Autophagy Stimulation by Intermittent Fasting and Its Potential Neuroprotective Role in Alzheimer’s Disease

Alzheimer’s disease (AD) is characterised by progressive accumulation of misfolded proteins and failure of cellular clearance pathways, particularly the autophagy–lysosomal system. Given the limited disease-modifying efficacy of current pharmacological strategies, intermittent fasting (IF) has emerged as a potentially relevant non-pharmacological intervention capable of modulating energy metabolism, proteostasis and cellular stress responses. This review analyses the mechanisms through which IF and fasting-like metabolic states may stimulate macroautophagy and chaperone-mediated autophagy, and evaluates their potential neuroprotective relevance in AD. Evidence from in vitro models and animal studies suggests that fasting-induced metabolic switching, particularly β-hydroxybutyrate production, can modulate AMPK–mTOR signalling, autophagic flux, oxidative stress, synaptic plasticity and Aβ/Tau-related proteostasis. However, the translation of these findings to humans remains incomplete. Current clinical studies suggest potential benefits in selected cognitive, sleep, and metabolic outcomes but rely mainly on indirect readouts such as neuropsychological testing, peripheral biomarkers, neuroimaging, metabolomics and microbiota-derived signatures. Larger, longer and biomarker-integrated randomised controlled trials using nutritionally supervised protocols are required to determine whether IF can safely produce clinically meaningful neuroprotection in AD without increasing frailty, sarcopenia or hypoglycaemic risk in older adults.