Introduction: Dementia is a neurodegenerative disease with insidious onset and progressive progression, of which the most common type is Alzheimer's disease (AD). Lithium, a trace element in the body, has neuroprotective properties. However, whether lithium can treat dementia or AD remains a highly controversial topic. Therefore, we conducted a meta-analysis. Methods: A systematic literature review was conducted on PubMed, Embase, and Web of Science. Comparison of the effects of lithium on AD or dementia in terms of use, duration, and dosage, and meta-analysis to test whether lithium therapy is beneficial in ameliorating the onset of dementia or AD. Sensitivity analyses were performed using a stepwise exclusion method. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of included studies. We determined the relative risk (RR) between patient groups using a random-effects model. Results: A total of seven studies were included. The forest plot results showed that taking lithium therapy reduced the risk of AD (RR 0.59, 95% confidence interval [CI]: 0.44–0.78) and is also protective in reducing the risk of dementia (RR 0.66, 95% CI: 0.56–0.77). The duration of lithium therapy was able to affect dementia incidence (RR 0.70, 95% CI: 0.55–0.88); however, it is unclear how this effect might manifest in AD. It is also uncertain how many prescriptions for lithium treatment lower the chance of dementia development. Conclusion: The duration of treatment and the usage of lithium therapy seem to lower the risk of AD and postpone the onset of dementia.

A cognitive impairment or syndrome of cognitive decline that impairs one's ability to live independently is known as dementia. It can result in a progressive loss of the capacity to engage with their environment and manage day-to-day tasks, as well as significant impairments in reasoning and conduct. Dementia develops slowly, with memory loss first impacting cognitive domains like language, visuospatial, and executive functions. Dementia is becoming increasingly common as the population ages, and by 2040, there will be over 80 million cases of dementia worldwide, according to estimates [1]. Alzheimer’s disease (AD) is the most prevalent type of dementia, which is characterized by an insidious and progressive irreversible decline in cognitive functioning [2]. In China, there are presently around 15 million people over 60 who have dementia, including about 10 million people with AD, according to data issued by the Department of Aging of the National Health and Health Commission in 2022. Elderly people’s health is greatly threatened by dementia. However, because there is currently no cure for dementia, treatment with potent drugs for dementia may result in severe neurological abnormalities [3], the focus is shifting to “preclinical” risk analyses and the use of “dementia prevention” strategies [4].

Several mood stabilizers, such as lithium, valproate, and lamotrigine, are being tested for dementia or AD. However, lamotrigine, an antiepileptic medication, is primarily used to prevent epilepsy-induced memory loss [5], lessen anxiety and irritability [6], and prevent AD patients from having seizures that accelerate the disease [5]; valproate, on the other hand, can be used as an adjuvant to treat behavioral and psychological symptoms in both AD patients [7] and dementia patients [8], though its effectiveness is not statistically significant [9]. Furthermore, a firm agreement has not yet been established about the use of lamotrigine or valproate to treat AD and dementia in contemporary clinical practice, and there are also comparatively few studies on the subject. Unlike the other two, though, lithium has drawn some interest and demonstrated some promise in the management of dementia or AD.

Lithium, a trace element found in the body, is neuroprotective [10, 11], may help treat bipolar disorder patients [12], and may have anti-AD properties by lowering amyloid-β and hyperphosphorylated tau proteins [13]. Moreover, lithium is seen to be a potential therapeutic option for the treatment of AD and its prodromal stages [14], as it enhances cognitive function in people with AD [15]. In addition, lithium is thought to slow the progression from mild cognitive impairment to dementia in patients [12]. Studies [16, 17] have even discovered variations in the impact of drinking water containing lithium on the prevalence of AD according to a person’s gender. Nonetheless, certain research [18, 19] has also determined that lithium poses a risk for dementia. Lithium therapy is therefore still a topic of debate when it comes to treating dementia or AD. Dementia still has no known treatment, although persons with dementia and their families can have a higher quality of life if preventive measures are taken to postpone the disease’s onset slightly. Thus, to offer a foundation for postponing the onset of dementia and reducing the incidence of AD, this study examined the association between lithium therapy and the incidence of dementia and AD.

The Preferred Reporting Items for Meta-Analyses (PRISMA) were followed in the conduct of this meta-analysis.

Search Strategy

Two researchers searched PubMed, Web of Science, and Embase databases for all relevant papers that were published from the build date to October 2023, focusing only on English-language publications, regarding the correlation between lithium therapy and dementia. Search terms included (“lithium”) AND (“Alzheimer’s Disease” OR “senile dementia” OR “dementia” OR “Alzheimer” OR “cognitive decline” OR “cognitive impairment”). Following a preliminary screening of all the literature to exclude blatantly irrelevant articles, two researchers independently examined the whole text, abstract, and title in order to perform additional screening and confirm the inclusion of the literature. When there was disagreement between the two researchers, problems were resolved by discussion or by consulting a third researcher.

Selection Criteria

If a study satisfies these requirements, it will be included. (1) The research was observational (case-control or cohort). (2) The 95% confidence intervals (CIs) and the relative risk (RR), hazard ratio (HR), or odds ratio (OR) of dementia linked to lithium therapy were provided. (3) Lithium usage is the reported exposure of interest. (4) Dementia or AD is the result of a clinical diagnosis. (5) The article is available in English in its entirety. Gray literature and studies with full text unavailable were removed. We also excluded studies including case reports, guidelines, basic research, and other types of literature. Additionally, we eliminated studies that were repeated, had different therapies, or had interference from other illnesses. Two researchers chose the studies on their own, based on the inclusion criteria.

Data Extraction

For each of the included studies, data extraction was carried out separately by two researchers, and the results were then cross-checked for accuracy. In the event of a disagreement, it can be settled by communication or by consulting a third researcher. First author, publication year, nation, study design type, population and number of individuals exposed, outcome type reported, RR/HR/OR value, 95% CI, note, and presence or absence of bi-directional affective disorder were among the data collected.

Quality Assessment

For every study that was included, the quality of the literature was evaluated separately by two researchers. The Newcastle-Ottawa (NOS) scale [20] was used to assess the methodological quality of the relevant literature because the included studies were either cohort or case-control studies, which are non-randomized. Eight items total, divided into three dimensions: four for research participant selection, one for between-group comparability, and three for outcome measures. The total score is between 0 and 9. Greater overall ratings correspond to better-quality research.

Statistical Analyses

All the included literature was statistically analyzed, and the forest was plotted using Stata16 software. We uniformly used the RR value for subsequent analyses since the included literature consisted of either cohort or nested case-control studies, and because the OR is almost equivalent to the RR when the disease prevalence in the community is minimal. Since α = 0.05 in the results, p < 0.05 was regarded as statistically significant. The heterogeneity between studies was evaluated using the I2 statistic. When I2 > 50% or p ≤ 0.1, there is significant variability. If there was heterogeneity in the data, we used a random-effects model with subgroup analysis depending on research type and sample size to investigate possible sources of heterogeneity. Otherwise, we employ a fixed-effects model. One item at a time removal during sensitivity analyses can be used to evaluate the stability of results in disputed investigations. A funnel plot and Egger’s test were used to test for publication bias.

Literature Search Results

In this study, an initial database search yielded 3,677 publications, and after removing 871 duplicates, 2,768 non-original observational studies or studies unrelated to lithium and dementia were excluded through preliminary screening based on titles or abstracts. After reviewing the remaining 38 articles in their entirety, it was discovered that 15 of the studies were case reports or other studies, 11 of the studies lacked data that could be used for further computations, 3 of the studies were randomized controlled trials, and 2 of the studies were eliminated because they contained duplicate samples. In the end, seven papers were included [18, 19, 21‒25], two of which were nested case-control studies [18, 19] and five of which were cohort studies [21‒25]. The relevant screening procedure and outcomes are shown in Figure 1.

Fig. 1.

Flowchart of study selection.

Fig. 1.

Flowchart of study selection.

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Study Characteristics

The primary descriptive features of the seven qualified studies [18, 19, 21‒25] are enumerated in Table 1. The study populations ranged from 114 to 1,503,415 individuals. Seven studies ended up comparing the incidence of dementia or AD. In addition, lithium exposure was explicitly measured and assessed in the studies. Table 1 displays the relevant literature as a whole.

Table 1.

Characteristics of included studies in meta-analysis examining the association between lithium and dementia risk

Author, yearCountryStudy designPopulationSample sizeDementia casesAgeFemale, %Lithium exposure assessmentAscertainment of dementiaAdjustment for covariates
Dunn et al. [18] 2001 UK Nested case-control study Primary care patients in general practices 19,328 9,954 >60 67.2 Prescription records for any preparation of lithium NA Age 
Cheng et al. [19] 2017 China Nested case-control study Older general population 190,041 63,347 ≥65 53.8 Lithium was defined as the prescription of any lithium in anatomic ICD-9 Health care utilization, use of other common mood stabilizers, hypothyroidism, type of diabetes, hypertension, hyperlipidemia, chronic kidney disease, epilepsy, schizophrenia, and bipolar disorder 
Therapeutic chemical classification system 
Angst et al. [21] 2007 Switzerland Cohort study Patients with mood disorder 406 88 ≥65 71.1 Charts of inpatient and outpatient services and from family doctors’ reports in a special study ICD-9 NA 
Nunes et al. [22] 2007 Brazil Cohort study Elderly euthymic patients with bipolar disorder 114 19 ≥60 66.7 NA DSM-IV Age 
Kessing et al. [23] 2008 Denmark Cohort study General population 1,503,415 62,966 >40 NA The medicinal product statistics register ICD-10 Age, sex, calendar period, and purchase of antidepressants or anticonvulsants 
Gerhard et al. [24] 2015 USA Cohort study Individuals with bipolar disorder 41,251 1,538 ≥50 71.4 Lithium was defined medication supply over the 365 days ICD-9 Gender, ethnicity, age, medicaid eligibility, long-term care residency, depression, anxiety, alcohol-related disorders, drug-related disorders, arrhythmia, heart failure, myocardial infarction, other acute ischemic heart disease, other chronic ischemic heart disease, hypertension, cerebrovascular disease, diabetes mellitus, Parkinson’s disease, antidepressant use, antipsychotic use, use of antianxiety medications 
Chen et al. [25] 2022 UK Cohort study General health population 29,618 6,271 ≥50 59.8 Natural language processing tools detect medication mentions or lithium test results ICD-10 Age, sex, marital status, ethnicity, smoking status, alcohol disorders, antipsychotic use, depression, mania or bipolar disorder, hypertension, central vascular disease, diabetes mellitus, and hyperlipidemias 
Author, yearCountryStudy designPopulationSample sizeDementia casesAgeFemale, %Lithium exposure assessmentAscertainment of dementiaAdjustment for covariates
Dunn et al. [18] 2001 UK Nested case-control study Primary care patients in general practices 19,328 9,954 >60 67.2 Prescription records for any preparation of lithium NA Age 
Cheng et al. [19] 2017 China Nested case-control study Older general population 190,041 63,347 ≥65 53.8 Lithium was defined as the prescription of any lithium in anatomic ICD-9 Health care utilization, use of other common mood stabilizers, hypothyroidism, type of diabetes, hypertension, hyperlipidemia, chronic kidney disease, epilepsy, schizophrenia, and bipolar disorder 
Therapeutic chemical classification system 
Angst et al. [21] 2007 Switzerland Cohort study Patients with mood disorder 406 88 ≥65 71.1 Charts of inpatient and outpatient services and from family doctors’ reports in a special study ICD-9 NA 
Nunes et al. [22] 2007 Brazil Cohort study Elderly euthymic patients with bipolar disorder 114 19 ≥60 66.7 NA DSM-IV Age 
Kessing et al. [23] 2008 Denmark Cohort study General population 1,503,415 62,966 >40 NA The medicinal product statistics register ICD-10 Age, sex, calendar period, and purchase of antidepressants or anticonvulsants 
Gerhard et al. [24] 2015 USA Cohort study Individuals with bipolar disorder 41,251 1,538 ≥50 71.4 Lithium was defined medication supply over the 365 days ICD-9 Gender, ethnicity, age, medicaid eligibility, long-term care residency, depression, anxiety, alcohol-related disorders, drug-related disorders, arrhythmia, heart failure, myocardial infarction, other acute ischemic heart disease, other chronic ischemic heart disease, hypertension, cerebrovascular disease, diabetes mellitus, Parkinson’s disease, antidepressant use, antipsychotic use, use of antianxiety medications 
Chen et al. [25] 2022 UK Cohort study General health population 29,618 6,271 ≥50 59.8 Natural language processing tools detect medication mentions or lithium test results ICD-10 Age, sex, marital status, ethnicity, smoking status, alcohol disorders, antipsychotic use, depression, mania or bipolar disorder, hypertension, central vascular disease, diabetes mellitus, and hyperlipidemias 

NA, not available; DSM, diagnostic and statistical manual of mental disorders criteria; ICD, international statistical classification of diseases.

Evaluation of Included Studies’ Quality

The seven papers that made up the literature were assessed using the Newcastle-Ottawa Rating Scale in this study, and each of them received a score between 6 and 7.

Results of the Meta-Analysis and Sensitivity Analysis for AD

The investigation comprised four papers [19, 22, 23, 25] in all, of which two [19, 25] mentioned cumulative duration and the other four [19, 22, 23, 25] mentioned usage. The findings are shown in Figure 2. One study [19] required separate analysis since it was a case-control study involving two populations: the general population and people with bi-directional affective disorder. The picture illustrates the variability of usage (I2 = 90.1%) and the cumulative duration heterogeneity (I2 = 82.0%). Sensitivity studies were performed to look for sources of heterogeneity because there was a high level of heterogeneity in both domains.

Fig. 2.

Results of the forest plot illustrate the connection between lithium medication and AD.

Fig. 2.

Results of the forest plot illustrate the connection between lithium medication and AD.

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Sensitivity analysis used case-by-case determined that one article [19] could be a source of potential heterogeneity. The meta-analysis results following exclusion are shown in Figure 3. The picture illustrates the variability of usage (I2 = 79.1%, RR 0.59, 95% CI: 0.44–0.78) and the cumulative duration heterogeneity (I2 = 0%, RR 0.30, 95% CI: 0.12–0.73). Significantly less heterogeneity existed in both dimensions.

Fig. 3.

Results of the forest plot for the association, after exclusion, between lithium therapy and AD.

Fig. 3.

Results of the forest plot for the association, after exclusion, between lithium therapy and AD.

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Results of the Meta-Analysis and Sensitivity Analysis for Dementia

A total of five papers [18, 21, 23‒25] were included in the study in which usage was mentioned in four studies [18, 21, 23, 25], cumulative duration was covered in three studies [18, 24, 25] and the number of prescriptions was mentioned in two studies [18, 23]. The findings are shown in Figure 4. As the diagram illustrates, there is variability in the following areas: I2 = 82.7% for usage; I2 = 76.7% for the cumulative duration; and I2 = 62.7% for the number of prescriptions. Sensitivity analyses of one of the studies – a case-control study [18] – should be done with caution because it was based on the general population. Sensitivity studies were performed to look for sources of heterogeneity because there was a high level of heterogeneity in all three categories.

Fig. 4.

Findings from a forest plot illustrate the connection between lithium therapy and dementia.

Fig. 4.

Findings from a forest plot illustrate the connection between lithium therapy and dementia.

Close modal

After sensitivity analysis was applied on an individual basis, one article [18] was discovered to be a potential source of heterogeneity. The meta-analysis results following exclusion are shown in Figure 5. There was heterogeneity in usage (I2 = 0%, RR 0.66, 95% CI: 0.56–0.77); in the cumulative duration (I2 = 77.6%, RR 0.70, 95% CI: 0.55–0.88); and the number of prescriptions (I2 = 0%, RR 1.25, 95% CI: 0.93–1.69). There was a marked decrease in two of the three measures of heterogeneity.

Fig. 5.

Results of the forest plot for the association, after exclusion, between dementia and lithium therapy.

Fig. 5.

Results of the forest plot for the association, after exclusion, between dementia and lithium therapy.

Close modal

Publication Bias

Funnel plots illustrating the relationship between AD, dementia, and lithium are shown in Figures 6 and 7. The chart illustrates that while there was no discernible publication bias in the case of lithium and AD, there was incomplete symmetry in the case of lithium and dementia. We ran a second Egger test because of the limited number of included papers and the subjective variations in the funnel plots. The findings demonstrated that there was no discernible publication bias because the Egger for lithium and AD (p = 0.123) and lithium with dementia (p = 0.535) were both greater than 0.1.

Fig. 6.

Funnel diagram of AD usage.

Fig. 6.

Funnel diagram of AD usage.

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Fig. 7.

Funnel plot of dementia usage.

Fig. 7.

Funnel plot of dementia usage.

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To find out if lithium therapy reduced the incidence of AD and dementia, we conducted a meta-analysis of seven research, classifying all the studies based on different notes.

Meta-Analysis Results of Usage

Results for the subgroup of consumption indicated that using lithium as a treatment measure could somewhat lower the risk of developing AD. Those on lithium therapy had a significantly lower incidence of AD than those who were not on lithium therapy. This is consistent with the numerous studies [13‒15] that have demonstrated lithium’s ability to prevent AD. Lithium treatment has been directly shown to prevent dementia in one trial [13] including mild cognitive impairment and AD. One potential treatment for AD and its prodromal stages is lithium [14]. Moreover, lithium treatment has a pro-cognitive effect [15], may have therapeutic implications for the prevention of AD [26], and might help decrease the rate of cognitive deterioration in AD patients. By analyzing the findings of earlier research, some investigations have also discovered that lithium can reduce the pathogenic process of AD by regulating disrupted calcium homeostasis [27]. Lithium therapy for AD has the potential to alter the course of the disease, lower the risk of acquiring AD, and delay the advancement of early AD and moderate cognitive impairment [28]. Furthermore, based on a meta-analysis of randomized controlled trials, the trend of cognitive impairment was greatly slowed by lithium treatment. Lithium therapy may also be more likely to improve cognitive function in AD patients since it had a stronger impact on cognitive function in the AD subgroup than in the other subgroups [29]. Additionally, it has been proposed that lithium, an inhibitor [30], lessens the aberrant Aβ amyloid formation observed in transgenic animal models [31]. Furthermore, a variety of lithium formulations may be used to treat neurodegenerative brain disorders [32]. These results imply that lithium might be a useful medication for AD [33].

The use of lithium therapy has a protective effect on reducing the risk of developing dementia, which is consistent with the conclusions of some studies [34‒36], which concluded that the prevalence of dementia is reduced in patients who take lithium every day for a while compared to those who do not undergo lithium therapy and that regular lithium therapy may help patients to resist the onslaught of dementia. However, the results do not support the use of lithium to prevent dementia as they are inconsistent with some studies [18, 21, 37] that concluded that patients treated with lithium had a higher risk of being diagnosed with dementia compared to patients who did not receive lithium therapy [18], and could not prove that lithium therapy reduces the risk of dementia [37] or that lithium has a preventive effect on the development of dementia [21]. The possible reason for the discrepancy is the influence of other confounding factors in the study.

Meta-Analysis Results for Cumulative Duration

The results indicated that it is uncertain if the period of lithium therapy lowers the chance of developing AD in the cumulative duration subgroup. This is because there was only one study [25] on the duration of lithium medication use in AD patients at this time, and there was no supporting data from a homogenous study, making the analysis impossible to complete. This study did show that exposure to lithium for both short-term (<1 year) and long-term (>5 years) reduced the risk of AD. Within roughly a year of adhering to lithium exposure therapy, the majority of studies [24, 38] have also discovered that lithium can act as a neuroprotective agent and enhance cognition in people with early-stage AD [26, 39]. Lithium’s ability to slow the onset of AD has also been investigated in experiments [40]. However, no research has found a link between a shorter risk of dementia and the length of intermediate lithium medication (1–5 years). Possibly because people receiving lithium medication need to be able to tolerate the drug, be effective when taking it, and need to utilize it for an extended amount of time. Furthermore, it is more challenging to do long-term follow-ups with this group of lithium medication patients throughout one to 5 years. Thus, there are not many patients [25]. Additionally, it has been proposed that the longer a person uses lithium, the higher their chance of getting AD [19]. High-dose lithium use over an extended period may cause thyroid and kidney problems [41]. Thus, more research is required to determine whether the duration of lithium treatment can lower the chance of acquiring AD.

The duration of lithium therapy significantly decreased the probability of dementia development. This indicates that long-term lithium use is linked to a decreased risk of dementia. This proves that a lower incidence of dementia is linked to sustained lithium use. This conclusion is in line with the majority of study findings [10, 24, 25, 40]. Longer lithium exposure was associated with a linear decrease in the risk of dementia or AD. Furthermore, lithium may have a cumulative effect over time that improves its ability to lower the risk of dementia [38]. It does not, however, agree with some study’s findings [18, 19]. According to certain research, the duration of treatment and the average age of a patient may have an impact on how successful lithium is for dementia [42]. Lithium treatment does not seem to have an impact on the onset of prevalent forms of dementia, according to one study [18]. Confounding variables such as a limited sample size, patient adherence to lithium therapy, and whether or not bi-directional affective illness was taken into account could all have an impact on this.

Meta-Analysis Results for the Number of Prescriptions

The findings indicated that there was no discernible difference in the number of prescriptions for lithium treatment in terms of lowering the risk of dementia. The fact that this subgroup consisted of just one study [23] could be the reason for this conclusion. The cohort study did, however, come to the conclusion that the incidence of dementia did not decrease with the number of lithium prescriptions, even though it did start to reduce early after taking the pills prescribed for one prescription. Unfortunately, only one study set of data was available for this subgroup in this investigation due to the lack of support from later, pertinent studies, which precluded further analysis. Thus, it is anticipated that this field will be further explored in future studies.

This study has some limitations. Initially, two case-control studies – which are vulnerable to recall bias – were incorporated. It is possible that patients will not remember precisely how many prescriptions they were given or how long their lithium treatment lasted. Second, even after subgroup analysis, there was still considerable heterogeneity in this study. Third, fewer studies were included. Fourth, it has not been investigated how other variables may affect the association between exposure to lithium therapy and the risk of dementia. Further well-planned research is required to validate these findings and offer greater proof that lithium therapy lowers the incidence of dementia.

A statement of ethics is not applicable because this study is based exclusively on published literature.

The authors have no conflict of interest to report.

This work was supported by the Shandong Undergraduate Teaching Reform Research Program (Z2021225).

Qiuying Lu was responsible for the research concept, design, data extraction, collaborative analysis, and writing the full paper; participated in drafting and final version of the paper; and coordinated the whole research. Huijing Lv was responsible for data extraction, analysis, and writing the full paper. Xiaotong Liu, Lili Zang, and Yue Zhang collaborated in drafting and completing the final version of the paper.

The data supporting the findings of this study are available within the article. Further inquiries can be directed to the corresponding author.

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