Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study.
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.


METHODS
A total of 71 patients with mild Alzheimer's disease (Mini-Mental State Examination score > or = 21 and < or = 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 beta-amyloid(1-42) (Abeta(1-42)), plasma levels of Abeta(1-42), 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.


BACKGROUND
(Controlled-Trials.com) Identifier: ISRCTN72046462.
Hampel
Harald
H
Trinity Center for Health Sciences, The Adelaide and Meath Hospital Incorporating The National Children's Hospital (AMiNCH), Tallaght, Dublin 24, Ireland. harald.hampel@med.uni-muenchen.de
Ewers
Michael
M
Bürger
Katharina
K
Annas
Peter
P
Mörtberg
Anette
A
Bogstedt
Anna
A
Frölich
Lutz
L
Schröder
Johannes
J
Schönknecht
Peter
P
Riepe
Matthias W
MW
Kraft
Inga
I
Gasser
Thomas
T
Leyhe
Thomas
T
Möller
Hans-Jürgen
HJ
Kurz
Alexander
A
Basun
Hans
H
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D016651:Lithium Carbonate / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008609:Mental Status Schedule / Q000706:statistics & numerical data; D008875:Middle Aged; D009483:Neuropsychological Tests / Q000706:statistics & numerical data; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D011594:Psychometrics; D016037:Single-Blind Method; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; C054369:MAPT protein, human; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D016651:Lithium Carbonate; D038362:Glycogen Synthase Kinase 3