# Role of classical complement pathway underling glial phenotypes and multiple pathologies in Alzheimer's disease and cerebrovascular disease

> **NIH NIH U19** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $412,144

## Abstract

The pathologies underlying Alzheimer disease (AD) are common in the aged population and can occur more
than a decade prior to clinical symptoms. In addition, aging increases the likelihood of multiple pathologies which
may all contribute to cognitive impairment. Recent studies demonstrate that apolipoprotein E (APOE) and
classical complement pathway genes are involved in synaptic loss and tau pathology. The objective of this project
is to investigate role of APOE and complement pathway genes in determining glial, neuroinflammatory, and
neuropathological alterations that ultimately lead to altered cognitive and imaging biomarker trajectories. We
propose a cross-disciplinary approach in 3 specific aims. For Aim 1, we will determine how genetic and
transcriptional risk profiles of complement pathway genes and their interaction with APOE genotype contribute
to synaptic loss, neuroinflammation, cerebrovascular disease, and tau pathology in AD using the entire FHS
cohort as well as within deceased FHS participants with brain donation (current number of autopsy cases is 241;
with blood and brain tissue, n=208). For Aim 2, we will determine how glial and neuroinflammatory phenotypes
associated with AD and cerebrovascular disease result in distinctive patterns of astrocytosis, microgliosis, and
neuroinflammation that lead to AD and AD-related disorders using newly defined phenotypes together with
traditional pathological measures developed in collaboration with the Neuropathology Core. For Aim 3, we will
validate clinical implications by determining associations of the identified genetic variants and alternative
transcripts and novel cellular phenotypes from Aims 1 and 2 with longitudinal changes of imaging biomarkers
and cognitive function (n=3,189) as well as with quantitative vascular risk factors (e.g., blood glucose, lipid
fractions, blood pressure, BMI, cigarette smoking). We anticipate that results from this project will provide
opportunities for developing new genetic screening markers and biomarkers and insights about potential novel
therapeutic targets for AD.

## Key facts

- **NIH application ID:** 10047360
- **Project number:** 1U19AG068753-01
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Thor Stein
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,144
- **Award type:** 1
- **Project period:** 2020-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10047360

## Citation

> US National Institutes of Health, RePORTER application 10047360, Role of classical complement pathway underling glial phenotypes and multiple pathologies in Alzheimer's disease and cerebrovascular disease (1U19AG068753-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10047360. Licensed CC0.

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