LITHIUM AND ALZHEIMER’S DISEASE: POTENTIAL NEUROPROTECTIVE EFFECTS AND THERAPEUTIC PERSPECTIVES

Lithium is an established mood stabilizer whose possible use in Alzheimer’s disease (AD) has emerged from convergent molecular, animal, observational, and early clinical evidence. The principal rationale is that lithium may act on several processes implicated in AD rather than on a single lesion: glycogen synthase kinase-3β (GSK-3β) signaling, tau phosphorylation, amyloid precursor protein processing, neuroinflammation, oxidative and mitochondrial stress, autophagy, neurogenesis, and synaptic plasticity. Animal studies generally report preserved memory and reduced amyloid-related pathology, while small human studies suggest that subtherapeutic lithium may attenuate cognitive decline or modify cerebrospinal-fluid biomarkers. Observational cohorts also associate lithium exposure with lower dementia incidence, but these findings are vulnerable to confounding by indication, comorbidity, treatment adherence, and healthcare use. Evidence is not uniformly positive: a Scottish cohort exposed to extremely low environmental lithium did not support dementia protection, and a recent randomized feasibility trial in mild cognitive impairment found no significant effect on any of six prespecified coprimary outcomes, although one memory measure declined more slowly with lithium. The therapeutic challenge is therefore not simply whether lithium is neuroprotective, but which patients, dose, formulation, exposure duration, and biomarker-defined disease stage are most likely to benefit. Lithium remains an investigational strategy for AD prevention or treatment, not a substitute for established clinical care.