Objective: Lithium, a first-line drug for the treatment of bipolar depression, has recently been shown to regulate glycogen synthase kinase-3 (GSK-3), a kinase that is involved in the phosphorylation of the tau protein. Since hyperphosphorylation of tau is a core pathological feature in Alzheimer’s disease, lithium-induced inhibition of GSK-3 activity may have therapeutic effects in Alzheimer’s disease. In the current study, we tested the effect of short-term lithium treatment in patients with Alzheimer’s disease. Method: A total of 71 patients with mild Alzheimer’s disease (Mini-Mental State Examination score≥ 21 and≤ 26) were successfully randomly assigned to placebo (N= 38) or lithium treatment (N= 33) at 6 academic expert memory clinics. The 10-week treatment included a 6-week titration phase to reach the target serum level of lithium (0.5–0.8 mmol/L). The primary outcome measures were cerebrospinal fluid (CSF) levels of phosphorylated tau (p-tau) and GSK-3 activity in lymphocytes. Secondary outcome measures were CSF concentration of total tau and β-amyloid1–42 (Aβ1–42), plasma levels of Aβ1–42, Alzheimer’s Disease Assessment Scale (ADAS)-Cognitive summary scores, MMSE, and Neuropsychiatric Inventory (NPI). Patients were enrolled in the study from November 2004 to July 2005. Results: No treatment effect on GSK-3 activity or CSF-based biomarker concentrations (P>. 05) was observed. Lithium treatment did not lead to change in global cognitive performance as measured by the ADAS-Cog subscale (P=. 11) or in depressive symptoms.

Conclusions: The current results do not support the notion that lithium treatment may lead to reduced hyperphosphorylation of tau protein after a short 10-week treatment in the Alzheimer’s disease target population. Trial Registration: controlled-trials. com Identifier: ISRCTN72046462