# Cognitively Defined Alzheimer's Subgroups: Natural history, neuropathology, and life course ramifications

> **NIH NIH U19** · KAISER FOUNDATION RESEARCH INSTITUTE · 2024 · $673,014

## Abstract

Clinical heterogeneity is common in late-onset Alzheimer's disease (AD). This heterogeneity leads to the
question of whether there are biologically distinct subsets of people with Alzheimer's disease. Precision
medicine strategies can categorize people with a condition into subgroups and treat each subgroup differently
to improve overall treatment success. Project 2 addresses whether cognitive data can be used to similarly
categorize “Alzheimer's disease.” The investigators use cognitive testing data from the time of Alzheimer's
diagnosis to define subgroups. They use scores from memory, executive functioning, language, and
visuospatial functioning and compare those scores to each other. The modal pattern has all scores relatively
similar to each other (AD-No Domains). There are four groups where scores in one domain are much worse
than the other domains – AD-Memory, AD-Executive Functioning, AD-Language, and AD-Visuospatial. There
are people who have multiple domains with worse scores (AD-Multiple Domains). The investigators have
previously found important genetic, clinical, and imaging differences that correspond to these subgroups. The
overall goal of Project 2 is to leverage Adult Changes in Thought (ACT) U19 Research Program resources to
further scientific understanding of cognitively defined Alzheimer's disease subgroups. Specific Aims are: Aim 1.
Define the evolution of regional brain atrophy across cognitively-defined subgroups. The investigators will
leverage clinical MRI scans, research MRI scans including some obtained for this project, ex vivo scans, and
3D brain data derived from digital photographs of brain slices at autopsy. Aim 2. Determine neuropathological
change across cognitively-defined subgroups. The investigators will leverage ACT's tremendous
neuropathology resources, including extensive new sampling, digital slide scanning, and approaches that
robustly quantify neuropathology findings including deep learning methods. Aim 3. Determine the clinical,
functional, living situation, caregiver network, and economic ramifications of cognitively defined subgroups. The
investigators will leverage ACT's infrastructure to collect data from extensive medical records, collect new data
from people with Alzheimer's and their families and caregivers, and perform careful quantitative and qualitative
analyses to determine whether there are differences across subgroups in clinical, functional, living situation,
caregiver network, or economic implications. Taken together, these investigations will more firmly establish the
implications of cognitively defined subgroups, furthering our progress towards personalized medicine
approaches to ameliorate the scourge of Alzheimer's disease.

## Key facts

- **NIH application ID:** 10876385
- **Project number:** 5U19AG066567-04
- **Recipient organization:** KAISER FOUNDATION RESEARCH INSTITUTE
- **Principal Investigator:** Paul K Crane
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $673,014
- **Award type:** 5
- **Project period:** 2021-05-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10876385

## Citation

> US National Institutes of Health, RePORTER application 10876385, Cognitively Defined Alzheimer's Subgroups: Natural history, neuropathology, and life course ramifications (5U19AG066567-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10876385. Licensed CC0.

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