# The Stanford Extreme Phenotypes in Alzheimer's Disease (StEP AD) Cohort

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $754,370

## Abstract

Project Summary/Abstract
Alzheimer's disease (AD) is a common, progressive, and ultimately fatal brain disease. Currently approved
treatments provide only minimal symptomatic benefits and do not stop the disease from progressing. The field
is in dire need of novel drug targets which could lead to disease-modifying therapies. The most common
genetic risk factor for AD is the ε4 variant of the apolipoprotein E gene (APOE4). The current study will take
advantage of the strong effect of APOE4 to discover new genetic variants that either increase risk for AD or
reduce risk for AD. The research team—based at Stanford University but including collaborators at 13 other
research centers—will recruit and study participants that fall into one two rare categories: cognitively normal
people carrying one or two copies of the high risk APOE4 gene (protected APOE4 carriers) and young patients
who early-onset AD (EOAD) before age 65 despite not carrying APOE4 gene. These subjects, the Stanford
Extreme Phenotypes in AD (StEP AD) cohort, will undergo whole-exome sequencing and their exomes will be
combined with large, publicly available exomes from ~4500 healthy older controls and ~5000 AD patients. In
Aim 1 the research team will look for rare genetic variants seen more often in protected APOE4 carriers than in
AD patients. In Aim 2 the team will look for rare genetic variants seen in APOE4-negative EOAD patients but
not in healthy older controls. Most of the StEP AD cohort will undergo “deep phenotyping” to include structural
and molecular brain imaging, spinal fluid analysis, immunophenotyping, and culturing of participant-specific
neurons. In Aim 3, the deep phenotyping data will be used to begin to understand the molecular effects of the
rare protective or causal genetic variants identified in Aims 1 and 2. Rare but powerful genetic variants
identified and characterized in this study will provide novel drug targets for the design of potentially disease-
modifying treatments.

## Key facts

- **NIH application ID:** 10225285
- **Project number:** 5R01AG060747-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Michael D Greicius
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $754,370
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225285

## Citation

> US National Institutes of Health, RePORTER application 10225285, The Stanford Extreme Phenotypes in Alzheimer's Disease (StEP AD) Cohort (5R01AG060747-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10225285. Licensed CC0.

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