APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline.

Vascular contributions to dementia and Alzheimer's disease are increasingly recognized1-6. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer's disease5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15-19, which maintain BBB integrity20-22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-ß or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRß7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-ß and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.

Robust reference group normative data for neuropsychological tests accounting for primary language use in Asian American older adults.

OBJECTIVE: The present study aimed to develop neuropsychological norms for older Asian Americans with English as a primary or secondary language, using data from the National Alzheimer's Coordinating Center (NACC). METHOD: A normative sample of Asian American participants was derived from the NACC database using robust criteria: participants were cognitively unimpaired at baseline (i.e., no MCI or dementia) and remained cognitively unimpaired at 1-year follow-up. Clinical and demographic characteristics were compared between Primary and Secondary English speakers using analyses of variance for continuous measures and chi-square tests for categorical variables. Linear regression models compared neuropsychological performance between the groups, adjusting for demographics (age, sex, and education). Regression models were developed for clinical application to compute demographically adjusted z-scores. RESULTS: Secondary English speakers were younger than Primary English speakers (p < .001). There were significant differences between the groups on measures of mental status (Mini-Mental State Examination, p = .002), attention (Trail Making Test A, Digit Span Forward Total Score, p <.001), language (Boston Naming Test, Animal Fluency, Vegetable Fluency, p < .001), and executive function (Trail Making Test B, p = .02). CONCLUSIONS: Separate normative data are needed for Primary vs. Secondary English speakers from Asian American backgrounds. We provide normative data on older Asian Americans to enable clinicians to account for English use in the interpretation of neuropsychological assessment scores.

Role of Notch signaling in neurovascular aging and Alzheimer's disease.

The Notch signaling pathway is an evolutionarily conserved cell signaling system known to be involved in vascular development and function. Recent evidence suggests that dysfunctional Notch signaling could play a critical role in the pathophysiology of neurodegenerative diseases. We reviewed current literature on the role of Notch signaling pathway, and specifically Notch receptor genes and proteins, in aging, cerebrovascular disease and Alzheimer's disease. We hypothesize that Notch signaling may represent a key point of overlap between age-related vascular and Alzheimer's pathophysiology contributing to their comorbidity and combined influence on cognitive decline and dementia. Numerous findings from studies of genetics, neuropathology and cell culture models all suggest a link between altered Notch signaling and Alzheimer's pathophysiology. Age-related changes in Notch signaling may also trigger neurovascular dysfunction, contributing to the development of neurodegenerative diseases; however, additional studies are warranted. Future research directly exploring the influence of aberrant Notch signaling in the development of Alzheimer's disease is needed to better understand this mechanism.

Increasing coordination and responsivity of emotion-related brain regions with a heart rate variability biofeedback randomized trial.

Heart rate variability is a robust biomarker of emotional well-being, consistent with the shared brain networks regulating emotion regulation and heart rate. While high heart rate oscillatory activity clearly indicates healthy regulatory brain systems, can increasing this oscillatory activity also enhance brain function? To test this possibility, we randomly assigned 106 young adult participants to one of two 5-week interventions involving daily biofeedback that either increased heart rate oscillations (Osc+ condition) or had little effect on heart rate oscillations (Osc- condition) and examined effects on brain activity during rest and during regulating emotion. While there were no significant changes in the right amygdala-medial prefrontal cortex (MPFC) functional connectivity (our primary outcome), the Osc+ intervention increased left amygdala-MPFC functional connectivity and functional connectivity in emotion-related resting-state networks during rest. It also increased down-regulation of activity in somatosensory brain regions during an emotion regulation task. The Osc- intervention did not have these effects. In this healthy cohort, the two conditions did not differentially affect anxiety, depression, or mood. These findings indicate that modulating heart rate oscillatory activity changes emotion network coordination in the brain.

The small HDL particle hypothesis of Alzheimer's disease.

We propose the hypothesis that small high-density lipoprotein (HDL) particles reduce the risk of Alzheimer's disease (AD) by virtue of their capacity to exchange lipids, affecting neuronal membrane composition and vascular and synaptic functions. Concentrations of small HDLs in cerebrospinal fluid (CSF) and plasma were measured in 180 individuals ≥60 years of age using ion mobility methodology. Small HDL concentrations in CSF were positively associated with performance in three domains of cognitive function independent of apolipoprotein E (APOE) ε4 status, age, sex, and years of education. Moreover, there was a significant correlation between levels of small HDLs in CSF and plasma. Further studies will be aimed at determining whether specific components of small HDL exchange across the blood, brain, and CSF barriers, and developing approaches to exploit small HDLs for therapeutic purposes.

Older adults with perivascular spaces exhibit cerebrovascular reactivity deficits.

BACKGROUND: Perivascular spaces on brain magnetic resonance imaging (MRI) may indicate poor fluid drainage in the brain and have been associated with numerous neurological conditions. Cerebrovascular reactivity (CVR) is a marker of cerebrovascular function and represents the ability of cerebral blood vessels to regulate cerebral blood flow in response to vasodilatory or vasoconstrictive stimuli. We aimed to examine whether pathological widening of the perivascular space in older adults may be associated with deficits in CVR. METHODS: Independently living older adults free of dementia or clinical stroke were recruited from the community and underwent brain MRI. Pseudo-continuous arterial spin labeling MRI quantified whole brain cerebral perfusion at rest and during CVR to hypercapnia and hypocapnia induced by visually guided breathing exercises. Perivascular spaces were visually scored using existing scales. RESULTS: Thirty-seven independently living older adults (mean age = 66.3 years; SD = 6.8; age range 55-84 years; 29.7% male) were included in the current analysis. Multiple linear regression analysis revealed a significant negative association between burden of perivascular spaces and global CVR to hypercapnia (B = -2.0, 95% CI (-3.6, -0.4), p = .015), adjusting for age and sex. Perivascular spaces were not related to CVR to hypocapnia. DISCUSSION: Perivascular spaces are associated with deficits in cerebrovascular vasodilatory response, but not vasoconstrictive response. Enlargement of perivascular spaces could contribute to, or be influenced by, deficits in CVR. Additional longitudinal studies are warranted to improve our understanding of the relationship between cerebrovascular function and perivascular space enlargement.

Visit-To-Visit Blood Pressure Variability and Subthreshold Depressive Symptoms in Older Adults.

OBJECTIVES: Depression is related to increased risk for dementia, possibly through links with cerebrovascular disease. Blood pressure variability is an emerging risk factor for cerebrovascular disease and dementia, but relationships with affective symptoms remain understudied. DESIGN: Retrospective analysis of prospective cohort study. SETTING: Alzheimer's Disease Neuroimaging Initiative. PARTICIPANTS: 505 older adults without history of dementia or recent depression underwent three to four blood pressure measurements over 12 months and completed a self-report measure of depressive symptoms (Geriatric Depression Scale - 15 Item) at study baseline and 24-months follow-up. MEASUREMENTS: Blood pressure variability was calculated as variability independent of mean and maximum minus minimum. Regression models investigated relationships between blood pressure variability and severity of self-reported depressive symptoms at 24-months follow-up after controlling for several variables, including average blood pressure, antihypertensive use, antidepressant use, and baseline depressive symptom severity. RESULTS: Elevated diastolic blood pressure variability was related to greater total depressive symptom score at follow-up (ß = .16 [95% CI 0.02, .30]; p = 0.03), with specific contribution from increased severity of symptoms of dysphoria (odds ratio = 1.35 [95% CI 1.07, 1.75]; p = 0.02). Blood pressure variability was not significantly related to other symptom subscales, including those reflecting life satisfaction or withdrawal. CONCLUSIONS: Findings suggest that elevated diastolic blood pressure variability is related to subthreshold depressive symptomatology in older adults without history of dementia or recent depression, independent of average blood pressure. Blood pressure variability may be an understudied vascular risk factor linked with depression and cognitive impairment, with potential therapeutic implications.

A novel sensitive assay for detection of a biomarker of pericyte injury in cerebrospinal fluid.

INTRODUCTION: Blood-brain barrier (BBB) breakdown and loss of brain capillary pericytes contributes to cognitive impairment. Pericytes express platelet-derived growth factor receptor-ß (PDGFRß) that regulates brain angiogenesis and blood vessel stability. Elevated soluble PDGFRß (sPDGFRß) levels in cerebrospinal fluid (CSF) indicate pericyte injury and BBB breakdown, which is an early biomarker of human cognitive dysfunction. METHODS: A combination of reagents and conditions were tested, optimized, and validated on the Meso Scale Discovery electrochemiluminescence platform to develop a new sPDGFRß immunoassay that was used to measure sPDGFRß in human CSF from 147 individuals. RESULTS: We developed standard operating procedures for a highly sensitive and reproducible sPDGFRß immunoassay with a dynamic range from 100 to 26,000 pg/mL, and confirmed elevated CSF sPDGFRß levels in individuals with cognitive dysfunction. DISCUSSION: This assay could be applied at different laboratories to study brain pericytes and microvascular damage in relation to cognition in disorders associated with neurovascular and cognitive dysfunction.

Undetectable gadolinium brain retention in individuals with an age-dependent blood-brain barrier breakdown in the hippocampus and mild cognitive impairment.

INTRODUCTION: Blood-brain barrier (BBB) breakdown is an early independent biomarker of human cognitive dysfunction, as found using gadolinium (Gd) as a contrast agent. Whether Gd accumulates in brains of individuals with an age-dependent BBB breakdown and/or mild cognitive impairment remains unclear. METHODS: We analyzed T1-weighted magnetic resonance imaging (MRI) scans from 52 older participants with BBB breakdown in the hippocampus 19-28 months after either cyclic or linear Gd agent. RESULTS: There was no change in T1-weighted signal intensity between the baseline contrast MRI and unenhanced MRI on re-examination in any of the studied 10 brain regions with either Gd agent suggesting undetectable Gd brain retention. DISCUSSION: Gd does not accumulate in brains of older individuals with a BBB breakdown in the hippocampus. Thus, Gd agents can be used without risk of brain retention within a ∼2-year follow-up to study BBB in the aging human brain in relation to cognition and/or other pathologies.

Vascular dysfunction-The disregarded partner of Alzheimer's disease.

Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.

Neuropsychological Profiles and Trajectories in Preclinical Alzheimer's Disease.

OBJECTIVES: The present study investigated the independent and synergistic effects of amyloid beta (Aß1-42) and phosphorylated tau (Ptau) pathologies on neuropsychological profiles and trajectories in cognitively normal older adults. METHODS: Alzheimer's Disease Neuroimaging Initiative participants identified as cognitively normal at baseline underwent longitudinal assessment (N=518; 0, 12, 24, 36 months), baseline lumbar puncture and follow-up cognitive exams. Cerebral spinal fluid (CSF) biomarker profiles (Aß-Ptau-, Aß+Ptau-, Aß-Ptau+, Aß+Ptau+) were compared on baseline profiles and trajectories for memory (Rey Auditory Verbal Learning Test), attention/executive function (Trail Making Test, A and B), language (Animal Fluency, Vegetable Fluency, Boston Naming Test) and processing speed (Digit Symbol) using multilevel models. RESULTS: The Aß+Ptau+ group exhibited significantly worse baseline performance on tests of memory and executive function relative to the Aß-Ptau+ and Aß-Ptau- groups. The Aß+Ptau- group fell between the Aß+Ptau+ participants and the Aß-Ptau- and Aß-Ptau+ groups on all three cognitive domains and exhibited worse baseline executive function. The Aß-Ptau+ group performed worse than Aß-Ptau- participants on processing speed. Over 36-month follow-up, the Aß+Ptau+ group exhibited the greatest declines in memory and semantic fluency compared to all other groups. CONCLUSIONS: Cognitively normal older adults with both Aß and Ptau pathology exhibited the weakest profile, marked by the worst memory decline compared to the other groups. Other subtle changes in this group included declines in executive function and semantic fluency. Those with Ptau pathology alone showed slowed processing speed, and those with Aß pathology alone showed worse attention and executive function compared to biomarker negative participants. (JINS, 2018, 24, 693-702).

Cerebrovascular resistance: effects on cognitive decline, cortical atrophy, and progression to dementia.

See Markus (doi:10.1093/awx161) for a scientific commentary on this article.Evidence for vascular contributions to Alzheimer's disease has been increasingly identified, with increased blood pressure and decreased cerebral blood flow both linked to in vivo biomarkers and clinical progression of Alzheimer's disease. We therefore hypothesized that an elevated ratio of blood pressure to cerebral blood flow, indicative of cerebrovascular resistance, would exhibit earlier and more widespread associations with Alzheimer's disease than cerebral blood flow alone. Further, we predicted that increased cerebrovascular resistance and amyloid retention would synergistically influence cognitive performance trajectories, independent of neuronal metabolism. Lastly, we anticipated associations between cerebrovascular resistance and later brain atrophy, prior to amyloid accumulation. To evaluate these hypotheses, we investigated associations between cerebrovascular resistance and amyloid retention, cognitive decline, and brain atrophy, controlling for neuronal metabolism. North American older adults (n = 232) underwent arterial spin labelling magnetic resonance imaging to measure regional cerebral blood flow in brain regions susceptible to ageing and Alzheimer's disease. An estimated cerebrovascular resistance index was then calculated as the ratio of mean arterial pressure to regional cerebral blood flow. Positron emission tomography with 18F-florbetapir and fludeoxyglucose was used to quantify amyloid retention and neuronal metabolism, respectively. Cognitive performance was evaluated via annual assessments of global cognition, memory, and executive function. Results indicated diminished inferior parietal and temporal cerebral blood flow for patients with Alzheimer's disease (n = 33) relative to both non-demented groups, but no cerebral blood flow differences between non-demented amyloid-positive (n = 87) and amyloid-negative (n = 112) cases. In contrast, the cerebrovascular resistance index was significantly elevated in amyloid-positive versus amyloid-negative cases, with additional elevation in patients with Alzheimer's disease. Furthermore, cerebrovascular resistance index group differences were of greater statistical effect size and encompassed a greater number of brain regions than those for cerebral blood flow alone. Cognitive decline over 2-year follow-up was accelerated by elevated baseline cerebrovascular resistance index, particularly for amyloid-positive individuals. Increased baseline cerebrovascular resistance index also predicted greater progression to dementia, beyond that attributable to amyloid-positivity. Finally, increased cerebrovascular resistance index predicted greater regional atrophy among non-demented older adults who were amyloid-negative. Findings suggest that increased cerebrovascular resistance may represent a previously unrecognized contributor to Alzheimer's disease that is independent of neuronal hypometabolism, predates changes in brain perfusion, exacerbates and works synergistically with amyloidosis to produce cognitive decline, and drives amyloid-independent brain atrophy during the earliest stage of disease.

Correction to: Detectable Neuropsychological Differences in Early Preclinical Alzheimer's Disease: a Meta-Analysis.

Errors were discovered in the reporting of processing speed data that do not impact the interpretation of findings.

Detectable Neuropsychological Differences in Early Preclinical Alzheimer's Disease: A Meta-Analysis.

The development of methods for in vivo detection of cerebral beta amyloid retention and tau accumulation have been increasingly useful in characterizing preclinical Alzheimer's disease (AD). While the association between these biomarkers and eventual AD has been demonstrated among cognitively intact older adults, the link between biomarkers and neurocognitive ability remains unclear. We conducted a meta-analysis to test the hypothesis that cognitively intact older adults would show statistically discernable differences in neuropsychological performance by amyloid status (amyloid negative = A-, amyloid positive = A+). We secondarily hypothesized a third group characterized by either CSF tau pathology or neurodegeneration, in addition to amyloidosis (A+/N+ or Stage 2), would show lower neuropsychology scores than the amyloid positive group (A+/N- or Stage 1) when compared to the amyloid negative group. Pubmed, PsychINFO, and other sources were searched for relevant articles, yielding 775 total sources. After review for inclusion/exclusion criteria, duplicates, and risk of bias, 61 studies were utilized in the final meta-analysis. Results showed A+ was associated with poorer performance in the domains of global cognitive function, memory, language, visuospatial ability, processing speed, and attention/working memory/executive functions when compared to A-. A+/N+ showed lower performances on memory measures when compared to A+/N- in secondary analyses based on a smaller subset of studies. Results support the notion that neuropsychological measures are sensitive to different stages of preclinical AD among cognitively intact older adults. Further research is needed to determine what constitutes meaningful differences in neuropsychological performance among cognitively intact older adults.

Mechanisms of Memory Dysfunction during High Altitude Hypoxia Training in Military Aircrew.

OBJECTIVES: Cognitive dysfunction from high altitude exposure is a major cause of civilian and military air disasters. Pilot training improves recognition of the early symptoms of altitude exposure so that countermeasures may be taken before loss of consciousness. Little is known regarding the nature of cognitive impairments manifesting within this critical window when life-saving measures may still be taken. Prior studies evaluating cognition during high altitude simulation have predominantly focused on measures of reaction time and other basic attention or motor processes. Memory encoding, retention, and retrieval represent critical cognitive functions that may be vulnerable to acute hypoxic/ischemic events and could play a major role in survival of air emergencies, yet these processes have not been studied in the context of high altitude simulation training. METHODS: In a series of experiments, military aircrew underwent neuropsychological testing before, during, and after brief (15 min) exposure to high altitude simulation (20,000 ft) in a pressure-controlled chamber. RESULTS: Acute exposure to high altitude simulation caused rapid impairment in learning and memory with relative preservation of basic visual and auditory attention. Memory dysfunction was predominantly characterized by deficiencies in memory encoding, as memory for information learned during high altitude exposure did not improve after washout at sea level. Retrieval and retention of memories learned shortly before altitude exposure were also impaired, suggesting further impairment in memory retention. CONCLUSIONS: Deficits in memory encoding and retention are rapidly induced upon exposure to high altitude, an effect that could impact life-saving situational awareness and response. (JINS, 2017, 23, 1-10).

Brain imaging of neurovascular dysfunction in Alzheimer's disease.

Neurovascular dysfunction, including blood-brain barrier (BBB) breakdown and cerebral blood flow (CBF) dysregulation and reduction, are increasingly recognized to contribute to Alzheimer's disease (AD). The spatial and temporal relationships between different pathophysiological events during preclinical stages of AD, including cerebrovascular dysfunction and pathology, amyloid and tau pathology, and brain structural and functional changes remain, however, still unclear. Recent advances in neuroimaging techniques, i.e., magnetic resonance imaging (MRI) and positron emission tomography (PET), offer new possibilities to understand how the human brain works in health and disease. This includes methods to detect subtle regional changes in the cerebrovascular system integrity. Here, we focus on the neurovascular imaging techniques to evaluate regional BBB permeability (dynamic contrast-enhanced MRI), regional CBF changes (arterial spin labeling- and functional-MRI), vascular pathology (structural MRI), and cerebral metabolism (PET) in the living human brain, and examine how they can inform about neurovascular dysfunction and vascular pathophysiology in dementia and AD. Altogether, these neuroimaging approaches will continue to elucidate the spatio-temporal progression of vascular and neurodegenerative processes in dementia and AD and how they relate to each other.

Patterns of Cortical and Subcortical Amyloid Burden across Stages of Preclinical Alzheimer's Disease.

OBJECTIVES: We examined florbetapir positron emission tomography (PET) amyloid scans across stages of preclinical Alzheimer's disease (AD) in cortical, allocortical, and subcortical regions. Stages were characterized using empirically defined methods. METHODS: A total of 312 cognitively normal Alzheimer's Disease Neuroimaging Initiative participants completed a neuropsychological assessment and florbetapir PET scan. Participants were classified into stages of preclinical AD using (1) a novel approach based on the number of abnormal biomarkers/cognitive markers each individual possessed, and (2) National Institute on Aging and the Alzheimer's Association (NIA-AA) criteria. Preclinical AD groups were compared to one another and to a mild cognitive impairment (MCI) sample on florbetapir standardized uptake value ratios (SUVRs) in cortical and allocortical/subcortical regions of interest (ROIs). RESULTS: Amyloid deposition increased across stages of preclinical AD in all cortical ROIs, with SUVRs in the later stages reaching levels seen in MCI. Several subcortical areas showed a pattern of results similar to the cortical regions; however, SUVRs in the hippocampus, pallidum, and thalamus largely did not differ across stages of preclinical AD. CONCLUSIONS: Substantial amyloid accumulation in cortical areas has already occurred before one meets criteria for a clinical diagnosis. Potential explanations for the unexpected pattern of results in some allocortical/subcortical ROIs include lack of correspondence between (1) cerebrospinal fluid and florbetapir PET measures of amyloid, or between (2) subcortical florbetapir PET SUVRs and underlying neuropathology. Findings support the utility of our novel method for staging preclinical AD. By combining imaging biomarkers with detailed cognitive assessment to better characterize preclinical AD, we can advance our understanding of who is at risk for future progression. (JINS, 2016, 22, 978-990).

Pulse Pressure Is Associated With Early Brain Atrophy and Cognitive Decline: Modifying Effects of APOE-ε4.

We investigated whether midlife pulse pressure is associated with brain atrophy and cognitive decline, and whether the association was modified by apolipoprotein-E ε4 (APOE-ε4) and hypertension. Participants (549 stroke-free and dementia-free Framingham Offspring Cohort Study participants, age range=55.0 to 64.9 y) underwent baseline neuropsychological and magnetic resonance imaging (subset, n=454) evaluations with 5- to 7-year follow-up. Regression analyses investigated associations between baseline pulse pressure (systolic-diastolic pressure) and cognition, total cerebral volume and temporal horn ventricular volume (as an index of smaller hippocampal volume) at follow-up, and longitudinal change in these measures. Interactions with APOE-ε4 and hypertension were assessed. Covariates included age, sex, education, assessment interval, and interim stroke. In the total sample, baseline pulse pressure was associated with worse executive ability, lower total cerebral volume, and greater temporal horn ventricular volume 5 to 7 years later, and longitudinal decline in executive ability and increase in temporal horn ventricular volume. Among APOE-ε4 carriers only, baseline pulse pressure was associated with longitudinal decline in visuospatial organization. Findings indicate arterial stiffening, indexed by pulse pressure, may play a role in early cognitive decline and brain atrophy in mid to late life, particularly among APOE-ε4 carriers.

Aggregate effects of vascular risk factors on cerebrovascular changes in autopsy-confirmed Alzheimer's disease.

We examined the relationships of antemortem vascular risk factors to postmortem cerebrovascular and Alzheimer's disease (AD) pathologies. Eighty-four AD patients underwent an assessment of vascular risk (blood pressure, cholesterol, smoking, cardiovascular disease, diabetes, atrial fibrillation, transient ischemic attack [TIA], or stroke) and later underwent brain autopsy. Given our aim to examine mild cerebrovascular changes (CVCs), individuals were excluded if autopsy revealed large stroke. The most common forms of CVC were circle of Willis atherosclerosis followed by arteriosclerosis, lacunes, and microinfarcts. Excluding the history of TIA/clinical stroke, individual vascular risk factors were not associated with CVC. However, the presence of multiple vascular risk factors was associated with CVC. Furthermore, the presence of CVC was associated with lower Braak and Braak stage. These findings highlight the importance of aggregate risk in the vascular contribution to dementia. Interventions designed to maintain cerebrovascular health may represent important opportunities for preventing or delaying dementia, even when AD is the dominant pathology.