Old Drug May Hold New Promise in Alzheimer's Disease

Lithium Appears to Slow Memory Loss, Reduce Tau

Caroline Cassels

April 27, 2011

April 28, 2011 — Low-dose lithium appears to slow the progression of memory loss and cognitive decline in individuals with amnestic mild cognitive impairment (aMCI), a significant risk factor for Alzheimer's disease (AD), a new study suggests.

A randomized, placebo-controlled trial showed treatment with lithium, an old drug historically used to treat bipolar disorder (BD) and major depression, was associated with a significant decrease in cerebrospinal fluid (CSF) concentrations of phosphorylated tau (P-tau) and better cognitive performance in individuals with aMCI. Furthermore, the drug was well tolerated and had a side effect profile similar to placebo.

"This study supports the idea that giving lithium to a person who is at risk for AD may have a protective effect and slow down the progression of memory loss to dementia. Although our study has a relatively small sample size, we believe our results are promising and point to a need for further trials with larger numbers of participants," study investigator Orestes V. Forlenza, MD, PhD, University of Sao Paulo, Brazil, said in a statement.

The study is published in the May issue of the British Journal of Psychiatry.

Growing Body of Evidence

According to the study authors, a large body of experimental research suggests that by inhibiting glycogen synthase kinase 3 beta (GSK3B) lithium may modify AD-specific pathological processes, including hyperphosphorylation of tau, overproduction of the amyloid-β (Aβ-42) peptide, and Aβ neurotoxicity.

"Thus, lithium, via the inhibition of GSK3B, may hamper mechanisms that lead to the formation of amyloid plaques and neurofibrillary tangles and, consequently, having neuroprotective effects against AD," the investigators write.

They also note that several clinical trials also suggest the drug may help guard against AD from developing, including 1 study that showed a lower prevalence of AD in BD patients receiving long-term lithium therapy.

To assess the effect of long-term therapy on the progression of cognitive deficits in people at high risk for but not with AD, the investigators conducted a study that included 41 subjects with aMCI, all of whom were older than 60 years and had no evidence of ongoing psychiatric disorders.

Subjects were randomized to receive lithium (n = 21) with starting daily doses of 150 mg, titrated to target serum levels of 0.25 to 0.5 mmol/L through weekly visits, controlling for tolerability, or placebo (n = 20). The researchers note that the lithium dose was lower than that commonly used for the treatment of affective disorders.

The study's primary outcome measures were the modification of cognitive or functional status and concentrations of Aβ-42, total tau (T-tau), and P-tau in the CSF.

The Clinical Dementia Rating (CDR) scale, including the sum of boxes (SoB) score, and the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) were used to assess global functional and cognitive state.

Memory, attention, and executive function were evaluated using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) delayed recall test, Sequence of Letters and Numbers (SLN), and the Trail Making Test.

Secondary outcomes included conversion from aMCI to AD, as well as safety and tolerability analysis.

Protective Effect

The investigators report that 11 participants (24%) of the total sample progressed to AD after 12 months. "As expected, these individuals displayed at baseline the typical 'Alzheimer's disease signature' in the CSF, ie, higher concentrations of T-tau and P-tau and lower concentrations of Aβ-42, as compared with nonconverters."

The number of conversions was higher in the placebo group (7/20) compared with the lithium group (4/21), but this difference was not significant.

After 12 months the researchers found that all participants experienced a decline in memory and cognitive functioning as indicated by mean CDR-SoB scores (P < .04). However, they note the decline was significantly smaller in the group treated with lithium vs those in the placebo group as indicated by ADAS-cog and SLN test scores.

Lithium treatment was also associated with a significant decrease in concentrations of P-tau in CSF. In contrast, there was a slight increase in P-tau observed in participants receiving placebo, which was significant (P = .02). They found no effect of lithium on T-tau.

Adverse effects were similar in number in both groups, most of which were mild and only lasted for a short period. In addition, the study authors note that at 91% the adherence rate was high.

"In conclusion, the present findings reinforce the notion that in an individual at risk for Alzheimer's disease, lithium may have a protective effect on the progression of cognitive impairment to dementia.

"We acknowledge that the relatively small sample size of this single-center study is a limitation to the generalization of the current findings. Therefore, we think that the present results warrant replication in multicentric trials with a larger sample," the study authors write.

Plea for Research

In an accompanying editorial, Professor Allan Young, MB ChB, MPhil, PhD, director for the Centre for Mental Health Imperial College, London, United Kingdom, said the study is encouraging and noted the findings are "suggestive of likely benefit.

"This trial adds to the increasing evidence that lithium may have beneficial effects on the brain and begs to be replicated in further randomized trials," he writes.

Professor Young appealed to governments and charitable organizations to take the lead in funding such trials.

"The pharmaceutical industry is clearly very much focused on developing treatments for dementia...If such treatments were to be given to large numbers of at-risk individuals for prolonged periods of time, the commercial rewards to those owning the patents for such treatments are likely to be very considerable.

"Lithium, of course, is under no patent and will not attract industry funds for further development as a treatment except perhaps as a comparator to commercial compounds or possibly in combination with another agent. The onus is therefore on governmental and charitable funding agencies. Such trials will not be cheap, but, were they to prove positive, the possible benefits in health to our ever aging population would be beyond any such price," writes Professor Young.

The authors and Professor Young have disclosed no relevant financial relationships.

Br J Psychiatry. 2011;198:351-356.

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