Disease-modifying Properties of Lithium in the Neurobiology of Alzheimer's Disease
Status:
Unknown status
Trial end date:
1969-12-31
Target enrollment:
Participant gender:
Summary
Lithium salts have been used for the treatment of psychiatric disorders for over five
decades, mostly as a mood-stabilizing drug. Recent evidence points to the inhibition of the
enzyme glycogen synthase kinase-3beta (GSK3) as one of its mechanisms of action. The
overactivity of this enzyme has been implicated in the pathogenesis of Alzheimer's disease
(AD), given its involvement in mechanisms related to the hyperphosphorylation of Tau protein
and the production of beta-amyloid peptide. These are key events leading respectively to the
formation of neurofibrillary tangles and senile plaques, which are the neuropathological
hallmarks of the disease. Several in vitro and animal studies have shown that the inhibition
of GSK3 by lithium and other agents attenuates these pathological processes, reinforcing the
notion that GSK3 is a likely target for future disease-modifying therapies for AD. Indeed, a
recent study published by our group showed that chronic lithium use is associated with a
decrement in the expected prevalence of dementia, in a sample of elderly individuals with
bipolar disorder. To investigate this putative neuroprotective effect in a prospective way,
the investigators started 24-month randomized, double-blinded controlled trial of lithium for
the prevention of dementia in a sample of elderly individuals with amnestic mild cognitive
impairment (MCI), a condition associated with increased risk for the development of AD. The
clinical and biological outcomes of this trial include the attenuation of cognitive deficits,
and the modification of certain biological markers of the disease (as measured in the
cerebrospinal fluid, leukocytes and platelets). The objective of the present application is
to enable the extension of this ongoing trial to an additional 2-year follow-up. A longer
follow-up (48 months) will increase the statistical power to ascertain the primary outcome
variables of this study, particularly the con-version from MCI to Alzheimer's disease. This
will warrant a more consistent conclusion about the potential of lithium treatment in the
prevention of dementia, in addition to a better evaluation of safety and tolerability
profiles of the long-term use of lithium in older individuals.