Physical inactivity in preclinical Alzheimer's disease: Risk factor, early symptom, or both?

Physical inactivity is a key modifiable risk factor for Alzheimer's disease (AD). However, emerging evidence suggests a bidirectional relationship where inactivity also serves as an early manifestation of AD pathology. This perspective synthesizes recent findings from long-term epidemiological cohorts, brainstem neuropathology, and digital phenotyping to reconceptualize the role of inactivity in preclinical AD. Early tau accumulation in catecholaminergic nuclei (locus coeruleus and ventral tegmental area) disrupts circuits essential for reward valuation and effort calculation. We hypothesize that this neurobiological failure may manifest as prodromal apathy and declining physical activity years before cognitive impairment. Standard metrics like step counts fail to capture these nuances. We propose a multidimensional digital phenotype - incorporating temporal complexity, circadian rhythms, and life-space mobility - to distinguish "behavioral" from "biologically constrained" inactivity. This framework has critical implications for trial enrichment and the design of personalized lifestyle interventions.