# Understanding the mechanistic link between vascular dysfunction and Alzheimers disease-related protein accumulation in the medial temporal lobe

> **NIH NIH K99** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $123,714

## Abstract

Project Summary/Abstract
Title: Understanding the mechanistic link between vascular dysfunction and Alzheimer’s disease-related protein
accumulation in the medial temporal lobe.
Cerebral small vessel disease (CSVD), which affects small vessels of the brain in the form of cerebral amyloid
angiopathy (CAA) or arteriolosclerosis, is either primarily responsible or a significantly contributing factor to
Alzheimer’s disease and related dementias (AD/ADRD). However, it remains unclear whether vascular pathology
and AD-related pathology independently contribute to dementia or causally interact with each other. Dysfunction
in perivascular clearance, one of the systems responsible for the disposal of metabolic waste products from the
brain, and blood-brain barrier (BBB) leakage, both occur when CSVD pathology is present and are candidate
mechanisms that could explain this interaction. The objective of the proposed research is to pinpoint the
reciprocal interaction between CSVD and AD-related pathology, in order to infer its underlying
mechanisms. The focus will be on the medial temporal lobe (MTL), a critical brain region for the development
of AD/ADRD, because it is fundamental for cognition and it is a site where a multiplicity of AD-related pathologies
coexist (e.g. Aβ-plaques, neurofibrillary tau tangles, TAR DNA binding protein 43, and neuronal loss), some of
which in very early stages of the disease (e.g. tangles). Firstly, the applicant will investigate whether CSVD in
the MTL worsens AD-related pathology (Hypothesis 1). Secondly, she will infer the contributing role of
perivascular clearance dysfunction and BBB-leakage to these interactions (Hypothesis 2) and aims to create
and validate neuroimaging markers of microvascular health in the MTL (Hypothesis 3). The innovation of this
proposal lies in the use of quantitative neuroimaging and neuropathological methods, including ultra-high
resolution ex vivo MRI, polarization-sensitive optical coherence tomography, and deep-learning based measures
of MRI and serial histology. The proposed investigations address a significant knowledge gap, related to the
complex interactions between AD and CSVD, which has been emphasized as a research priority by the NIH.
Successful completion of the aims will result in histologically validated neuroimaging markers of microvascular
health of the MTL, which can be applied to in vivo studies to understand the impact of disease-modifying
interventions. This proposal leverages the candidate’s existing skillset and demonstrated expertise in vascular
pathology and will provide an invaluable training opportunity to acquire new skills and analytic methods. This
award will be instrumental for a successful transition into an independent investigator. Importantly, the support
of an internationally recognized team of (co-)mentors in human CSVD and AD and the unique resources
available at Massachusetts General Hospital and Harvard Medical School are key ingredients to ensure impactf...

## Key facts

- **NIH application ID:** 10906126
- **Project number:** 5K99AG080134-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Valentina Perosa
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $123,714
- **Award type:** 5
- **Project period:** 2023-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906126

## Citation

> US National Institutes of Health, RePORTER application 10906126, Understanding the mechanistic link between vascular dysfunction and Alzheimers disease-related protein accumulation in the medial temporal lobe (5K99AG080134-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10906126. Licensed CC0.

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