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

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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 3 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.