Lithium Deficiency and the Onset of Alzheimer's Disease
The non-genetic causes of Alzheimer's disease (AD) are poorly understood1-4. Here, we show that endogenous lithium (Li) is a dynamically regulated metal in the brain.  Li uptake is the most significantly impaired of all metals analyzed in aged individuals with mild cognitive impairment (MCI) and AD, but not in aging individuals with normal cognitive function.  In addition, lithium is sequestered by aggregated amyloid ß-protein (Aß) in human AD and AD mouse models, significantly reducing Li bioavailability. The loss of Li observed in human AD was recapitulated in AD mouse models by feeding a lithium-deficient diet.  Loss of only 50% of endogenous brain Li resulted in markedly elevated Aß deposition through a predominant effect on Aß42, as well as elevated tau phosphorylation in neurofibrillary tangle-like structures.  Li deficiency also resulted in synapse loss, oligodendrocyte and myelin loss, and microglia with impaired Aß degradative capacity and a proinflammatory phenotype, as well as significantly accelerated memory loss.  Diet-induced Li deficiency in aging wild-type mice also gave rise to elevated Aß42 generation, synapse loss, proinflammatory astroglial and microglial responses, and accelerated memory loss.   A major consequence of endogenous Li deficiency is activation of the tau kinase GSK3ß. At the systems level, Li deficiency induced a state of neural hyperexcitation.  To explore a new therapeutic approach to AD, we screened lithium salts and identified lithium orotate as a salt with low amyloid binding and high brain uptake. LiO prevents and reverses AD pathology and memory loss in AD mouse models and wild-type mice, and is approximately 100-fold more potent than the clinical standard Li carbonate.  LiO did not show evidence of toxicity after treatment with a therapeutic dose for most of the adult mouse lifespan. Thus, Li deficiency may be an early molecular event in the ontogeny of AD with protean multisystem effects in the brain. Overall design: We performed snRNA-seq on the hippocampus of n=4 3xTg mice with regular diet and n=5 3xTg mice after 1 month of lithium deficient diet.