The Promise of Precision Medicine and Genetic Testing in Alzheimer Disease

Precision medicine and genetic testing will reign supreme when it comes to the future of Alzheimer disease care and treatment advancement, according to Richard S. Isaacson, MD, director of the Alzheimer's Prevention Clinic and associate professor of Neurology at Weill Cornell Medicine and New York-Presbyterian.

Isaacson’s session “Treatment Updates in Alzheimer's Disease: Tailoring Management and Care Approaches to Improve Outcomes,” was presented at this year's National Association of Managed Care Physicians Spring Managed Care Forum, held in Orlando, Florida, April 21-22.

Kicking off his presentation, Isaacson remarked on the recent FDA approval and CMS coverage determination of Aduhelm (aducanumab), the first new treatment for the disease brought to market in nearly 2 decades. The treatment functions by targeting the buildup of amyloid beta plaques in the brain, which are thought to be a pathophysiological driver of the neurodegenerative disease.

Following its controversial launch, CMS announced it would only cover administration if the drug were delivered in a clinical trial setting.

Despite the attention that development garnered from the press and public alike, Isaacson stressed a lesser-known development in Alzheimer disease detection—that a blood-based biomarker for amyloid exists, offering an alternative to testing of cerebral spinal fluid.

“Most people are unaware of [the blood-based biomarker],” he said, equating the advancement to a “cholesterol test for the brain.”

Diagnostic testing is important because even though individuals may exhibit symptoms of the disease at age 85, the disease first starts in the brain at age 55 or 60. “It begins in the brain 20 to 30 years before the first symptom of memory loss begins,” providing a wide window of potential intervention time, Isaacson explained.

The disease is also a spectrum, based on the presentation of certain clinical symptoms over decades, he stressed. Individuals can have amyloid present in the spinal fluid for years and not exhibit symptoms, with recent data showing the amyloid levels in the blood actually increase prioir to those in spinal fluid.

“Alzheimer’s disease affects 46 million Americans,” Isaacson said. “Not all of those people are going to get dementia because they're going to die from something else.”

With regard to genetic testing, studies have shown presence of the APOE4 gene may increase individuals’ risk of dementia. However, if individuals have multiple copies of the APOE variant—and 10% of the Alzheimer disease population does—they are at an increased risk of side effects for aducanumab, underscoring the importance of precision medicine.

“Genetic testing is controversial,” Isaacson said, but the practice opens up a realm of possibilities for precision medicine for those with the highly heterogenous disease.

Lots of different genes can contribute to development of Alzheimer disease, and based on these, patients can and should receive different treatments, he stressed. In a few years, Isaacson expects computer programs to be able to determine polygenetic risk for the disease, taking these genetic factors into account as opposed to singular variants in isolation. But just because an individual is at risk does not mean they will develop the disease.

Another aspect of developing personalized care for this patient population is tracking of bodily metrics like blood sugar, as research has proved poor blood sugar control is associated with cognitive problems.

Currently, no curative medications for Alzheimer disease exist, only disease modifying therapies which provide modest benefits to patients. For these, Isaacson stressed the notion of “start low, go slow,” to help mitigate or even avoid any potential adverse effects. However, as more and more therapeutic targets are identified in the research, the potential for new treatment grows.

With regard to preventive measures, Isaacson highlighted the protective effects of the Mediterranean diet, regular exercise and sleep schedules, and low levels of stress and blood pressure. Cognitive engagement activities like listening to and practicing music can also help prevent decline.

Although the metabolic benefits of medications like semaglutide have been proven, and this could in turn help reduce Alzheimer disease risk, Isaacson prefers to recommend his patients follow behavioral changes and use devices like continuous glucose monitors to help assess metabolic metrics.

Overall, “precision medicine and vascular risk factor care will kind of turn Alzheimer's disease and cognitive decline on its head. I think we’re just a couple of years away from that,” he said.

Based on modifiable risk factors, 4 out of every 10 cases of Alzheimer disease may be preventable, he concluded, but cautioned that even though someone may do everything right, they can still get the disease.