Brain Teasers

Experimental Alzheimer’s drugs targeting brain plaque keep failing. Prevention may be the new cure for dementia.

Five Figures to Consider

100+ compounds tested to treat Alzheimer’s disease have been abandoned in development or failed in clinical trials
20 years or more before symptoms occur, brain changes associated with Alzheimer’s begin
⅓ of dementia cases may be preventable through lifestyle modifications
27 is the average age for the onset of cognitive decline
15+ years of exercise training improved memory in middle-aged rugby players

Drugs targeting amyloid brain plaque accumulation were heralded as the silver bullet cure for Alzheimer’s disease. No more. Clinical trial after clinical trial has failed. The latest flop is aducanumab. After encouraging preclinical results on patients with mild Alzheimer’s, Biogen and Japanese partner Eisai poured millions of dollars into clinical trials of the compound. Then, disappointment. Aducanumab wasn’t outperforming a placebo so last week the companies announced they were halting phase 3 trials. This failure follows a January decision by the drugmaker Roche to end development of its own anti-amyloid drug crenezumab. Unfortunately, these two drugs are just the latest in a series of more than 100 failed Alzheimer’s drugs. In spite of billions of dollars spent on development, just four drugs for Alzheimer’s are on the market, each treating symptoms without providing a cure. The newest is already fifteen years old.

Failure can be a teacher. So what have Alzheimer’s researchers learned? Fewer scientists are now confident about the so-called “amyloid hypothesis,” the theory that amyloid accumulation on the brain is the cause of Alzheimer’s disease and the path to treatment. After all, many studies have documented people who have died with amyloid plaque-coated brains but without dementia. The Biogen drug aducanumab removed brain plaque, but it didn’t show significant cognitive benefits. Were the patients too far along in the disease to benefit? Is amyloid plaque the wrong target? What other brain processes are associated with Alzheimer’s? These questions are driving scientists to look for earlier interventions and to think about dementia and brain plaque as part of a more complex and long-developing process. Indeed, the brain changes associated with Alzheimer’s begin 20 or more years before symptoms occur. Given this long lead time, the greatest reduction in the scourge of Alzheimer’s and dementia may come from prevention rather than a cure.

The good news is that according to the Lancet Commission on Dementia, more than one-third of global dementia cases may be preventable by addressing modifiable factors including high blood pressure, lack of physical exercise, hearing loss, diabetes, depression and obesity.  “Dementia prevalence could be halved if its onset were delayed by five years,” reported the study’s lead author Professor Gill Livingston, MD. Now the question is what are the most effective interventions. To that end, the Alzheimer’s Association is recruiting 2,000 volunteers ages 60 to 79 for U.S. Pointer, a clinical trial that will test the effectiveness of prevention efforts including exercise, nutrition, cognitive stimulation and heart risk monitoring.

Although the U.S. Pointer study focuses on older people, dementia prevention begins early in life. (Sadly, the average age for the onset of cognitive decline is 27, according to researchers at the University of Virginia.) This month a study published in Nature demonstrated that middle-aged men who had played amateur rugby for an average of 35 years (and at least 15 years) performed better on memory tests than their peers who exercised for less than an hour per week. The men in both groups were healthy and of similar height, weight, body mass index and education level. The groups scored similarly on tests of attention and speed processing, but when it came to a memory test that signals future dementia onset, the exercisers outperformed. Memo to people who don’t like going to the gym:  team sports are effective dementia prevention. “As long as you get your heart rate up,” cautions Dr. Keith Fargo, Director of Scientific Programs & Outreach at the Alzheimer’s Association.

In addition to revealing a memory benefit from team sports, the rugby player study offered new information about two molecules that are activated by exercise and appear to be protective against age-related memory loss. The molecules, Cathepsin B (CTSB) and Brain-Derived Neurotrophic Factor (BDNF), may be helpful to scientists investigating neurogenesis, which is our brain’s ability to replace and repair cells and synapses damaged by things like concussion, infection, inflammation and aging. It appears that exercise makes our brains better at repairing themselves. Encouraging these natural repair processes is a new focus of drug development. Neurotrope, for example, is testing an experimental drug to boost synapse repair in the brain.

What can people do to protect their brains in the absence of a silver bullet drug? Exercise. Manage high blood pressure. Stay socially and intellectually stimulated. And eat mushrooms. It’s true. Just, not in front of the television.  Heavy T.V. watching, unsurprisingly, appears to have a negative effect on memory. We see you. Put down that remote, and go join a sports team.

Sources

Alzheimer’s Association, Biogen, JAMA Network, Johns Hopkins Medicine, National Institutes of Health, Nature: International Journal of Science