The Interplay Between Frailty and Alzheimer’s Disease: Pathophysiological Mechanisms, Biomarker Landscapes, and Integrated Therapeutic Strategies

Abstract

Background: Frailty and Alzheimer’s disease (AD) represent two of the most prevalent and debilitating conditions associated with human aging. Frailty is a dynamic, multidimensional syndrome characterized by a loss of physiological reserve and homeostatic resilience across multiple organ systems. Emerging epidemiological and clinical evidence demonstrates that physical frailty substantially accelerates cognitive decline and increases the incidence of AD in cognitively intact older adults. Conversely, neuropathological burden lowers the threshold for manifest physical frailty. Key Findings: This review systematically examines the intricate crosstalk between frailty and AD. We detail shared molecular pathophysiological mechanisms, including chronic low-grade systemic inflammation (“inflammaging”), oxidative stress, cellular senescence, mitochondrial decay, and neuroendocrine axis dysregulation. Furthermore, we evaluate common diagnostic landscapes and biomarker signatures, focusing on cerebrospinal fluid (CSF)Aβ42dynamics, plasma markers, blood-based metabolomics—notably the selective depletion of the dietary antioxidant ergothioneine (ERG)—and subcortical-frontal network alterations manifested through motoric cognitive risk (MCR) phenotypes. Finally, we analyze therapeutic implications, contrasting the potential adverse impacts of conventional anti-dementia pharmacotherapies on physical frailty with emerging multimodal lifestyle, nutritional (e.g., ERG supplementation), and targeted metabolic interventions. Conclusions: Recognizing frailty and AD as interrelated manifestations of accelerated biological aging provides a critical paradigm shift. Developing standardized, high-sensitivity screening tools and dual-target therapeutic strategies will be essential for advancing precision geriatric care and mitigating the global burden of neurodegenerative and functional decline.