The bioenergetic argument rests on a well-documented observation that has long puzzled researchers: the brains of people with Alzheimer’s disease are energy-starved. Fluorodeoxyglucose positron emission tomography, a scanning technique that tracks glucose consumption, consistently shows reduced metabolic activity in brain regions affected early by the disease, and this hypometabolism can appear years before memory symptoms emerge. At the cellular level, mitochondria, the organelles that generate adenosine triphosphate, or ATP, show impaired function across the electron transport chain. Enzymes of the tricarboxylic acid cycle, including the pyruvate dehydrogenase complex and the alpha-ketoglutarate dehydrogenase complex, are inhibited in Alzheimer’s tissue, and amyloid-binding alcohol dehydrogenase, an enzyme whose activity is blocked by amyloid-beta, further undermines mitochondrial metabolism. The result is a vicious cycle in which failing mitochondria produce more reactive oxygen species, which damage proteins, lipids, and DNA, which in turn further cripple the cell’s power plants.

Where does lithium enter this picture? The review’s central claim is that lithium ion, at physiological concentrations, acts as a regulator of multiple bioenergetic pathways, and that a decline in endogenous lithium with aging or disease removes this regulation. Epidemiological studies have reported inverse associations between trace lithium levels in drinking water and dementia prevalence across regions, an observation that first drew attention to lithium’s potential relevance beyond psychiatry, where lithium salts have been a mainstay treatment for bipolar disorder for more than seventy years. The authors argue that the convergence of these population-level signals with mechanistic data on lithium’s intracellular targets justifies treating lithium deficiency as a modifiable risk factor rather than a biochemical curiosity.

The best-characterized molecular target of lithium is glycogen synthase kinase-3, and specifically its beta isoform, GSK-3beta. This enzyme sits at a remarkable intersection of Alzheimer’s pathology. It phosphorylates tau protein, promoting the aggregation that forms neurofibrillary tangles; it modulates amyloid precursor protein processing in ways that can favor production of amyloid-beta; and it regulates insulin signaling and glucose metabolism, linking directly to the bioenergetic deficits described above. Lithium inhibits GSK-3 through direct competition with magnesium binding and through indirect mechanisms involving the Wnt signaling pathway, which stabilizes beta-catenin and supports neuronal survival. By damping GSK-3 activity, lithium simultaneously addresses protein aggregation, metabolic dysfunction, and synaptic resilience, a breadth of action that conventional single-target drugs have struggled to replicate.

Beyond GSK-3, the review details lithium’s effects on mitochondria themselves. Lithium has been reported to improve mitochondrial membrane potential, support the electron transport chain, and modulate the mitochondrial permeability transition pore, whose pathological opening triggers cell death. It engages the PINK1-dependent mitophagy pathway, the quality-control system that identifies and recycles damaged mitochondria, and it activates AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1-alpha, master switches that coordinate mitochondrial biogenesis and energy sensing. On the antioxidant front, lithium appears to engage the Nrf2 pathway, which drives expression of cytoprotective enzymes such as heme oxygenase-1 through the antioxidant response element, thereby blunting the oxidative damage that accompanies mitochondrial failure. These mechanisms collectively suggest that lithium does not merely protect neurons from stress but actively rebuilds the energy infrastructure of the cell.

Neuroinflammation provides a third pillar of the hypothesis. Activated microglia, the brain’s resident immune cells, release inflammatory cytokines including interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha, and they assemble the NLRP3 inflammasome, a molecular platform that amplifies inflammatory signaling. Chronic neuroinflammation is now recognized as a core feature of Alzheimer’s disease, and it both drives and is driven by metabolic failure, because inflamed glial cells consume energy and disrupt neuronal metabolism. The review summarizes evidence that lithium suppresses nuclear factor kappa B signaling and NLRP3 inflammasome activation, reducing the inflammatory cascade. At the same time, lithium increases brain-derived neurotrophic factor and its receptor TrkB, supporting synaptic plasticity and neuronal survival, and it modulates cyclin-dependent kinase 5 and ubiquitin-specific protease 11, additional enzymes implicated in tau pathology. The picture that emerges is of a single ion touching nearly every major node of the disease network.

The therapeutic challenge is that classic lithium carbonate, the formulation used in psychiatry, requires blood levels that carry a narrow therapeutic window and risks of thyroid, kidney, and gastrointestinal toxicity, particularly in older adults whose renal function, measured by estimated glomerular filtration rate, is already declining. The review therefore devotes substantial attention to next-generation lithium formulations designed to deliver lithium to the brain at microdose levels while minimizing systemic exposure. Among these, tri-lithium pyrroloquinoline quinone, or Li3PQQ, receives particular emphasis. Pyrroloquinoline quinone is a redox-active compound with its own mitochondrial and neuroprotective properties, and coupling it to lithium creates a dual-action molecule in which the carrier itself supports bioenergetics. Such formulations, the authors argue, could achieve cerebral bioenergetic restoration without the serum concentrations that make conventional lithium therapy impractical for dementia patients.

Clinical evidence to date remains preliminary but suggestive. Small trials and observational studies of microdose lithium in mild cognitive impairment, the stage preceding overt Alzheimer’s dementia, have reported slowing of cognitive decline on measures such as the Mini-Mental State Examination and the Alzheimer’s Disease Assessment Scale-Cognitive Subscale, and reductions in progression markers such as the Clinical Dementia Rating-Sum of Boxes. The review is careful to acknowledge that these studies are limited in size and duration, and that definitive conclusions require larger, randomized, biomarker-stratified trials. It also emphasizes that lithium’s effects must be monitored with therapeutic drug monitoring, thyroid-stimulating hormone measurement, and renal function testing, even at low doses, to ensure safety in the elderly population most at risk.

Perhaps the most forward-looking element of the review is its proposed precision framework for lithium-based therapy. The authors argue that intervention should begin early, ideally at the mild cognitive impairment stage or even earlier, because bioenergetic failure is among the earliest detectable changes and becomes progressively harder to reverse as neurons die. They advocate biomarker-guided patient selection, using fluorodeoxyglucose PET to identify individuals whose disease is dominated by metabolic dysfunction, and potentially measuring endogenous lithium levels in cerebrospinal fluid or blood to identify those most likely to benefit. They further propose rational combination therapies, pairing lithium with anti-amyloid antibodies, non-steroidal anti-inflammatory drugs, or other metabolic interventions, on the logic that a multi-mechanism disease demands multi-mechanism treatment. In this framework, lithium would not replace existing therapies but anchor a bioenergetic arm of a combination regimen.

The lithium deficiency hypothesis is not without open questions. The mechanisms by which the body regulates endogenous lithium, how its levels change with age, and whether deficiency is a cause or consequence of neurodegeneration remain incompletely understood, and population associations between environmental lithium and dementia risk do not by themselves establish causation. Yet the review’s synthesis arrives at a moment when the Alzheimer’s field is actively searching beyond amyloid for disease-modifying approaches, following the modest clinical benefits of recently approved anti-amyloid therapies. If the bioenergetic framing proves correct, the implications are striking: one of psychiatry’s oldest and cheapest medicines, reengineered for the brain and deployed early, could address the metabolic engine failure that precedes and perhaps drives the pathology everyone has been watching. The authors’ conclusion is measured but ambitious, proposing that by targeting cerebral bioenergetic failure, lithium-based strategies may open a new door for disease-modifying therapy against Alzheimer’s disease.

Subject of Research: The role of endogenous lithium deficiency in cerebral bioenergetic failure and therapeutic intervention in Alzheimer's disease

Article Title: Lithium deficiency in Alzheimer’s disease: from cerebral bioenergetic failure to therapeutic intervention

Article References: Li, S., Lei, Z., Cai, C., Tan, J., & Chen, J. (2026). Lithium deficiency in Alzheimer’s disease: from cerebral bioenergetic failure to therapeutic intervention. BMC Medicine. https://doi.org/10.1186/s12916-026-05245-5

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05245-5

Keywords: Alzheimer's disease, lithium, bioenergetics, mitochondria, GSK-3, neuroinflammation, disease-modifying therapy, mild cognitive impairment, Li3PQQ, metabolic dysfunction, neuroprotection, BMC Medicine