Serum inflammation markers associated with altered brain white matter microstructure in people with HIV on antiretroviral treatment.

BACKGROUND: Many studies have reported reduced brain white matter fractional anisotropy (FA) and increased mean diffusivity (MD) on diffusion tensor imaging (DTI) of people with HIV (PWH). Few, however, have linked individual blood inflammatory markers with white matter tract-specific FA and MD. METHODS: PWH 50 years old or older from New York, NY, USA, were invited to a cross-sectional study. Demographic data, blood samples, and brain DTI were obtained. Least absolute shrinkage and selection operator (LASSO) regression was used to examine associations between biomarkers and white matter tract-specific FA and MD. All models included age, sex, race, ethnicity, diabetes, hypertension, smoking, and viral load as control variables. RESULTS: Seventy-two cases were analyzed. Mean age was 60 ± 6 years, 47% were women, 21% were Hispanic, and 78% were black. All had asymptomatic HIV infection and were on antiretroviral therapy. Eighty-nine percent had CD4 count >200 cell/mm3 and 78% were virally suppressed. Vascular endothelial growth factor (VEGF) and macrophage inflammatory proteins (MIP) 1ß and 1α were consistently associated with lower FA and higher MD across white matter tracts. CONCLUSIONS: Elevated serum VEGF, MIP-1α, and MIP-1ß were associated with altered white matter microstructure. These blood biomarkers may help predict HIV-associated white matter damage.

Patterns of tau pathology identified with 18 F-MK-6240 PET imaging.

INTRODUCTION: Positron emission tomography (PET) imaging for neurofibrillary tau allows investigation of the in vivo spatiotemporal progression of Alzheimer's disease (AD) pathology. We evaluated the suitability of 18 F-MK-6240 in a clinical sample and determined the relationships among 18 F-MK-6240 binding, age, cognition, and cerebrospinal fluid (CSF)-based AD biomarkers. METHODS: Participants (n = 101, 72 ± 9 years, 52% women) underwent amyloid PET, tau PET, structural T1-weighted magnetic resonance imaging, and neuropsychological evaluation. Twenty-one participants had lumbar puncture for CSF measurement of amyloid beta (Aß)42 , tau, and phosphorylated tau (p-tau). RESULTS: 18 F-MK-6240 recapitulated Braak staging and correlated with CSF tau and p-tau, normalized to Aß42 . 18 F-MK-6240 negatively correlated with age across Braak regions in amyloid-positive participants, consistent with greater tau pathology in earlier onset AD. Domain-specific, regional patterns of 18 F-MK-6240 binding were associated with reduced memory, executive, and language performance, but only in amyloid-positive participants. DISCUSSION: 18 F-MK-6240 can approximate Braak staging across the AD continuum and provide region-dependent insights into biomarker-based AD models.

Probing the proteome to explore potential correlates of increased Alzheimer's-related cerebrovascular disease in adults with Down syndrome.

Cerebrovascular disease is associated with symptoms and pathogenesis of Alzheimer's disease (AD) among adults with Down syndrome (DS). The cause of increased dementia-related cerebrovascular disease in DS is unknown. We explored whether protein markers of neuroinflammation are associated with markers of cerebrovascular disease among adults with DS. Participants from the Alzheimer's disease in Down syndrome (ADDS) study with magnetic resonance imaging (MRI) scans and blood biomarker data were included. Support vector machine (SVM) analyses examined the relationship of blood-based proteomic biomarkers with MRI-defined cerebrovascular disease among participants characterized as having cognitive decline (n = 36, mean age ± SD = 53 ± 6.2) and as being cognitively stable (n = 78, mean age = 49 ± 6.4). Inflammatory and AD markers were associated with cerebrovascular disease, particularly among symptomatic individuals. The pattern suggested relatively greater inflammatory involvement among cognitively stable individuals and greater AD involvement among those with cognitively decline. The findings help to generate hypotheses that both inflammatory and AD markers are implicated in cerebrovascular disease among those with DS and point to potential mechanistic pathways for further examination.

Alzheimer-Related Cerebrovascular Disease in Down Syndrome.

OBJECTIVE: Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology by their 5th decade. Compared with the general population, traditional vascular risks in adults with DS are rare, allowing examination of cerebrovascular disease in this population and insight into its role in AD without the confound of vascular risk factors. We examined in vivo magnetic resonance imaging (MRI)-based biomarkers of cerebrovascular pathology in adults with DS, and determined their cross-sectional relationship with age, beta-amyloid pathology, and mild cognitive impairment or clinical AD diagnostic status. METHODS: Participants from the Biomarkers of Alzheimer's Disease in Down Syndrome study (n = 138, 50 ± 7 years, 39% women) with MRI data and a subset (n = 90) with amyloid positron emission tomography (PET) were included. We derived MRI-based biomarkers of cerebrovascular pathology, including white matter hyperintensities (WMH), infarcts, cerebral microbleeds, and enlarged perivascular spaces (PVS), as well as PET-based biomarkers of amyloid burden. Participants were characterized as cognitively stable (CS), mild cognitive impairment-DS (MCI-DS), possible AD dementia, or definite AD dementia based on in-depth assessments of cognition, function, and health status. RESULTS: There were detectable WMH, enlarged PVS, infarcts, and microbleeds as early as the 5th decade of life. There was a monotonic increase in WMH volume, enlarged PVS, and presence of infarcts across diagnostic groups (CS < MCI-DS < possible AD dementia < definite AD dementia). Higher amyloid burden was associated with a higher likelihood of an infarct. INTERPRETATION: The findings highlight the prevalence of cerebrovascular disease in adults with DS and add to a growing body of evidence that implicates cerebrovascular disease as a core feature of AD and not simply a comorbidity. ANN NEUROL 2020;88:1165-1177.

Do correlates of white matter features differ between older men and women living with human immunodeficiency virus?

OBJECTIVE: Given estrogen's role in human immunodeficiency virus (HIV) disease progression and the higher rates of neurocognitive decline in affected women, the purpose of this study was to assess whether the relationship of white matter features and reproductive hormone levels differed between men versus women (sex as a moderator), controlling for selected cardiometabolic risk factors, HIV-related health indicators, and demographics in an aging population of persons living with HIV (PLWH). METHODS: Older PLWH (50 y and older; 44 women and 35 men; mean ± SD age, 59.8 ± 0.6 y; 55.7% women; 72.2% non-Hispanic Black) participated in a cross-sectional study involving a fasting blood draw and a demographic survey (visit 1) and a magnetic resonance imaging scan (visit 2) to determine white matter volume and white matter hyperintensity (WMH) volume. Associations between reproductive hormones (follicle-stimulating hormone [FSH], estradiol, testosterone, dehydroepiandrosterone sulfate [DHEA-S]) and white matter features were assessed in linear regression models. Covariates were age, body mass index, hypertension, diabetes, dyslipidemia, current smoking status, CD4 count, and cranial size. RESULTS: For white matter volume, a sexually dimorphic interaction was seen for DHEA-S (B = 21.23; P = 0.012) and observed for FSH (B = -22.97, P = 0.08) with a trend for significance after controlling for risk factors. In women, higher white matter volume was associated with higher DHEA-S (B = 13.89, P = 0.017) and lower FSH (B = 23.58, P = 0.01). No hormone associations were shown in men for white matter volume. For WMH volume, no significant interaction effects between sex and reproductive hormones were identified. For WMH, sex did not predict associations with reproductive hormones after controlling for risk factors. CONCLUSIONS: Although sexually dimorphic interactions of reproductive hormones and total white matter volume were demonstrated, our study findings do not support a role for sex-based differences in reproductive hormones as predictive correlates of WMH in a small sample of older PLWH.

Automatic quantification of white matter hyperintensities on T2-weighted fluid attenuated inversion recovery magnetic resonance imaging.

White matter hyperintensities (WMH) are areas of increased signal visualized on T2-weighted fluid attenuated inversion recovery (FLAIR) brain magnetic resonance imaging (MRI) sequences. They are typically attributed to small vessel cerebrovascular disease in the context of aging. Among older adults, WMH are associated with risk of cognitive decline and dementia, stroke, and various other health outcomes. There has been increasing interest in incorporating quantitative WMH measurement as outcomes in clinical trials, observational research, and clinical settings. Here, we present a novel, fully automated, unsupervised detection algorithm for WMH segmentation and quantification. The algorithm uses a robust preprocessing pipeline, including brain extraction and a sample-specific mask that incorporates spatial information for automatic false positive reduction, and a half Gaussian mixture model (HGMM). The method was evaluated in 24 participants with varying degrees of WMH (4.9-78.6 cm3) from a community-based study of aging and dementia with dice coefficient, sensitivity, specificity, correlation, and bias relative to the ground truth manual segmentation approach performed by two expert raters. Results were compared with those derived from commonly used available WMH segmentation packages, including SPM lesion probability algorithm (LPA), SPM lesion growing algorithm (LGA), and Brain Intensity AbNormality Classification Algorithm (BIANCA). The HGMM algorithm derived WMH values that had a dice score of 0.87, sensitivity of 0.89, and specificity of 0.99 compared to ground truth. White matter hyperintensity volumes derived with HGMM were strongly correlated with ground truth values (r = 0.97, p = 3.9e-16), with no observable bias (-1.1 [-2.6, 0.44], p-value = 0.16). Our novel algorithm uniquely uses a robust preprocessing pipeline and a half-Gaussian mixture model to segment WMH with high agreement with ground truth for large scale studies of brain aging.

Amyloid, cerebrovascular disease, and neurodegeneration biomarkers are associated with cognitive trajectories in a racially and ethnically diverse, community-based sample.

We characterized the additive contribution of cerebrovascular biomarkers to amyloid and neurodegeneration biomarkers (AV(N)) when modeling prospective, longitudinal cognitive trajectories within 3 major racial/ethnic groups. Participants (n = 172; age = 69-96 years; 62% women; 31%/49%/20% Non-Hispanic White/Non-Hispanic Black/Hispanic) from the Washington Heights-Inwood Columbia Aging Project were assessed for amyloid (Florbetaben PET), neurodegeneration (cortical thickness, hippocampal volume), and cerebrovascular disease (white matter hyperintensity (WMH), infarcts). Neuropsychological assessments occurred every 2.3 ± 0.6 years for up to 6 visits (follow-up time: 4.2 ± 3.2 years). Linear mixed-effects models were stratified by race/ethnicity groups. Higher amyloid was associated with faster memory decline in all 3 racial/ethnic groups, but was related to faster cognitive decline beyond memory in minoritized racial/ethnic groups. Higher WMH was associated with faster language, processing speed/executive function, and visuospatial ability decline in Non-Hispanic Black participants, while infarcts were associated with faster processing speed/executive function decline in Non-Hispanic White participants. Complementary information from AD, neurodegenerative, and cerebrovascular biomarkers explain decline in multiple cognitive domains, which may differ within each racial/ethnic group. Importantly, treatment strategies exist to minimize vascular contributions to cognitive decline.

Plasma Amyloid and in vivo Brain Amyloid in Late Middle-Aged Hispanics.

BACKGROUND: Determining amyloid positivity is possible with cerebrospinal fluid and brain imaging of amyloid, but these methods are invasive and expensive. OBJECTIVE: To relate plasma amyloid-ß (Aß), measured using Single-molecule array (Simoatrademark) assays, to in vivo brain Aß, measured using positron emission tomography (PET), examine the accuracy of plasma Aß to predict brain Aß positivity, and the relation of APOE ɛ4 with plasma Aß. METHODS: We performed a cross-sectional analysis in a cohort of 345 late middle-aged Hispanic men and women (age 64 years, 72% women). Our primary plasma variable was Aß42/Aß40 ratio measured with Simoa. Brain Aß burden was measured as global SUVR with 18F-Florbetaben PET examined continuously and categorically. RESULTS: Plasma Aß42/Aß40 ratio was inversely associated with global Aß SUVR (ß= -0.13, 95% Confidence Interval (CI): -0.23, -0.03; p = 0.013) and Aß positivity (Odds Ratio: 0.59, 95% CI: 0.38, 0.91; p = 0.016), independent of demographics and APOE ɛ4. ROC curves (AUC = 0.73, 95% CI: 0.64, 0.82; p < 0.0001) showed that the optimal threshold for plasma Aß42/Aß40 ratio in relation to brain Aß positivity was 0.060 with a sensitivity of 82.4% and specificity of 62.8%. APOE ɛ4 carriers had lower Aß42/Aß40 ratio and a higher Aß positivity determined with the Aß42/Aß40 ratio threshold of 0.060. CONCLUSION: Plasma Aß42/Aß40 ratio assayed using Simoa is weakly correlated with in vivo brain amyloid and has limited accuracy in screening for amyloid positivity and for studying risk factors of brain amyloid burden when in vivo imaging is not feasible.

Obstructive sleep apnea, cerebrovascular disease, and amyloid in older adults with Down syndrome across the Alzheimer's continuum.

We determined the extent to which obstructive sleep apnea (OSA) is associated with increased cerebrovascular disease and amyloid burden, and the relation of the two processes across clinical Alzheimer's disease (AD) diagnostic groups in adults with Down syndrome (DS). Adults with DS from the Biomarkers of Alzheimer's Disease in Down Syndrome (ADDS) study were included given available research MRI (n = 116; 50 ± 8 years; 42% women) and amyloid PET scans (n = 71; 50 ± 7 years; 39% women) at the time of analysis. Participants were characterized as cognitively stable (CS; 64%), with mild cognitive impairment-DS (MCI-DS; 23%), with possible AD dementia (5%), or with definite AD dementia (8%). OSA was determined via medical records and interviews. Models tested the effect of OSA on MRI-derived cerebrovascular biomarkers and PET-derived amyloid burden, and the moderating effect of OSA and AD diagnosis on biomarkers. OSA was reported in 39% of participants, which did not differ by clinical AD diagnostic group. OSA was not associated with cerebrovascular biomarkers but was associated with greater cortical amyloid burden. White matter hyperintensity (WMH) volume (primarily in the parietal lobe), enlarged perivascular spaces, and cortical and striatal amyloid burden were greater across clinical AD diagnostic groups (CS

Sex differences in in vivo tau neuropathology in a multiethnic sample of late middle-aged adults.

It is unclear whether women have higher brain tau pathology. The objective of this study was to examine whether women have higher tau burden than men, and whether tau differences are independent of amyloid ß (Aß) burden. We conducted a cross-sectional analysis of a multiethnic sample of 252 nondemented late middle-aged (mean age: 64.1 years) adults with tau and amyloid Positron Emission Tomography (PET) data. Tau burden was measured as global standardized uptake value ratio (SUVR) in the middle/inferior temporal gyri and medial temporal cortex with 18F-MK-6240 PET. Aß was measured as global SUVR with 18F-Florbetaben PET. Women had higher middle/inferior temporal gyri tau SUVR compared to men. However, no sex differences in the medial temporal cortex were observed. Women had higher brain Aß SUVR compared to men. Continuous Aß SUVR was positively correlated with medial temporal cortex and middle/inferior temporal gyri tau SUVR. However, there was no evidence of effect modification by Aß SUVR on sex and tau. Compared with men, women in late middle age show higher tau burden, independent of Aß.

Cerebrovascular Contributions to Neurocognitive Disorders in People Living With HIV.

BACKGROUND: To investigate a comprehensive array of magnetic resonance imaging (MRI)-based biomarkers of cerebrovascular disease (CVD) in a cohort of people living with HIV (PLWH) and relate these imaging biomarkers to cognition. SETTINGS: Cross-sectional, community-based study. METHODS: Participants were PLWH in New York City, aged 50 years or older. They underwent a brain magnetic resonance angiography or MRI to ascertain 7 MRI markers of CVD: silent brain infarcts, dilated perivascular spaces, microhemorrhages, white matter hyperintensity volume, white matter fractional anisotropy and mean diffusivity (measures of white matter integrity), and intracranial large artery stenosis. Participants underwent a battery of neurocognitive tests to obtain individual and global cognitive scores representative of various aspects of cognition. RESULTS: We included 85 participants (mean age 60 ± 6 years, 48% men, 78% non-Hispanic Black), most of them with well-controlled HIV (75% with CD4 cell count > 200 cells/mm3 and viral load < 400 copies/mL at or near the time of the MRI scan). Silent brain infarcts, intracranial large artery stenosis, and poor white matter integrity were associated with poorer performance in at least one cognitive domain, but the sum of these 3 MRI markers of CVD was associated with lower working memory (B = -0.213, P = 0.028), list learning (B = -0.275, P = 0.019), and global cognition (B = -0.129, P = 0.007). CONCLUSIONS: We identified silent brain infarcts, intracranial large artery stenosis, and poor white matter integrity as exposures that may be modifiable and may, therefore, influence cognitive decline. In addition, these MRI markers of CVD may help in identifying PLWH at higher risk of cognitive decline, which may be more amenable to targeted therapies.

Metabolic syndrome and its components in relation to in vivo brain amyloid and neurodegeneration in late middle age.

Metabolic syndrome (MetS) is associated with dementia, but it is unclear whether MetS is related to Alzheimer's disease (AD). We investigated the association of MetS with brain amyloid, a key AD feature, and neurodegeneration. A community-based sample of 350 middle-aged Hispanics in New York City had cerebral amyloid ß (Aß) burden ascertained with 18F-Florbetaben positron emission tomography. Neurodegeneration was ascertained as cortical thickness in AD signature regions from 3T brain MRI. MetS and its components (glucose, blood pressure, triglycerides, high-density lipoprotein, adiposity) were defined using the National Institutes of Health criteria. Neither the presence of MetS nor the MetS score was associated with Aß or neurodegeneration. Among the MetS components, elevated glucose was associated with lower Aß burden, and this association was not explained by diabetes treatment. Glucose and triglycerides were related to smaller cortical thickness. Our findings suggest that MetS as an arbitrary measure of aggregate metabolic and vascular risk does not capture the risk of AD neuropathology in late middle age and that other approaches to measure the aggregate risk should be examined.

In Vivo Amyloid, Neurodegeneration, and Verbal Learning in Late Middle-Aged Hispanics.

BACKGROUND: The National Institute on Aging (NIA)/Alzheimer's Association (AA) 2018 framework conceptualizes Alzheimer's disease (AD) biologically. Evidence of brain amyloid by biomarkers defines AD pathologic change and the Alzheimer's continuum. The presence of tau or neurodegeneration in the absence of amyloid defines non-AD pathologic change. OBJECTIVE: To examine the relation of in vivo amyloid and neurodegeneration with verbal learning, one of the cognitive abilities affected early in AD, in late middle age. METHODS: This was a cross-sectional study of amyloid and neurodegeneration biomarkers in a community-based cohort of 350 late-middle aged Hispanics without dementia (mean age: 64.15±3.34; 72.0%women). Amyloid (A) was measured as global standardized uptake value ratio (SUVR) with 18F-Florbetaben positron emission tomography (PET). Neurodegeneration (N) was ascertained as cortical thickness (CT) in AD signature areas using brain magnetic resonance imaging. We examined A/N continuously, categorically, by A/N profiles, and profile categories. The amyloid threshold for positivity was defined using the K means method. The CT threshold was defined as 2 standard deviations below the mean CT. Verbal learning was ascertained using total recall and delayed recall in the Buschke Selective Reminding test (SRT). RESULTS: Higher cortical thickness was associated with higher performance in SRT delayed recall. Amyloid SUVR was not related to SRT performance. The low CT category was associated with lower performance in SRT delayed recall, while Amyloid categories were not related to any SRT score. The non-AD pathologic change group (A-N+) performed worse in SRT delayed recall compared to the Normal A/N profile group (A-N-). CONCLUSION: In late middle-aged Hispanics without dementia, non-AD pathologic change, but not the Alzheimer's continuum, was related to verbal learning.

Pre-Diabetes, but not Type 2 Diabetes, Is Related to Brain Amyloid in Late Middle-Age.

BACKGROUND: Type 2 diabetes is a dementia risk factor, but its relation to Alzheimer's disease (AD), the most common cause of dementia, is unclear. OBJECTIVE: Our primary objective was to examine the association of pre-diabetes and type 2 diabetes with brain amyloid-ß (Aß), the putative main culprit of AD. Our secondary objective was to examine the association of pre-diabetes and type 2 diabetes with neurodegeneration, cerebrovascular disease (CVD), and memory performance. METHODS: We conducted a cross-sectional study of 350 late middle-aged Hispanics without dementia in New York City. We classified diabetes status as normal glucose tolerance (NGT), pre-diabetes, and type 2 diabetes following American Diabetes Association criteria. Brain Aß was ascertained as global Aß standardized value uptake ratio using PET with 18F-Florbetaben. Neurodegeneration was operationalized as cortical thickness in regions affected by AD using MRI. CVD was operationalized as white matter hyperintensity volume (WMH) on MRI, and memory as performance with the selective reminding test (SRT). RESULTS: Mean age was 64.15±3.34 years, 72.00% were women, and 35.43% were APOEɛ4 carriers. Pre-diabetes, but not type 2 diabetes, was associated with higher Aß compared with NGT. Type 2 diabetes treatment was related to lower Aß. Type 2 diabetes was related to lower cortical thickness, higher WMH, and lower SRT score. CONCLUSION: Pre-diabetes, but not type 2 diabetes, is associated with higher brain Aß in late middle age, and this observation could be explained by the relation of diabetes treatment with lower brain Aß. Whether type 2 diabetes treatment lowers brain Aß requires further study.

White matter hyperintensities mediate the association of nocturnal blood pressure with cognition.

OBJECTIVE: To test the hypotheses that hypertension and nocturnal blood pressure are related to white matter hyperintensity (WMH) volume, an MRI marker of small vessel cerebrovascular disease, and that WMH burden statistically mediates the association of hypertension and dipping status with memory functioning, we examined the relationship of hypertension and dipping status on WMH volume and neuropsychological test scores in middle-aged and older adults. METHODS: Participants from the community-based Maracaibo Aging Study received ambulatory 24-hour blood pressure monitoring, structural MRI, and neuropsychological assessment. Four hundred thirty-five participants (mean ± SD age 59 ± 13 years, 71% women) with available ambulatory blood pressure, MRI, and neuropsychological data were included in the analyses. Ambulatory blood pressure was used to define hypertension and dipping status (i.e., dipper, nondipper, and reverse dipper based on night/day blood pressure ratio <0.9, 0.9-1, and >1, respectively). Outcome measures included regional WMH and memory functioning derived from a neuropsychological test battery. RESULTS: The majority of the participants (59%) were hypertensive. Ten percent were reverse dippers, and 40% were nondippers. Reverse dipping in the presence of hypertension was associated with particularly elevated periventricular WMH volume (F 2,423 = 3.78, p = 0.024) and with lowered memory scores (F 2,423 = 3.911, p = 0.021). Periventricular WMH volume mediated the effect of dipping status and hypertension on memory (ß = -4.1, 95% confidence interval -8.7 to -0.2, p < 0.05). CONCLUSION: Reverse dipping in the presence of hypertension is associated with small vessel cerebrovascular disease, which, in turn, mediates memory functioning. These results point toward reverse dipping as a marker of poor nocturnal blood pressure control, particularly among hypertensive individuals, with potentially pernicious effects on cerebrovascular health and associated cognitive function.

Sex Differences in in vivo Alzheimer's Disease Neuropathology in Late Middle-Aged Hispanics.

BACKGROUND: Females may have a higher risk of dementia than males. It is not clear if sex differences in Alzheimer's disease (AD) neuropathology explain the higher risk of dementia in females. Sex differences in AD neuropathology might begin in middle age, decades before the sex differences in dementia are apparent. OBJECTIVE: To examine sex differences in in vivo AD neuropathology in late middle age. METHODS: We conducted a cross-sectional comparison of AD biomarkers among 266 Hispanic males and females (mean age: 64.0; 71.8% females) without dementia. Amyloid burden was measured as global standardized uptake value ratio (SUVR) with18F-Florbetaben positron emission tomography (PET). Neurodegeneration was ascertained as cortical thickness in AD signature areas using brain magnetic resonance imaging. Tau burden was measured as tau SUVR in the middle/inferior temporal gyri and medial temporal cortex with 18F-MK-6240 in 75 of the 266 participants. RESULTS: Females had higher amyloid SUVR and tau SUVR in the middle/inferior temporal gyri than males. However, females had higher cortical thickness than males and performed better in a test of verbal memory despite having higher AD neuropathology burden. CONCLUSION: Higher amyloid and tau in females compared to males in late middle-age may explain the reported higher dementia risk in elderly females compared to males. Longitudinal follow-up is necessary to examine whether higher amyloid and tau burden in late middle age is followed by increased neurodegeneration and cognitive decline in females as compared with males.

Cerebrovascular disease promotes tau pathology in Alzheimer's disease.

Small vessel cerebrovascular disease, visualized as white matter hyperintensities on T2-weighted magnetic resonance imaging, contributes to the clinical presentation of Alzheimer's disease. However, the extent to which cerebrovascular disease represents an independent pathognomonic feature of Alzheimer's disease or directly promotes Alzheimer's pathology is unclear. The purpose of this study was to examine the association between white matter hyperintensities and plasma levels of tau and to determine if white matter hyperintensities and tau levels interact to predict Alzheimer's disease diagnosis. To confirm that cerebrovascular disease promotes tau pathology, we examined tau fluid biomarker concentrations and pathology in a mouse model of ischaemic injury. Three hundred ninety-one participants from the Alzheimer's Disease Neuroimaging Initiative (74.5 ± 7.1 years of age) were included in this cross-sectional analysis. Participants had measurements of plasma total-tau, cerebrospinal fluid beta-amyloid, and white matter hyperintensities, and were diagnosed clinically as Alzheimer's disease (n = 97), mild cognitive impairment (n = 186) or cognitively normal control (n = 108). We tested the relationship between plasma tau concentration and white matter hyperintensity volume across diagnostic groups. We also examined the extent to which white matter hyperintensity volume, plasma tau, amyloid positivity status and the interaction between white matter hyperintensities and plasma tau correctly classifies diagnostic category. Increased white matter hyperintensity volume was associated with higher plasma tau concentration, particularly among those diagnosed clinically with Alzheimer's disease. Presence of brain amyloid and the interaction between plasma tau and white matter hyperintensity volume distinguished Alzheimer's disease and mild cognitive impairment participants from controls with 77.6% and 63.3% accuracy, respectively. In 63 Alzheimer's Disease Neuroimaging Initiative participants who came to autopsy (82.33 ± 7.18 age at death), we found that higher degrees of arteriosclerosis were associated with higher Braak staging, indicating a positive relationship between cerebrovascular disease and neurofibrillary pathology. In a transient middle cerebral artery occlusion mouse model, aged mice that received transient middle cerebral artery occlusion, but not sham surgery, had increased plasma and cerebrospinal fluid tau concentrations, induced myelin loss, and hyperphosphorylated tau pathology in the ipsilateral hippocampus and cerebral hemisphere. These findings demonstrate a relationship between cerebrovascular disease, operationalized as white matter hyperintensities, and tau levels, indexed in the plasma, suggesting that hypoperfusive injury promotes tau pathology. This potential causal association is supported by the demonstration that transient cerebral artery occlusion induces white matter damage, increases biofluidic markers of tau, and promotes cerebral tau hyperphosphorylation in older-adult mice.