Hope in the Midst of Alzheimer's Drug Failures

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Just a few weeks ago, the pharmaceutical trial for one of the most promising Alzheimer's drugs—aducanumab—was halted because it was shown to be unlikely to slow cognitive decline. This was devastating news not only for the 3,200 people enrolled in the trial but for the worldwide Alzheimer’s community. It was especially devastating because aducanumab had shown great promise in slowing cognitive decline in earlier trials.

The failure of aducanumab has added to growing skepticism about the “amyloid hypothesis” of Alzheimer's, which proposes that beta-amyloid (a naturally-occurring protein that clumps together abnormally in Alzheimer's) is the primary driver of the cascade of abnormal cellular changes that characterize the disease. According to the amyloid hypothesis, blocking the effects of beta-amyloid should stop or change the trajectory of the disease process. Unfortunately, this has not been realized.

Currently, the primary medications used to treat Alzheimer's may improve symptoms for some individuals but are unable to alter the underlying disease process. It has been 16 years since the last medication was approved to treat Alzheimer's (Namenda, in 2003). The search for an Alzheimer's medication is made more difficult by the exit of multiple pharmaceutical companies from the Alzheimer’s market. Given that cellular changes related to Alzheimer’s have been shown develop in the brain 20-30 years or more before the condition is diagnosed, and given that multiple factors increase the risk of Alzheimer’s, many researchers believe Alzheimer's might best be managed with multi-component treatments, like other chronic conditions such as heart disease and diabetes. Treatments may be especially effective early in the disease process.

While researchers continue to study other potential targets for medication—including tau (a naturally occurring protein that is abnormally tangled in Alzheimer's), inflammation, and vascular issues (e.g. diabetes, high blood pressure, and cholesterol problems)—there has been a simultaneous, strong focus on the impact of lifestyle factors in reducing the risk of Alzheimer’s.

For years, studies have shown that exercise, diet, sleep, cognitive engagement, and stress management can decrease the risk of Alzheimer's. However, until recently, there were no large randomized-controlled trials demonstrating a cause and effect relationship between lifestyle factors and cognitive functioning for people at risk for cognitive impairment.

This changed in 2014 with The FINGER Study (The Finnish Geriatric Intervention Study To Prevent Cognitive Impairment and Disability). FINGER was a two-year randomized-controlled trial that examined the impact of lifestyle and vascular risk factors in 1,260 people aged 60–77 years. Although participants had normal cognitive functioning, they were at-risk for future cognitive decline—for example, due to the presence of cardiovascular risk factors such as high blood pressure and cholesterol issues.

Results showed that a multi-component approach focusing on nutrition (a variant of the Mediterranean diet), physical exercise, individualized cognitive training, and social activities resulted in a 30% reduced risk of cognitive decline. One of the most promising findings was that the reduced risk of decline was not limited by age, sex, cognitive performance, socioeconomic status, or even level of cardiovascular risk. In addition, a follow-up study showed that those with a genetic risk for Alzheimer’s had a similar therapeutic benefit to those without a genetic risk.

The success of The FINGER Study contributed to the development of a similar trial by the Alzheimer's Association, U.S. POINTER (The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk), and similar trials around the world. U.S. POINTER started enrolling participants in 2018 and is scheduled to continue until 2020. Both U.S. POINTER and FINGER are part of a global consortium, World Wide FINGERS (WW-FINGERS), which aims to combine research findings on lifestyle and cognitive functioning. Another upcoming trial, MIND-AD, will use the FINGER protocol for those who have already been diagnosed with mild Alzheimer’s disease.

As we await results of future multi-component lifestyle trials and possible future medications, it is encouraging to see the hope and guidance provided by research on the positive impact of exercise, diet, and cognitive engagement, especially for those at risk of cognitive impairment.