Targeting Biology of Aging Mechanisms Underlying Alzheimer's Disease Risk with Metformin

PROJECT SUMMARY/ABSTRACT Age is the strongest risk factor for Alzheimer’s disease and related dementias (ADRD), with a doubling of disease prevalence every five years after the age of 65 years. Nonetheless, the mechanisms linking biological aging with ADRD remain elusive, impeding the development of therapeutics targeting these core processes. Advances in the field of geroscience has led to the discovery of key biological aging pathways and hallmarks of aging, including cellular senescence, mitochondrial dysfunction, epigenetic alterations, inflammation, and deregulated nutrient sensing/metabolism, which act in concert to induce tissue degradation and ultimately, functional decline. Emerging research indicates that the pace of aging is modifiable through interventions that act upon these key aging pathways and hallmarks, which may serve to prevent or delay the onset of age-related disease such as ADRD. Given the pleiotropic effects of metformin on multiple aging pathways and hallmarks, our team has been conducting a randomized clinical trial of metformin vs. placebo for frailty prevention in prediabetic older adults (R01AG052697), as well as a related project (R01AG069690) examining metformin-induced changes on aging pathways and hallmarks in biospecimens collected from participants enrolled in the randomized trial. In response to PAR-22-093 and aligned with NIA AD+ADRD Milestone 2.A, we propose to examine whether biological aging pathways and hallmarks of aging, separately and collectively, contribute to indicators of ADRD pathology and whether modulating biological aging processes with metformin improves indicators of ADRD pathology. We will leverage data from our ongoing randomized trial of metforminvs. placebo for frailty prevention in older adults without dementia at baseline (mean age 72±5 years, 49% female, 35% Hispanic), in which we have performed comprehensive and longitudinal (24 month) assessments of hallmarks of aging (senescence, inflammation, metabolism, mitochondrial function, and epigenetics) and key cellular pathways that control them (AMPK, mTOR, NFκB). In Aim 1a, we will evaluate the hypothesis that that biological aging pathways and hallmarks of aging will be linked with ADRD markersincluding indicators of neuronal/axonal injury (neurofilament light chain), neuroinflammation (glial fibrillary acidic protein, YKL-40), vascular dysfunction (platelet-derived growth factor), neuropathology (phosphorylated tau 217, amyloid beta (Aβ) 42/40). Under Aim 1b, we will evaluate longitudinal trajectories in the pathways and hallmarks of aging and how they relate to changes in cognition and plasma ADRD markers over 24 months. Under Aim 2, we will examine whether modulating the biological aging pathways and hallmarks of aging with metformin relative to placebo alters ADRD markers. The proposed project will expand our understanding of the role that biology of aging mechanisms exert on ADRD pathology. In addition, we will experimentally assess if targeting the biology of aging with use of metformin can modulate ADRD markers, providing important proof-of-concept data on the novel approach of employing geroscience-guided interventions for ADRD prevention.