# Vascular factors, physical activity, and inflammation as modulators of neurodegenerative and cognitive trajectories (Project 2)

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $277,403

## Abstract

SUMMARY: PROJECT 2- MODULATING FACTORS
 Disappointing results from recent trials targeting b-amyloid alone underscore it is critical that we identify,
measure, and better understand factors outside of canonical Alzheimer’s pathology that influence the
emergence of late-life cognitive decline. This need is particularly acute for potentially-modifiable risk factors for
decline that can be targeted for intervention, either alone or in combination with therapies directed at b-amyloid
or tau. In this context, this new project will leverage several core strengths of the Harvard Aging Brain Study
(HABS) to assess the extent to which physical activity, inflammatory, and vascular factors modify longitudinal
cognitive decline, MRI-based measures of neurodegeneration, and whether these potentially-modifiable risk
factors interact with Alzheimer’s disease pathological cascades to cause accelerated neurodegeneration and
cognitive decline. Aims 1 and 2: Building on cross-sectional and longitudinal PET, MRI, and cognitive data
available in HABS, we will add objective, longitudinal assessments of vascular risk, white matter disruption due
to putative cerebrovascular injury, and assessment of day and night activity patterns. Primary analyses for
these aims will assess whether individual variations in vascular and activity parameters presage longitudinal
changes in cognition (jointly with Project 4), changes in hippocampal volume, and in the accumulation of tau
pathology as measured by PET (jointly with Project 1). Secondary analyses will assess regional variations in
brain atrophy, examine the interplay of activity patterns with functional network integrity (jointly with Project 3),
and identify cognitive domains which may be differentially impacted by these modulating factors. Together with
the Analytic Core, we will employ causal models to examine the directionality of vascular and activity effects on
cognitive and neurodegenerative trajectories and examine whether activity effects can be ascribed to reverse
causation. Aim 3: In this exploratory aim, we will use a focused set of biofluid markers of vascular,
inflammatory, and neurodegenerative processes to elucidate the mechanisms underlying the modulating
factors we examine here. Together, these studies will allow us to develop a broader understanding of how
these potentially-modifiable factors may interact with b-amyloid to modulate cognitive decline and
neurodegeneration, and to go deeper by using newly-available, high-sensitivity immunoassays to identify
biologic pathways underlying the effects of these potentially-modifiable risk factors.

## Key facts

- **NIH application ID:** 10144909
- **Project number:** 5P01AG036694-12
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** JASMEER P CHHATWAL
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $277,403
- **Award type:** 5
- **Project period:** 2010-07-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144909

## Citation

> US National Institutes of Health, RePORTER application 10144909, Vascular factors, physical activity, and inflammation as modulators of neurodegenerative and cognitive trajectories (Project 2) (5P01AG036694-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10144909. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*