A study published in Plos Medicine has shown that lithium decreases the risk of developing dementia and some of its subtypes, including Alzheimer’s disease and vascular dementia .
Enigmatic but effective
According to WHO, Alzheimer’s disease and other dementias were the second-leading cause of death in high-income countries and the seventh globally in 2019. To date, there are no preventive or disease-modifying treatments available for dementia.
In recent years, lithium has emerged as a potential therapeutic for several neurodegenerative diseases, including dementia , although randomized, controlled studies assessing its effectiveness have yet to arrive.
Lithium has long been known for its mood-stabilizing properties: it is the first-line treatment for bipolar disorder (mania) and major depression . The neuroprotective effect of lithium is not completely understood but seems to involve several mechanisms of action, such as the induction of autophagy and the reduction of oxidative stress .
On the molecular level, lithium (Li+) competes with magnesium (Mg2+) and can thus interfere with several pathways that rely on the activity of magnesium-dependent enzymes. Specifically, lithium inhibits glycogen synthase kinase-3 beta (GSK-3β) and inositol monophosphatase (IMP), modulating autophagy.
Does lithium fight dementia?
In this retrospective study, the researchers analyzed the clinical data of 29,618 patients collected over a 15-year period in the UK. The patients were ≥ 50 years of age (mean = 73.9 years) and were treated for mental health conditions. 548 of these patients were exposed to lithium as concluded from either a prescription or a documented blood level. 53 (9.7%) and 3,244 (11.2%) patients developed dementia in the lithium-exposed and unexposed groups, respectively.
The patients in the lithium group were subdivided into several categories based on the exposure duration: short-term (≤1 year), long-term (>5 years), and medium-term (1-year-long periods in between 1 and 5 years of exposure). All the patients were followed up until either the first record of dementia, the final record, or death.
The researchers controlled for several confounding variables: age, sex, marital status, ethnicity, smoking status, medications, and physical and mental comobidities. Among the latter, the presence of bipolar disorder was of particular importance, because it is a known risk factor for dementia and the most common reason for a lithium prescription. Indeed, 73% of the patients in the lithium group had this condition.
The study shows that the patients in the lithium group were more likely to have a partner, be a smoker, use antipsychotics, and have depression, bipolar disorder, diabetes, high blood pressure, central vascular disease, or a high cholesterol level. All these factors, except marital status, are associated with a higher risk of developing dementia.
Meanwhile, the most important finding of the study is a significantly lower risk of dementia in people exposed to lithium. Although several dementia subtypes were included in this study, the researchers also analyzed Alzheimer’s disease and vascular dementia incidents separately and confirmed that the risk of these two was also lower in the lithium group.
Next, the researchers show that both short-term and long-term lithium exposure is associated with lower risk of dementia. Medium-term exposures, on the other hand, were not that beneficial. However, this could be attributed to a smaller number of patients in these subgroups and/or a shorter follow-up period. Longer lithium exposure seems best at decreasing the risk of developing all dementias and Alzheimer’s disease but not vascular dementia.
Enlightening but limited
This study had quite a few limitations. First, there were many confounding variables that are difficult to control for. Second, the sample size of people using lithium was rather small. Third, the reason for, and level of, lithium exposure were not always documented. Fourth, both mental and physical comorbidities might have been underestimated. Finally, there was no proof of causation.
Nevertheless, the researchers acknowledge and address some of these limitations by including sensitivity tests to confirm the results obtained from the initial analysis. For example, they analyzed the data with the assumption that all the lithium-exposed patients were suffering from bipolar disorder or excluding all the patients diagnosed with depression.
Dementia is the leading cause of death in elderly Western populations. Preventative interventions that could delay dementia onset even modestly would provide a major public health impact. There are no disease-modifying treatments currently available. Lithium has been proposed as a potential treatment. We assessed the association between lithium use and the incidence of dementia and its subtypes.
This study, like many others, raises more questions than answers. Does the anti-dementia effect of lithium apply to the general population as opposed to people with mental health conditions analyzed in this study? Is there an optimal level of lithium and an ideal exposure duration for protecting against dementia? Can lithium decrease the risk of developing other dementias, such as Parkinson’s disease?
Overall, the results of this study are in line with previous research demonstrating the neuroprotective role of lithium, including in animal models of dementia and studies of clinical data conducted in other countries. This warrants the need to further investigate if lithium could be used as a disease-modifying treatment for dementia in randomized, controlled clinical trials.
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 Chen, S., Underwood, B. R., Jones, P. B., Lewis, J. R. & Cardinal, R. N. Association between lithium use and the incidence of dementia and its subtypes: A retrospective cohort study. PLoS Med. 19, e1003941 (2022).
 Forlenza, O. V., De-Paula, V. J. R. & Diniz, B. S. O. Neuroprotective effects of lithium: implications for the treatment of Alzheimer’s disease and related neurodegenerative disorders. ACS Chem. Neurosci. 5, 443–450 (2014).