Lithium Deficiency and the Onset of Alzheimer's Disease

The earliest molecular changes in Alzheimer's disease (AD) are poorly understood. Here we show that endogenous lithium (Li) is dynamically regulated in the brain and contributes to cognitive preservation during aging. We demonstrate that cortical uptake of Li is the most significantly impaired of all metals analyzed in mild cognitive impairment (MCI) and AD, and that Li bioavailability is further reduced by amyloid sequestration. Li deficiency was recapitulated by feeding AD model and wild-type mice a lithium-deficient diet. Reducing endogenous cortical Li by ~50% markedly elevated Aß deposition and phospho-tau accumulation, and led to proinflammatory microglial activation, synapse loss, and accelerated cognitive decline. These effects were mediated, at least in part, through activation of the kinase GSK3ß in neurons, microglia, and oligodendrocytes. Single nucleus RNA-seq showed that Li deficiency gives rise to significant transcriptome changes in all major brain cell types that overlap with transcriptome changes in AD. Replacement therapy with lithium orotate (LiO), a Li salt with reduced amyloid sequestration, prevents pathological changes and memory loss in AD mouse models and aging wild-type mice at a physiological concentration. Thus, Li deficiency may be among the earliest molecular events that link amyloid deposition to protean multisystem effects on the brain. Li replacement with amyloid-evading salts is a potentially novel therapeutic approach to AD and brain aging. Overall design: To investigate the transcriptomic changes in microglia caused by lithium deciciency, microglia are isolated from WT and 3xTG mice undergoing control or lithium deficient diet. Comparitive gene expression profiling analysis was performed between control and deficient diet.