**4. Clinical studies of lithium in MCI and AD**

**Authors, year, ref. no. Design of study Results**

on lithium, selected from a General Practice

receiving lithium and 48 matched patients

subjects with unipolar depression followed

in the past and 1,487,177 not using lithium

and 2006, and 2009 and 2015 and lithium in

Compared with nonuse, 301–365 days of lithium exposure was associated with significantly reduced dementia risk No corresponding association was observed for shorter lithium exposures or any exposure to anticonvulsants that may suggest that long-term lithium treatment

Recently, two papers appeared studying a relationship between lithium in drinking water and dementia. Kessing et al. [34] performed a Danish nationwide, case–control research, studying an association between the municipality of residence and measurements of lithium in drinking water. The data were obtained from all patients between 50 and 90 years of age who had a diagnosis of dementia during hospitalization, from 1970 to 2013. A total of 73, 731 patients with dementia and 733, 653 controls were included in the study. Lithium exposure was statistically significantly different between patients with a diagnosis of dementia and controls, and a nonlinear association was observed. Compared with individuals exposed to 2.0–5.0 μg/L, the incidence rate ratio of dementia was decreased in those exposed to more than 15.0 μg/L and 10.1–15.0 μg/L and increased with 5.1–10.0 μg/L. Similar patterns were found for Alzheimer's disease and vascular dementia as outcomes. In the second study, Fajardo et al. [35] examined the relationship between trace levels of lithium in drinking water and changes in AD mortality

Lithium treatment associated with

Current or previous lithium treatment associated with better performance on

Reduced AD prevalence associated

Reduced dementia severity among patients receiving lithium

Reduced risk for dementia associated with the continued use of lithium

Reduced risk for dementia associated with the continued use of lithium

Reduced risk of dementia with the long-term (10–12 months) use of

Decreased incidence of dementia in subjects exposed to >10 μg/L of lithium

Increase in AD mortality negatively associated with lithium concentration

increased dementia risk

with lithium treatment

MMSE

lithium

in drinking water

in drinking water

Dunn et al.[27] 9954 lithium-treated patients and 9374 not

Terao et al. [28] 1423 psychiatric outpatients from a university

Database

Nunes et al. [29] 66 elderly patients with bipolar disorder

without lithium

Angst et al. [30] 220 subjects with bipolar disorder and 186

for 20 years

Kessing et al. [31] 16,238 persons who had purchased lithium

Kessing et al. [32] 4856 patients with bipolar disorder, followed for 10 years

Gerhard et al. [33] 41,931 patients >50 years with bipolar disorder, followed for 3 years

Kessing et al. [34] 73,731 patients with dementia, 733,653 control subjects

Fajardo et al. [35] Changes in AD mortality between 2000

**Table 1.** Epidemiological studies of lithium and dementia.

drinking water

may reduce dementia risk in older adults with bipolar disorder.

clinic

84 Alzheimer's Disease - The 21st Century Challenge

In 2008, Macdonald et al. [36] first attempted to assess the safety and feasibility of prescribing long-term lithium (up to 1 year) to 22 elderly people with mild to moderate Alzheimer's disease (AD) in an open-label study. A comparison group not receiving lithium therapy was matched for cognition and age. The mean duration of treatment for 14 patients who discontinued prematurely was 16 weeks and for those continuing treatment at the end of the study was 39 weeks. The reason for discontinuation in three patients was possible side effects which disappeared on stopping therapy. The intensity of side effects did not differ between patients discontinuing therapy and the subjects remaining in the study. Two patients receiving lithium died; however, in neither case the treatment with lithium was related to the cause of death. The lithium and non-lithium groups were not different as to deaths, drop outs, or change in MMSE.

In 2009, the first randomized lithium trial in patients with mild AD appeared [37]. Seventyone patients were randomized to receive either lithium (0.5–0.8 mmol/l) (n = 33) or a placebo for (n = 38) 10 weeks. The results obtained showed that there were no differences as to global cognitive performance, as measured by the ADAS-Cog subscale, depressive symptoms, as well as plasma activity of GSK-3 and disease biomarker concentrations in the cerebrospinal fluid (CSF), between lithium and placebo groups [42]. However, interesting results were obtained by an analysis of a single site subsample (Tübingen) containing 27 patients, 13 of which were randomized to lithium and 14 to placebo. In AD patients treated with lithium, in comparison to placebo-treated patients, a significant increase of BDNF serum levels and a significant decrease of cognitive impairment measured by the ADAS-Cog sum scores, inversely correlated with lithium serum concentration, were found [38].

Two Brazilian studies performed in 2011 and 2013 brought about some promising results. Forlenza et al. [39] employed lithium in placebo-controlled trial of 45 patients with amnestic mild cognitive impairment (MCI), randomized to lithium (n = 24) or placebo (n = 21) for 12 months. They found that lithium treatment (0.25–0.5 mmol/l) was associated with significantly better performance on the cognitive subscale of the Alzheimer's Disease Assessment Scale and with a significant decrease of P-tau protein in cerebrospinal fluid (CSF). In the second study, Nunes et al. [40] assessed the effect of a microdose of 300 μg lithium, given to AD patients in one daily dose, for the period of 15 months. During this time, the group receiving lithium microdose showed no decrease in performance in the MMSE test. On the other hand, such a decrease was observed in the control group.

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In a meta-analysis performed by Matsunaga et al. [41], three clinical trials including 232 participants that met the study's inclusion criteria were identified. The results obtained suggested that lithium significantly decreased cognitive decline (standardized mean difference  =  −0.41) as compared to placebo. There were no significant differences in the rate of attrition, discontinuation due to all causes or adverse events, or CSF biomarkers between treatment groups.
