Brain lithium drops in mild cognitive impairment; lithium orotate protected memory in mice

A Harvard Medical School team reported in Nature that endogenous lithium (Li) is dynamically regulated in the brain and contributes to cognitive preservation during ageing. Among the metals the authors analysed, Li was the only one significantly reduced in the brain of people with mild cognitive impairment (MCI), a precursor to Alzheimer's disease (AD) nature.comNaturenature.comOpen source ↗. The work used donated brain tissue from people with AD, people with early memory difficulties and people with no apparent cognitive problems.

Lithium in human brain tissue

Li bioavailability was reduced further in AD because amyloid sequesters the element. Some lithium accumulated in deposits of amyloid beta, the protein that builds up in plaques. According to the authors, plaques can therefore trap Li and leave less of it available to surrounding cells.

The study also looked at whether Li has a biological role at the small amounts already present in the body. Lithium medicines used for mood disorders are given at doses and for purposes different from those examined here.

Experiments in mice and limits

The researchers removed Li from the diet of wild-type and AD mouse models. Reducing cortical Li by approximately 50% markedly increased amyloid-β deposition and phospho-tau accumulation. It also led to pro-inflammatory microglial activation, loss of synapses, axons and myelin, and accelerated cognitive decline nature.comNaturenature.comOpen source ↗. These effects were mediated, at least in part, by activation of the kinase GSK3β. Single-nucleus RNA-seq showed that Li deficiency changes the transcriptome in multiple brain cell types, and these changes overlap with those seen in AD.

The team then tested lithium orotate, a Li salt with reduced amyloid binding. In AD mouse models and in ageing wild-type mice it prevented pathological changes and memory loss. The authors conclude that disrupted Li homeostasis may be an early event in AD pathogenesis and that replacement with amyloid-evading salts is a potential approach to prevention and treatment.

These are results from mice and from post-mortem human tissue. The tissue data alone cannot show whether a fall in available Li starts the disease process, results from plaques or is part of a cycle. Trials would have to show that a safe dose reaches the human brain and affects symptoms or daily functioning. The study does not show that lithium orotate prevents or treats AD in people, and lithium can cause harm at excessive levels. Open questions include whether Li availability can be measured reliably in living people and whether it changes early enough to be useful.