# Imaging Microvascular Hemodynamics In Older Adults With Varying Genetic Risk For Alzheimer's Disease

> **NIH NIH R21** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $458,600

## Abstract

PROJECT SUMMARY
Alzheimer’s disease (AD) currently affects 5.6 million Americans aged 65 years and older, with a projected
increase to 13.8 million by 2050. Beta-amyloid plaques and neurofibrillary tangles are characteristic of AD
pathology, but white matter lesions (WMLs) indicative of cerebral small vessel disease have also been shown to
be an independent contributor to cognitive decline in AD patients. Possession of an ε4 allele of the apolipoprotein
E gene (APOE) is considered the strongest risk factor for developing late-onset AD. In addition, APOE-ε4 also
represents a major risk factor for cerebrovascular disease, and APOE-ε4 carriers are known to exhibit a greater
burden and faster progression of WMLs compared with non-carriers. However, the physiological mechanisms
through which APOE-ε4 leads to tissue hypoxia and the formation of these lesions remain incompletely
understood. The overall goal of this study is to elucidate differences in microvascular physiology between APOE-
ε4 carriers and non-carriers that may indicate potential mechanisms for the pathological effects of APOE-ε4 on
vascular function. Such hemodynamic impairment could be caused by mechanisms associated with abnormal
tissue perfusion. However, prior studies that have examined effects of APOE-ε4 on cerebral perfusion have
reported conflicting results on whether perfusion is reduced or elevated APOE-ε4 carriers versus non-carriers,
indicating that differences in blood flow alone may not fully explain the extent of hemodynamic compromise.
Hemodynamic impairment may also result from inefficiencies in oxygen exchange from vasculature into tissue
due to flow disturbances at the capillary level, which have previously been shown to be related to heterogeneities
in capillary flow patterns. Recently, we have characterized venous hyperintense signal (VHS) on cerebral blood
flow (CBF)-weighted images acquired using arterial spin labeling magnetic resonance imaging (MRI) as a marker
of capillary-level flow disturbances and oxygen exchange inefficiency. In this work, we propose to apply
noninvasive MRI methods and this novel construct to elucidate associations between tissue-level hemodynamic
physiology and WML burden in older APOE-ε4 carriers and non-carriers. Specifically, we will (i) study the effect
of microvascular flow disturbances on oxygen exchange efficiency, (ii) investigate the association between
microvascular dysfunction and CBF according to APOE genotype, and (iii) identify differences in associations
between microvascular physiology and WML burden between APOE-ε4 carriers and non-carriers. Successful
completion of this work will determine the degree to which the observed higher burden of WMLs in older adults
with APOE-ε4 is associated with mechanisms involving oxygen exchange inefficiency, which are indicated by
VHS, versus impaired CBF. These findings could have implications for the titration of different therapeutic
approaches for preventing vascular-related cognitive ...

## Key facts

- **NIH application ID:** 10194991
- **Project number:** 1R21AG072068-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Meher R Juttukonda
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $458,600
- **Award type:** 1
- **Project period:** 2021-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10194991

## Citation

> US National Institutes of Health, RePORTER application 10194991, Imaging Microvascular Hemodynamics In Older Adults With Varying Genetic Risk For Alzheimer's Disease (1R21AG072068-01). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10194991. Licensed CC0.

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