, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, diagnosis, apolipoprotein ε4 status, and T1‐weighted intracranial volume. Results: TNF‐α was related to right ICA thickness (b=0.01, p=0.03), left ICA thickness (b=0.01, p<0.05), and left ACA thickness (b=‐0.01, p=0.04); TNF‐α was unrelated to lumen diameters (p>0.51). IL‐6 was related to right ICA thickness (b=0.01, p=0.003) and was unrelated to lumen diameters (p>0.18). sTREM2 was related to left MCA lumen diameter (b=0.0001, p=0.03), right ACA lumen diameter (b=0.0001; p=0.001), and right ACA thickness (b=0.00003, p=0.03). YKL‐40 was unrelated to intracranial artery thickness (p>0.27) and lumen diameter (p>0.05). Conclusions: Results suggest TNF‐α, IL‐6, and sTREM2 are related to intracranial large artery thickening, and sTREM2 may further relate to large artery dilatation. Given the increased reliability of ICA and BA manual measurements on VWI MRI, these findings may be most robust. Proinflammatory cytokines and microglia‐mediated immune responses may be key pathophysiological mechanisms underlying age‐related arterial remodeling within the brain. [ABSTRACT FROM AUTHOR]

Background: Plasma total‐tau (t‐tau) is an emerging biomarker of neurodegeneration and cognitive decline; however, findings are mixed regarding what specific cognitive domains are affected and it is unknown whether plasma t‐tau predicts early functional changes in aging adults at risk for dementia. This study examined baseline plasma t‐tau in relation to longitudinal cognitive and functional trajectories among community‐dwelling older adults. Method: Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n=332, 73±8 years, 40% mild cognitive impairment (MCI)) underwent baseline fasting venous blood draw and serially completed a comprehensive neuropsychological protocol and a 50‐item informant functional abilities questionnaire at study entry, 18‐month, 3‐year, and 5‐year intervals (mean 4.5±1.2 year follow‐up). Plasma t‐tau concentration was measured using single molecule array technology. Linear mixed effects models related baseline t‐tau to cognitive and functional trajectories through interaction with follow‐up time adjusting for baseline age, sex, education, race/ethnicity, apolipoprotein E (APOE) ∑4 status, modified Framingham Stroke Risk Profile, and cognitive diagnosis. Subsequent models assessed t‐tau x cognitive diagnosis and t‐tau x APOE‐∑4 interactions on cognitive and functional trajectories. Result: A higher baseline concentration of t‐tau was associated with faster decline in processing speed (p<.05). Baseline t‐tau concentration interacted with diagnosis on longitudinal trajectories of processing speed (p‐values<.03). After excluding outliers, higher baseline t‐tau was associated with faster decline in language, processing speed, and functional abilities (p‐values<.05) with t‐tau interacting with diagnosis on each of these measures (p‐values<.05). Baseline t‐tau interacted with APOE‐∑4 status on longitudinal trajectories of language after outlier exclusion (p‐values<.04). Associations linking baseline t‐tau with faster decline were largely driven by participants with MCI (p‐values<.05) and APOE‐∑4 carriers (p‐values<.04). Conclusion: Among community‐dwelling aging adults free of clinical dementia, higher baseline plasma t‐tau concentration was associated with faster cognitive and functional decline over a mean 4.5‐year follow‐up. Processing speed was consistently implicated, especially in individuals with MCI. T‐tau may reflect non‐specific brain changes involving widely distributed neuronal networks, leading to slowed processing, a common complaint in aging adults. Taken together, results suggest that plasma t‐tau may be a useful biomarker for cognitive and functional decline in at‐risk individuals. [ABSTRACT FROM AUTHOR]

Background: Enlarged perivascular spaces (PVS) are a marker of small vessel disease (SVD). PVS in the basal ganglia are associated with hypertensive damage to arteries and arterioles; however, prior work relating arterial stiffness to changes in PVS have been inconclusive. Additionally, clinical consequences of PVS are poorly understood, possibly due to reliance on manual rating systems that lack precision. This study used an automated process to measure basal ganglia PVS count and volume and cross‐sectionally assess their associations with central arterial stiffness and cognition. Method: Vanderbilt Memory and Aging Project participants free of clinical stroke and dementia (n=327, 73±7 years, 41% female) completed T1‐weighted brain MRI to measure PVS burden, neuropsychological assessment, and cardiac MR to quantify pulse wave velocity (PWV) in the thoracic aorta, a marker of central arterial stiffness. PVS volume and count were quantified using an automated approach. Basal ganglia volume and count measures were log‐transformed. Linear regression models related PWV separately to PVS volume and count adjusting for demographic and health variables, apolipoprotein E‐e4 status, and intracranial volume. Models were repeated separately relating PVS volume and count to neuropsychological performance with identical covariates. Result: Higher PWV related to greater basal ganglia PVS volume (b=7.0e‐5, p=0.04) and count (b=0.02, p=0.03). When excluding outliers, PVS volume results were attenuated (p=0.17) but count results persisted (p=0.03). Higher PVS volume was associated with worse sequencing (b=1560, p=0.002), digit symbol (b=‐979, p=0.003), executive function (b=‐82.3, p<0.001), and visuospatial performances (b=‐193, p=0.02). Cognitive results were comparable for models using PVS count as the predictor. Conclusion: Central arterial stiffness is associated with greater PVS burden in the basal ganglia. Findings support the hypothesis that increased aortic stiffness and resulting changes in hemodynamics essential for maintaining perfusion pressure may result in PVS damage. Greater PVS burden is associated with worse cognitive performance, primarily on tests of executive function and information processing, aligning with our prior findings relying on a manual PVS rating system. PVS may account for damage to frontal subcortical networks which integrate the basal ganglia and play an important role in executive function and information processing. Funding: F31‐AG066358, T32‐AG058524, Alzheimer's Association IIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373, P20‐AG068082 [ABSTRACT FROM AUTHOR]

Background: APOE‐ε4 is the strongest common genetic risk factor for Alzheimer's disease (AD) and contributes to worse cognition. However, many carriers of the APOE‐ε4 allele remain cognitively normal throughout life, suggesting resilience factors may exist that protect the brain. We leverage a unique statistical design to identify modifiers of APOE effects on cognition by first discovering gene modifiers leveraging RNA sequencing (RNAseq) from whole blood and then replicating any observed modifiers with brain RNAseq from an independent cohort. Transcripts that modify the association between APOE and cognitive decline may highlight pathways of risk or resilience that could be repurposed as targets for intervention. Method: Cognition, RNAseq from whole blood, and APOE genotype were obtained from 336 individuals from the Vanderbilt Memory and Aging Project (VMAP; mean(SD) age=72.9(7.3), % male=59, % mild cognitive impairment=39). RNAseq data were quantile normalized and batch corrected. Regression and mixed‐effects regression models assessed the interaction between baseline gene expression and APOE‐ε4 or APOE‐ε2 positivity on both baseline and longitudinal decline in memory, adjusting for baseline age and sex. Results were replicated using bulk dorsolateral prefrontal cortex RNAseq data in 618 participants from the Religious Orders Study/Memory and Aging Project (ROS/MAP). Results were corrected for multiple comparisons (60,669 genes) using the false discovery rate method. Results: Cross‐sectionally, RNASE6 interacted with APOE‐ε4 status on memory (β=‐1.16, p=4.35x10‐8) whereby low RNASE6 expression was associated with better memory performance at baseline among APOE‐ε4 carriers, but high RNASE6 expression was associated with worse memory performance among APOE‐ε4 carriers (Figure 1). These results replicated in brain RNAseq data from ROS/MAP (β=‐0.2, p=0.0009, Figure 2). There were no significant interactions longitudinally or with APOE‐ε2. Conclusion: RNASE6 encodes a protein involved in innate immunity, including antimicrobial and antiviral activity. It has not been previously associated with AD or AD‐related cognitive decline, though it has been identified in a co‐expression network module with other inflammatory genes, such as TYROBP (DAP12), previously linked to AD. Together, these data implicate neuroinflammatory regulation in cognitive decline, and suggest that innate immune signaling may contribute to the regulation of resilience and susceptibility to AD among APOE‐ε4 carriers. [ABSTRACT FROM AUTHOR]

Background: Subjective cognitive decline (SCD), a potential harbinger of Alzheimer's disease (AD), has been cross‐sectionally associated with neurodegeneration and cerebrovascular disease markers on brain MRI. However, longitudinal associations are less clear with few existing studies that yield inconsistent findings. Here, we related baseline SCD to longitudinal structural and hemodynamic markers of brain health in older adults free of clinical dementia and stroke. Methods: Vanderbilt Memory & Aging Project participants (n=299,72±7 years, 58% male) completed a baseline SCD protocol and multimodal 3T brain MRI, including T1‐weighted imaging (grey matter volumes) and pseudo‐continuous arterial spin labeling (cerebral blood flow (CBF)) at baseline and multiple follow‐ups (18‐months, 3‐years, 5‐years). Baseline SCD (total and subdomain memory, language, and executive functioning scores) was longitudinally related to global and regional grey matter volumes and CBF (mL/100g/min). Linear mixed effects models, with random intercepts and slopes and a follow‐up time interaction, covaried for baseline age, sex, race/ethnicity, education, diagnosis, mood, and apolipoprotein E (APOE)‐e4 status. Grey matter volume models covaried for intracranial volume. CBF models covaried for associated tissue volume. Results: Mean follow‐up time was 3.8 years. Higher total SCD predicted hippocampal volume reductions (p=0.04), increased inferior lateral ventricular volume (p<0.001; Figure 1A), and global CBF reductions (p<0.001; Figure 1B). Higher scores within each SCD domain predicted hippocampal volume reductions, increased inferior lateral ventricular volume, and global CBF reductions (p‐values<0.04). Higher executive functioning‐SCD related only to frontal and occipital CBF reductions (p‐values<0.003; Figure 1C) but not temporal CBF or lobar atrophy (p‐values>0.07). Language‐SCD predicted reduced frontal CBF (p=0.01; Figure 1D) and temporal lobe volume (p=0.02). Surprisingly, memory‐SCD was not associated with temporal lobe volume or CBF (p‐values>0.05). Sensitivity analyses excluding outliers revealed the same associations. Conclusions: Higher baseline SCD predicted multiple pathways of longitudinal brain changes, including cerebral hemodynamics and volume loss within areas first affected by AD. Executive functioning‐SCD predicted hemodynamic changes and language‐SCD related to alterations within the frontal and temporal lobes. Results suggest the relevance of considering the type of SCD, as specific domains may predict different pathologies over time with important prognostic implications. Future research is needed to understand the clinical consequences of these findings. [ABSTRACT FROM AUTHOR]

Background: Oxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen (CMRO2) are markers of oxygen utilization and neuronal energy demands that may offer insights into normal and abnormal changes in aging. This study cross‐sectionally related OEF and CMRO2 to cognitive and structural neuroimaging variables among older adults. Because apolipoprotein E (APOE)‐ε4 status is an Alzheimer's disease (AD) genetic risk factor and a molecular mediator of vascular damage, we tested whether APOE‐ε4 status modified associations. Method: Vanderbilt Memory and Aging Project participants free of stroke and dementia (n=237, 75±7 years, 37% female) underwent neuropsychological testing and multimodal 3T brain MRI, including T1‐weighted imaging (grey matter volumes/thickness), fluid attenuated inversion recovery (white matter hyperintensities (WMHs)), T2‐relaxation‐under‐spin‐tagging (venous oxygenation (Yv)), and pseudo‐continuous arterial spin‐labeling (cerebral blow flow (CBF)). Participant‐specific Yv, arterial oxygenation, and hematocrit were used to calculate OEF, which multiplied by CBF yielded CMRO2. Linear regressions related OEF and CMRO2 individually to cognition, grey matter volumes, an AD imaging signature (Schwarz et al., 2016), and WMHs adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, Clinical Dementia Rating, APOE‐ε4 status, and (as appropriate) intracranial volume. Follow‐up models tested predictor x APOE‐ε4 status interactions on outcomes followed by APOE‐ε4 status stratification. Result: Main effects were mostly null (p‐values>0.04). APOE‐ε4 status interacted with both OEF and CMRO2 on language (p‐values<0.04), episodic memory (p<0.04), hippocampal volume (p‐values<0.03), and Schwarz AD signature (p‐values<0.05). APOE‐ε4 status also interacted with CMRO2 on total grey matter volume (p=0.04), inferior lateral ventricle volume (p=0.01), executive function (p=0.05), and visuospatial skills (p=0.01). For all interactions, lower OEF and CMRO2 related to worse cognitive performances and smaller regional grey matter structures in APOE‐ε4 carriers only. Conclusion: APOE‐ε4 status modifies associations linking cerebral oxygen metabolism markers (CMRO2, OEF) to worse episodic memory performance and smaller neuroimaging variables in regions susceptible to AD‐related neurodegeneration. Consistently, results are present in APOE‐ε4 carriers only. Congruence between cognitive and neuroimaging findings suggests that oxygen metabolism and APOE‐ε4 may interact early in the pathogenesis of AD and related neurodegeneration with important clinical consequences. [ABSTRACT FROM AUTHOR]

Background: Matrix metalloproteinases (MMPs) are enzymes that facilitate extracellular matrix remodeling. In Alzheimer's disease (AD), the MMP system becomes dysregulated and may contribute to disease pathophysiology; however, limited work has examined clinical consequences of MMPs. Thus, we investigated cerebrospinal fluid (CSF) MMP2, MMP3, and MMP9 concentrations in relation to cognitive performance as well as the interaction between MMPs and AD core neuropathology (CSF amyloid beta (Aβ42) and phosphorylated tau (p‐tau)) on cognitive outcomes. Methods: Vanderbilt Memory and Aging Project participants free of clinical dementia underwent fasting lumbar puncture for CSF acquisition and neuropsychological assessment (n=153, 73±7 years, 67% male). CSF samples were analyzed in batch using commercially available ELISAs. Linear regression models individually related CSF MMP levels to neuropsychological performance, adjusting for age, sex, race/ethnicity, education, cognitive diagnosis, Framingham Stroke Risk Profile, and apolipoprotein E (APOE)‐ε4 carrier status. Models were repeated with CSF Aβ42 and p‐tau concentrations as interaction terms. Results: Increased CSF MMP9 related to worse language (p‐values<0.03) and episodic memory performances (p=0.03); however, CSF MMP2 and MMP3 main effects were null (p‐values>0.07). CSF Αβ42 did not interact with MMP2, MMP3, or MMP9 concentrations on any neuropsychological outcome (p‐values>0.09). By contrast, CSF p‐tau interacted with CSF MMP2 and MMP3 levels on language performance (p‐values<0.02), and CSF p‐tau interacted with CSF MMP2 levels on episodic memory performance (p=0.01). Increased CSF MMP2 and MMP3 associations with worse language and episodic memory performances were driven by p‐tau negative participants, whereas (unexpectedly) increased CSF MMP2 was associated with better language performance among p‐tau positive participants. Conclusion: Among older adults without clinical dementia or stroke, increased CSF MMP9 related to worse cognitive performance, suggesting extracellular matrix remodeling may be one pathway underlying the development of cognitive impairment. CSF p‐tau, but not Αβ42, interacted with MMP2 and MMP3 concentrations on cognitive performance. P‐tau may interact with MMPs on clinical expression of pathology in complex ways, such that increased CSF levels of MMPs may only be associated with worse cognition in non‐demented older adults in the absence of concomitant neuropathology. Funding: Alzheimer's Association IIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373. [ABSTRACT FROM AUTHOR]

Background: Cerebral atrophy patterns can distinguish normal cognition from Alzheimer's disease (AD), but neuropathological drivers of these patterns are still not well understood. This study examined baseline cerebrospinal fluid (CSF) biomarkers of AD pathology (amyloid‐beta (Aβ), phosphorylated tau (p‐tau)); neurodegeneration (total tau (t‐tau)); synaptic dysfunction (neurogranin); and neuroaxonal injury (neurofilament light (NFL)) in relation to longitudinal atrophy patterns for two common AD neuroimaging signatures. Method: Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n=153, 72±6 years) underwent baseline fasting lumbar puncture for CSF collection and serial T1‐weighted neuroimaging at 3T (baseline, 18‐months, 3‐years, 5‐years). Images were post‐processed using FreeSurfer. AD imaging signatures were calculated using published guidelines (McEvoy et al., 2009; Schwarz et al., 2016). Linear mixed effects models related each baseline CSF biomarker to each AD signature trajectory using biomarker x follow‐up time interactions, adjusting for age, sex, race/ethnicity, education, diagnosis, apolipoprotein (APOE)‐ε4 status, and follow‐up time. Secondary models tested CSF biomarker x APOE‐ε4 interactions on longitudinal AD signature trajectory. Result: Mean follow‐up time was 3.4±1.1 years. Lower baseline CSF Aβ (p<0.001), higher t‐tau (p=0.04), and higher p‐tau levels (p=0.01) were associated with a faster rate of cortical thinning in the McEvoy AD signature. Baseline CSF biomarkers were unrelated to Schwarz AD signature trajectory (p‐values>0.16). APOE‐ε4 interacted with baseline CSF p‐tau, t‐tau, neurogranin, and NFL on both AD signatures (p‐values<0.04). APOE‐ε4 also interacted with CSF Aβ on the Schwarz AD signature (p=0.008). Associations linking baseline CSF Aβ, p‐tau, t‐tau, and neurogranin with faster atrophy patterns were driven by APOE‐ε4 carriers (p‐values<0.05). Conclusion: Increased baseline evidence of cerebral amyloidosis, phosphorylated tau, and neurodegeneration related to faster rates of cortical thinning in AD‐affected regions over a mean 3.4 year follow‐up period. Associations linking amyloidosis, phosphorylated tau, neurodegeneration, and synaptic dysfunction to cortical thinning are driven by APOE‐ε4 carriers, suggesting grey matter regions susceptible to the longitudinal neurodegenerative effects of AD pathology may be even more susceptible in APOE‐ε4 carriers, perhaps due to the effects of APOE‐ε4 on blood‐brain barrier compromise, vascular dysregulation, or inflammatory activation. [ABSTRACT FROM AUTHOR]

Background: Cerebral small vessel disease (SVD) is visible on brain magnetic resonance imaging (MRI) as white matter hyperintensities (WMHs), perivascular spaces (PVS), cerebral microbleeds (CMBs), and lacunes. This study expands our prior cross‐sectional work and examines how these four markers contribute to longitudinal cognitive trajectory to assess whether these markers represent common versus unique pathways of injury. Methods: Vanderbilt Memory and Aging Project participants free of baseline clinical stroke and dementia (n=327, 73±7 years, 41% female) completed multimodal 3T brain MRI to quantify WMHs, PVS, CMBs, and lacunes at baseline and neuropsychological assessment at multiple time points (baseline, 18‐month, 3‐year, 5‐year). Linear mixed‐effects regression models related each baseline SVD marker to longitudinal neuropsychological trajectory through interaction with follow‐up time, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, diagnosis, apolipoprotein E‐e4 status, and intracranial volume. Results: Mean follow‐up time was 3.9±1.1 years. Increases in each SVD marker related to faster episodic memory decline (p‐values≤0.04). Increased lacunes (p=0.04), WMHs (p≤0.008), and CMBs (p≤0.001) related to information processing speed decline. Increased WMHs (p=0.02) and CMBs (p=0.03) related to executive function decline. Increased WMHs related to language decline (p=0.02). Increased CMBs related to visuospatial decline (p=0.03). In combined models simultaneously considering multiple statistically significant SVD markers in relation to cognitive outcomes, WMHs independently predicted faster information processing speed (p=0.03), executive function (p=0.05), and episodic memory decline (p=0.02) beyond all other SVD biomarkers. CMBs independently predicted information processing speed decline beyond lacunes and WMHs (p‐values≤0.04). PVS independently predicted episodic memory decline beyond lacunes and CMBs (p=0.03). Conclusions: Increased SVD, including PVS, CMBs, lacunes, and especially WMHs, was associated with faster longitudinal cognitive decline. In competitive models, WMHs consistently predicted faster decline in multiple domains despite inclusion of other significant SVD predictors. In a subset of models, CMBs and PVS independently predicted faster longitudinal cognitive decline yet lacunes did not. Thus, WMHs, CMBs, and PVS may each reflect a unique pathway of injury whereas lacunes may not. Funding: F31‐AG066358, T32‐AG058524, Alzheimer's Association IIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373. [ABSTRACT FROM AUTHOR]