Findings Suggest that Cognition in Alzheimer’s Disease May Be Amenable to Future Restorative Treatment Interventions

Widespread media coverage of findings reported in Science (published online 2/9/2012) by researchers at Case Western Reserve University has renewed attention and interest in the development of compounds that address the pathological changes that cause Alzheimer’s disease.

The two pathological hallmarks of Alzheimer’s disease involve abnormal processing of the proteins amyloid and tau. In people who have Alzheimer’s disease, the body’s normal processing of the protein amyloid is not functioning correctly, leading to accumulation of the amyloid protein in the brain. This appears to be related to impaired clearance (removal), although some research has also identified overproduction of the more reactive (“sticky”) subtypes of the amyloid protein as playing a role as well.

The Case Western researchers reasoned that a molecule that might promote clearance of amyloid may have a beneficial effect in the disease pathogenesis. They used a mouse model of Alzheimer’s disease that has been genetically modified to produce amyloid pathology in the brain that resembles the changes seen in humans. They administered a compound, bexarotene, that interacts with a retinoid-X receptor (RXR), with the hypothesis that this would increase clearance of amyloid in these mice. Their study was positive, demonstrating changes in the levels of both free and aggregated amyloid in the mouse brains. This finding was seen both in young mice and older mice, suggesting the effect may translate to more chronically deposited amyloid (although it should be noted that “older mice” are 11 months old).

Fascinatingly, the mice also exhibited behavioral changes when treated with the drug. There were improvements in a memory task, a fear-conditioning task following more chronic treatment. As featured in an article in the Wall Street Journal, treated mice appear to have exhibited behavioral changes related to nest building as well. Thus, both instrumental and complex behaviors appear to have been improved in those mice treated with bexarotene.

These are exciting findings. The behavioral changes provide a persuasive suggestion that cognition in Alzheimer’s disease may be amenable to future restorative treatment interventions. The study illustrates a new potential therapeutic target (namely the RXRs), which will certainly spur further research and increase our understanding of the pathological causes of Alzheimer’s disease. The compound, bexarotene, will certainly merit further investigation. As we have seen previously, test results in mice do not always correlate to a similar effect in humans, and further study of dosing, safety and side effects will be required before a clinical trial using this compound in humans would be appropriate. Nonetheless, this important research finding will advance our understanding of Alzheimer’s disease, drawing us one step closer to identifying effective treatment strategies and ultimately a cure.

— Brendan Kelley, MD

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