# The biological underpinnings of Motoric Cognitive Risk syndrome: a multi-center study

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2022 · $71,207

## Abstract

ABSTRACT OF THE PARENT GRANT
Motoric Cognitive Risk syndrome (MCR) is a pre-dementia syndrome characterized by the presence of
subjective cognitive complaints and slow gait. MCR affects almost in 1 in 10 older adults and has a high
incidence in aging. MCR predicts risk of both Alzheimer’s disease (AD) and vascular dementia even after
accounting for clinical overlap with Mild Cognitive Impairment syndrome (MCI). Complex cognitive tests or
laboratory assays are not required for diagnosing MCR, increasing its clinical utility. MCR has incremental
predictive validity for dementia over its individual cognitive (cognitive complaints) and motoric (slow gait)
components. Yet, the biological underpinnings of MCR are not yet established. To address this knowledge
gap, we propose to establish a consortium of eight cohorts with ~11,000 community-dwelling older adults with
clinical phenotypes, biological/genetic, and neuroimaging data; a time and cost-efficient approach to examine
the biology of MCR.
Aim 1. Identify biological mechanisms underlying MCR incidence. Modifiable risk factors for incident MCR
include depressive symptoms, obesity, and low physical activity, which are correlated with each other as well
as share common biological derangements in inflammatory, oxidative stress and vascular pathways. We also
linked Alzheimer and obesity-related polygenic risk scores to prevalent MCR at cross-section. Building on
these findings, we will examine biomarkers and polygenic risk of developing incident MCR. We will test our
hypotheses primarily in individual cohorts and secondarily in a pooled sample of 8,300 individuals with
biomarker data.
Aim 2. Establish neuroanatomical substrates of MCR syndrome. We linked a novel gray matter atrophy
network to MCR at cross-section in three of our cohorts, which was composed of areas linked primarily, but not
exclusively, to motor control. Herein, we will examine if this brain network is vulnerable early in MCR and
predicts incident MCR. This aim will be tested primarily in individual cohorts, and secondarily in a pooled
subsample of ~2,120 individuals with 3T MRIs. Furthermore, in a subset of 1,100 individuals with up to 3 serial
MRIs, we will examine longitudinal changes in this unique brain network in the context of MCR and small
vessel disease.
Aim 3. Compare and contrast biology and brain substrates for MCR and MCI syndromes. We will explore
similarities and differences in new biological associations as well as known AD risk factors with MCR and MCI.
There is only partial clinical overlap between MCR and MCI. While we expect partial biological overlap, our
studies show exclusive genetic predispositions, brain pathologies and brain substrates for MCR not seen with
MCI. The MCR syndrome is not conceptualized as an alternate to MCI but complementary.

## Key facts

- **NIH application ID:** 10486479
- **Project number:** 3R01AG057548-02S2
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** JOE VERGHESE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $71,207
- **Award type:** 3
- **Project period:** 2020-06-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10486479

## Citation

> US National Institutes of Health, RePORTER application 10486479, The biological underpinnings of Motoric Cognitive Risk syndrome: a multi-center study (3R01AG057548-02S2). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10486479. Licensed CC0.

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