Alzheimer's-linked genetic mutation a potential target for early treatments

Amyloid plaques in Alzheimer's disease
Patients with the Met allele mutation and beta-amyloid (pictured) showed a steeper decline in thinking and memory function as did those without the mutation. (Jensflorian CC BY-SA 3.0 via Wikimedia Commons)

NIH-backed researchers found a gene mutation that may spur the decline of memory and thinking skills in people at risk for Alzheimer’s. Because mutations can be caught before symptoms appear, this could become a target for early treatments, they believe.

The mutation, dubbed the Met allele, affects the gene that produces brain derived neurotrophic factor (BDNF), a protein that supports the growth, differentiation and survival of nerve cells.

The team tracked 1,023 people aged 55 or older who were at risk of developing Alzheimer’s, but had not yet developed symptoms, according to a statement. They tested the participants for the mutation, finding 32% had the Met allele. They also assessed their thinking and memory skills at the start of the study and retested them up to five more times over as many as 13 years.

Sponsored By Syneos Health

Blazing a Trail to Clinical Trial Diversity: Four-Part Webinar Series from Syneos Health, Featuring Pharma, Clinical Research and Community Health Leaders

This series will identify obstacles that stifle appropriate patient diversity in trials; unpack the organizational overhaul needed; share how sponsors, patients & investigators have come together to overcome hurdles; and explore how policy innovations can move the industry forward.

They found that patients with the Met allele lost their skills more quickly than those who did not have the mutation. The Alzheimer's Association and the Department of Veterans Affairs, among others, joined the NIH in supporting the study. The findings were published in the journal Neurology.

"When there is no mutation, it is possible the BDNF gene and the protein it produces are better able to be protective, thereby preserving memory and thinking skills," said study author Ozioma Okonkwo, an assistant professor at the University of Wisconsin School of Medicine, in the statement. "This is especially interesting because previous studies have shown that exercise can increase levels of BDNF. It is critical for future studies to further investigate the role that the BDNF gene and protein have in beta-amyloid accumulation in the brain."

A small number—14%—of the patients also underwent neuroimaging to detect beta-amyloid, which forms plaques in brains of people who have Alzheimer’s. People with the Met allele and beta-amyloid showed an even sharper decline in memory and thinking skills.

There is a broad push in the Alzheimer's research community to improve early detection and intervention in the disease. Pfizer and Boston-based Akili, for example, presented data in December on “digital biomarkers” for the noninvasive detection of amyloid in the brain. The pair found that Akili’s technology could differentiate between patients with and without amyloidosis, which could lay the groundwork for a noninvasive way to detect Alzheimer’s early.

Other biotech and pharma companies are working on Alzheimer’s therapies, but several have recently hit roadblocks:

  • Just this week, Neurotrope’s candidate failed to beat a placebo in improving patients’ performance on a neuropsychological test
  • In February, Merck halted a 2,000-patient trial of its verubecestat because external reviewers concluded it had “virtually no chance” of succeeding
  • Lundbeck dropped its candidate idalopirdine after it missed the mark in three late-stage studies
  • Back in November, Eli Lilly dumped its solanezumab after Phase 3 data showed the drug had no significant effect on cognitive decline

Treatments that have been approved for Alzheimer’s usually center on controlling symptoms, but they do not delay or stop progression of the disease. The Met allele is a promising target for early intervention, Okonkwo said, because physicians can screen for the gene in healthy people and try to head off the disease in the “critical” period before symptoms develop.