Orestes Forlenza, Ph.D.
University of São Paulo
São Paulo, Brazil

2008 New Investigator Research Grant

Lithium has long been used as a drug to stabilize mood in people with Alzheimer's disease and various psychiatric disorders. Recent evidence indicates that lithium inhibits the activities of an enzyme called the glycogen synthase kinase-3beta (GSK3). This enzyme is involved in the production of abnormal tau protein and the protein fragment beta-amyloid. Abnormal tau and beta-amyloid produce the harmful tangles and clump-like plaques that are characteristic of Alzheimer brains.

Several studies have shown that the inhibition of GSK3 activities can moderate the formation of tau tangles and amyloid plaques. Thus GSK3 may prove to be an effective target in the search for Alzheimer treatments.

In a preliminary clinical trial, Orestes Forlenza, Ph.D., and colleagues found that long-term lithium treatment reduced the prevalence of dementia in elderly participants with bipolar disorder (manic depression). They then studied the dementia-fighting effects of lithium with participants that had mild cognitive impairment, a condition that often precedes Alzheimer's. Results found that the treatment reduced both cognitive decline and the risk for developing Alzheimer's. The treatment also moderated the development of toxic plaques and tangles.

For this proposed investigation, Dr. Forlenza's team plans to conduct a larger, more extensive lithium study with participants that have mild cognitive impairment. They hope to confirm the findings of their earlier research. The results of this effort could lead to a better understanding of how lithium and GSK3 inhibition may prevent or delay the onset of Alzheimer’s. The researchers also hope to obtain a better evaluation of the treatment's safety.