# Transdiagnostic memory, mood and motor circuits in Alzheimer's and neurodegenerative disease

> **NIH NIH R56** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $873,295

## Abstract

Transdiagnostic memory, mood, and motor circuits in Alzheimer’s and neurodegenerative diseases
Clinical diagnoses such as Alzheimer’s disease are based on symptoms, but patients with the same diagnosis
can have different symptoms and similar symptoms can be present across diagnoses. This includes memory,
mood, and motor impairment, each of which can each be disabling. Understanding this symptom
heterogeneity and overlap could lead to improved clinical trial design, personalized prognosis, and better
treatment. Here, we test the hypothesis that specific symptoms in Alzheimer’s disease can be predicted based
on individualized patterns of brain atrophy to trans-diagnostic human brain circuits. To test this hypothesis, we
leverage three recent advances. First, there are now longitudinal databases of symptoms and anatomical MRI
data from thousands of patients with Alzheimer’s and other neurodegenerative diseases. Second, advances in
MRI processing allow us to detect patterns of brain atrophy at the single-subject level. Finally, we now have a
wiring diagram of the human brain (the human connectome) that allows us to map symptoms to brain circuits in
ways not previously possible. We have previously shown that focal brain lesions causing memory, mood, and
motor symptoms map to specific human brain circuits. Our preliminary data shows that this same approach
works well for atrophy patterns in Alzheimer’s disease. These atrophy circuits appear to be symptom-specific,
transdiagnostic, and prognostic. Interestingly, regions of increased brain volume (rather than atrophy) are also
detected using this method and may map to compensatory circuits associated with resilience or preservation of
function. Here, we will test whether locations of brain atrophy in Alzheimer’s diseases map to transdiagnostic
brain circuits for memory (Aim 1), mood (Aim 2), and motor symptoms (Aim 3). Successful completion of these
aims will determine 1) whether individual differences in the location of neurodegeneration, as measured by
brain atrophy, are responsible for individual differences in symptoms, 2) whether similarities in brain atrophy
are responsible for similar symptoms across diagnoses, 3) whether baseline atrophy to brain circuits predicts
future symptoms, and 4) whether increased brain volume in related circuits is associated with preserved
function. This knowledge can be used to control for symptom heterogeneity in clinical trials, predict which
symptoms an individual patient is likely to develop, and identify therapeutic targets for symptomatic treatment
of Alzheimer’s and other neurodegenerative diseases.

## Key facts

- **NIH application ID:** 10358675
- **Project number:** 1R56AG069086-01A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** MICHAEL D FOX
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $873,295
- **Award type:** 1
- **Project period:** 2021-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10358675

## Citation

> US National Institutes of Health, RePORTER application 10358675, Transdiagnostic memory, mood and motor circuits in Alzheimer's and neurodegenerative disease (1R56AG069086-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10358675. Licensed CC0.

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