Linking To And Excerpting From Nature’s “Lithium deficiency and the onset of Alzheimer’s disease”

Posted on September 22, 2026 by Tom Wade MD

Today, I review, link to, and excerpt from Nature‘s “Lithium deficiency and the onset of Alzheimer’s disease”. [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. Nature. 2025 Aug 6;645(8081):712–721. doi: 10.1038/s41586-025-09335-x

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Abstract

The earliest molecular changes in Alzheimer’s disease (AD) are poorly understood1,2,3,4,5. Here we show that endogenous lithium (Li) is dynamically regulated in the brain and contributes to cognitive preservation during ageing. Of the metals we analysed, Li was the only one that was significantly reduced in the brain in individuals with mild cognitive impairment (MCI), a precursor to AD. Li bioavailability was further reduced in AD by amyloid sequestration. 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.

Subject terms: Alzheimer’s disease, Molecular neuroscience

Lithium has an essential role in the brain and is deficient early in Alzheimer’s disease, which can be recapitulated in mice and treated with a novel lithium salt that restores the physiological level.

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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,. Several factors relating to diet, lifestyle and the environment have been identified, but their contributions to AD pathogenesis are unclear,,. Altered homeostasis of metals is one such factor–. 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–. 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 (Fig. 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.

Fig. 1. Lithium deficiency and the onset of AD.

Fig. 1

a,b, Volcano plots showing changes in metal cortex-to-serum ratios in the PFC of MCI versus NCI (a) and AD versus NCI (b) cases, along with their statistical significance, determined by one-way analysis of variance (ANOVA) with Tukey’s post-hoc test, followed by the Benjamini–Hochberg correction for the number of metals assessed. c,d, Li cortex-to-serum ratios (c) and total cortical Li levels (d) in cases from ROSMAP. Each point represents an individual case. e, Total cortical Li in cases from a replication cohort. f, Li is concentrated in Aβ plaques in MCI and AD. Aβ immunolabelling in the PFC of an AD case (left). LA-ICP–MS was done on an adjacent unfixed section to quantify Li in Aβ plaques (white circles) and neighbouring non-plaque regions (yellow circles). Scale bar, 50 μm. The ratios of Li level in plaque (P) to non-plaque (NP) regions are shown (right) in MCI and AD cases. g, Cortical brain samples were subfractionated into plaque-enriched and non-plaque fractions. Li levels in non-plaque fractions were measured by ICP–MS and normalized to the mean of NCI. P values were calculated by one-way (a–d) or two-way (f) ANOVA with Tukey’s post-hoc and Benjamini–Hochberg corrections (a–c) or Tukey’s post-hoc corrections (d,f), or by two-tailed unpaired t-test (e,g). c–g, Box plots show individual values, median (line), box limits (25th and 75th percentiles) and whiskers (minimum and maximum). a–c, NCI n = 133, MCI n = 58, AD n = 94. d, NCI n = 177, MCI n = 66, AD n = 105. e, NCI n = 22, AD n = 21. f, MCI n = 7, AD n = 5. g, NCI n = 74, AD n = 42.

Source Data

Extended Data Fig. 1. Analysis of brain and serum lithium levels.

Extended Data Fig. 1

a-c Li cortex-to-serum ratio in the cerebellum (a), total Li levels in the cerebellum (b), and serum Li levels (c) are not significantly different in NCI, MCI, and AD. a, n = 125 NCI, n = 55 MCI and n = 101 AD cases. b, n = 129 NCI, n = 58 MCI and n = 102 AD cases. c, n = 141 NCI, n = 62 MCI and n = 101 AD cases. d, Lithium is concentrated in Aβ plaques in AD mice. Aβ immunolabeling in the cortex of 12-month-old J20 mice. Laser ablation ICP-MS was performed on an adjacent unfixed section to quantify Li in Aβ plaques (P; white circles) and in neighboring non-plaque regions (NP; yellow circles). The ratios of Li levels in P to NP regions are shown (right) for n = 4 mice. e, Aβ immunolabeling of the cortex in J20 mice at 3 months of age, prior to onset of Aβ deposition, and 12 months of age, following widespread Aβ deposition. Cortical samples were subfractionated from 3-month-old (WT n = 6; J20 n = 7) and 12-month-old (WT n = 9, J20 n = 7) mice and Li in non-plaque fractions was measured by ICP-MS (middle and right panels). The data was normalized to the mean of WT. Box plots show individual values, median (line), box limits (25th-75th percentiles), and whiskers (min-max). P-values by one-way ANOVA with Tukey’s post-hoc test (a-c) or two-tailed unpaired t-tests (d,e). Scale bars, 50 μm.

Source Data

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,. 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 mice 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 Fig. 1e). Together, these results indicate that Li is sequestered by Aβ deposits, reducing its bioavailability.

Lithium deficiency in mouse models

To explore the biology of endogenous Li, mice were maintained on a chemically defined diet that is calorically and nutritionally equivalent to the typical grain-based mouse diet, including the same Li concentration. Serum and cortical Li levels in mice on this diet were in a similar range to those in the ageing human population, and the mean values were not significantly different (see Methods section on Mouse diet). Selective removal of Li from the mouse diet (a 92% reduction) led to an 89% reduction in mean serum Li and a 47–52% reduction in mean cortical Li in the non-plaque fraction (Extended Data Fig. 2a–c and Supplementary Fig. 2).

Extended Data Fig. 2. Lithium deficiency does not impair exploratory behavior or motor function in mice.

Extended Data Fig. 2

a–c, Li levels measured by ICP-MS in serum (a) and cortex (b) of 15-month-old 3xTg mice, and in cortex of 20-month-old WT mice (c) fed CTRL or DEF diets (n = 5 per group). d, Amyloid plaque burden in the hippocampus of 12-month-old 3xTg mice after 5 weeks of CTRL or DEF diet (n = 7 per group). e, Aβx-40 and Aβx-42 levels in the hippocampus of 26-month-old WT mice (treated from 12–26 months of age; CTRL n = 7; DEF n = 6), normalized to total protein. f, Immunofluorescence for pSer202-tau (CP13) in CA1 of 12-month-old 3xTg mice after 5 weeks of CTRL or DEF diet (n = 7 per group). g, pSer202-tau pathology in 15-month-old 3xTg mice fed either standard PicoLab® Rodent Diet 20 (CTRL 5053, n = 7) or a chemically-defined control diet (CTRL AIN-93M, n = 10), compared to those on Li-deficient chemically-defined AIN-93M diet (n = 9) for 9 months. h–l, Behavioral testing of 3xTg mice fed CTRL or DEF diets from 6–13.5 months of age: Open field activity (h–j), Morris water maze swim speed (k), and latency to reach a visible platform elevated above water level (l). m–q, Behavioral testing of 20-month-old WT mice fed CTRL or DEF diets from 12–20 months of age: Open field activity (m–o), swim speed (p), and latency to reach a visible platform (q). a–g, Data normalized to CTRL group means. l,q, Data are the mean ± s.e.m. a-k,m-p, Box plots show individual values, median (line), box limits (25th-75th percentiles), and whiskers (min-max). P-values by unpaired two-tailed t-test, except g (one-way ANOVA with Tukey’s post-hoc test). h-l, n = 16 CTRL. h, j-l, n = 21 DEF. i, n = 20 DEF. m-o, n = 33 CTRL, n = 43 DEF. p,q, n = 25 CTRL, n = 34 DEF.

Source Data

 

 

 

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