Physical activity, physical function, and frailty in relation to cognitive impairment and AD/ADRD biomarkers in DPPOS

The goal of Project 4 is to study the interrelationships of physical activity (PA), lower extremity physical function (PF), and frailty, with cognitive impairment and its underlying neuropathology in older adults in the continuum of pre-diabetes (PreD) and type 2 diabetes (T2D) in the Diabetes Prevention Program (DPP) Outcomes Study (DPPOS). PA is a common lifestyle target in T2D prevention and treatment and was a key component of the lifestyle intervention in the DPP. Higher sustained PA levels are hypothesized to be associated with a lower risk of cognitive impairment. PF decline and frailty, increased in older adults with PreD/T2D, are closely related to PA, and are also associated with cognitive impairment. Thus, this project seeks to better understand the individual and joint associations of PA, PF, and frailty with cognitive outcomes and underlying neuropathology among persons with PreD/T2D. Our preliminary data show that lower PA and PF levels and higher frailty at midlife are concurrently associated with poorer global and domain-specific cognitive function. We now propose to examine the association among PA, PF, and frailty trajectories, across the mid- to late-life transition period, with cognitive decline, mild cognitive impairment (MCI) and dementia, and with plasma and imaging biomarkers of neuropathology. Further, we will evaluate (1) exercise-induced myokines as mediators, and (2) T2D-related metabolic factors and complications as moderators and mediators. We will leverage >25 years of PA data, >15 years of PF and frailty data, and extensive metabolic phenotyping in the longitudinal framework of DPPOS among participants (N = 1,979) expected to enroll in DPPOS-AD/ADRD. We will achieve our goal through the following specific aims: (1) To relate PA, PF, and frailty trajectories, separately and jointly, to amnestic and non-amnestic cognitive decline and risk of MCI and dementia (AD continuum vs. non-AD pathology as exploratory) in PreD/T2D; 2) To relate PA, PF, and frailty trajectories, separately and jointly, to changes in plasma biomarkers of amyloid (Aβ42/40 ratio), tau (phosphorylated tau 181 [ptau-181]), neurodegeneration (neurofilament light [NfL]), and neuroinflammation (glial fibrillary acidic protein [GFAP]). Among participants with brain imaging (N = 650), we will relate PA, PF, and frailty trajectories to amyloid burden, cortical thickness, and cerebrovascular disease; (3) To examine the association of PA, PF, and frailty with exercise-induced myokines (e.g., brain- derived neurotrophic factor [BDNF], insulin-like growth factor 1 [IGF-1]) and the relationship of myokines with cognitive outcomes examined in Aim 1 and biomarkers in Aim 2. (4) To explore whether glycemic burden, vascular burden, microvascular/macrovascular complications, and peripheral inflammation moderate and/or mediate the associations examined across aims 1-3; (5) Exploratory Aim: Aims 1-4 will also explore interactions by APOE-ε4, sex, body mass index (BMI), original randomized treatment assignment, race/ethnicity, and measures of cognitive reserve (e.g., education level).