Lithium Deficiency and the Onset of Alzheimer’s Disease

We explored the role of endogenous Li in the brain by depleting it from the diet of wild-type and AD mouse models. Reducing endogenous cortical Li by approximately 50% markedly increased the deposition of amyloid-β and the accumulation of phospho-tau, and led to pro-inflammatory microglial activation, the loss of synapses, axons and myelin, and accelerated cognitive decline.

These effects were mediated, at least in part, through activation of the kinase GSK3β. Single-nucleus RNA-seq showed that Li deficiency gives rise to transcriptome changes in multiple brain cell types that overlap with transcriptome changes in AD.

Replacement therapy with lithium orotate, which is a Li salt with reduced amyloid binding, prevents pathological changes and memory loss in AD mouse models and ageing wild-type mice.

These findings reveal physiological effects of endogenous Li in the brain and indicate that disruption of Li homeostasis may be an early event in the pathogenesis of AD. Li replacement with amyloid-evading salts is a potential approach to the prevention and treatment of AD.

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ALZHEIMER’s Section

The identification of treatable causes of AD requires a fundamental understanding of the pathogenic processes leading to memory loss. Although substantial progress has been made in defining gene variants that confer risk for AD, the environmental factors that affect the timing of disease onset are not as well understood. [1, 6] Several factors relating to diet, lifestyle and the environment have been identified, but their contributions to AD pathogenesis are unclear. [1, 6, 7] Altered homeostasis of metals is one such factor. [7–12] These studies have focused primarily on the toxic effects of metals such as iron, copper and zinc, which can promote amyloid-β (Aβ) aggregation, tau phosphorylation or oxidative stress in model systems. [6–12] However, metals also have essential roles in brain function, and disruption of this normal physiology in AD is relatively unexplored.

Lithium deficiency in MCI and AD

To explore the role of metal-ion homeostasis in AD, we used inductively coupled plasma mass spectrometry (ICP–MS) to assess 27 abundant and trace metals in the brain and blood of aged individuals with no cognitive impairment (NCI) and individuals with amnestic MCI or AD. Metal levels were determined in the prefrontal cortex (PFC), which is a prominently affected region in AD, and the cerebellum, which is relatively unaffected. Of all the metals surveyed, only one, Li, showed significantly reduced levels in the PFC of individuals with both MCI and AD (Figure 1a,b and Supplementary Table 1).

The mean and median Li cortex-to-serum ratio and total cortical Li were significantly reduced in the PFC of people with MCI and AD (Fig. 1c,d), but not in the cerebellum (Extended Data Fig. 1a,b). In a second independent cohort, Li levels were also significantly reduced in the PFC of people with AD (Fig. 1e). By contrast, the mean serum Li levels in MCI and AD were not significantly different from controls (Extended Data Fig. 1c). Li levels were not significantly affected by sex or the range of postmortem intervals in this study (see Methods). The cortex-to-serum ratios of several other metals also changed in AD, but not in MCI (Fig. 1a,b and Supplementary Table 1). However, the change in Li showed the lowest adjusted P value of all the metals analysed (Fig. 1b). Together, these results indicate that endogenous Li homeostasis is perturbed in the brain in MCI and AD.

We next investigated whether endogenous Li homeostasis in the brain might be perturbed by AD pathology. Previous studies have implicated the interaction of several metals with Aβ. [8, 9] To determine whether amyloid deposition affects the distribution of Li, we performed laser absorption (LA)-ICP–MS and quantified Li in amyloid plaques compared with plaque-free regions in the frontal cortex. A highly significant concentration of Li in Aβ plaques was detected in every case of MCI and AD, which increased from MCI to AD (Fig. 1f).

To complement this in situ analysis, PFC samples were subfractionated into a plaque-enriched insoluble fraction and a soluble fraction devoid of amyloid plaques (Supplementary Fig. 1). The mean and median Li levels in the PFC non-plaque fraction were significantly reduced in AD relative to control NCI cases (Fig. 1g).

Furthermore, lower Li levels in the non-plaque cortical fraction correlated with reduced cognitive test scores for episodic and semantic memory, and for a global index of cognitive function, across the entire ageing population (Supplementary Table 2). In patients with AD, lower Li levels in the non-plaque cortical fraction correlated with reduced scores for episodic memory and the index of global cognitive function (Supplementary Table 2).

To further explore the relationship of Li to Aβ, we examined the cortical distribution of endogenous Li in J20 Aβ precursor protein (App)-transgenic mice13 that exhibit widespread Aβ deposition. LA-ICP–MS showed an approximately 3–4-fold concentration of Li in cortical Aβ deposits in 12-month-old J20 mice relative to adjacent plaque-free cortical regions (Extended Data Fig. 1d). Furthermore, subfractionation of the cortex showed that Li in the non-plaque cortical fraction was significantly reduced in J20 relative to wild-type mice, consistent with Li sequestration by amyloid deposits (Extended Data Fig. 1e). By contrast, 3-month-old J20 mice before the onset of amyloid deposition did not exhibit reduced Li in the soluble cortical fraction relative to age-matched wild-type mice (Extended Data ig. 1e). Together, these results indicate that Li is sequestered by Aβ deposits, reducing its bioavailability.

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