Can Symptoms of Alzheimer’s Disease Be Prevented?

The U.S. Food and Drug Administration (FDA) recently approved lecanemab, a drug that slows the progression of Alzheimer’s disease (AD) symptoms. This intravenously administered medication is a monoclonal antibody that removes beta-amyloid, one of two proteins that accumulate in the brain in AD. Amyloid accumulation begins more than a decade before the onset of symptoms of dementia. Another protein, tau, accumulates in the brain shortly before clinical symptoms appear.

Reducing Beta-Amyloid Levels

Results from a recent clinical trial published in the New England Journal of Medicine demonstrated the effectiveness of lecanemab in reducing beta-amyloid levels in the brain (as measured by positron emission tomography [PET]) and slowing the progression of AD symptoms. The 1,795 participants enrolled in the 18-month, multicenter, double-blind, placebo-controlled CLARITY AD study were in the very mild or mild stages of AD-related dementia. The main outcome measure was the change in the Clinical Dementia Rating–Sum of Boxes (CDR-SB) scores. The six domains evaluated with this scale were memory, orientation, judgment and problem-solving, community affairs, home and hobbies, and personal care.

Baseline CDR-SB scores were approximately 3.2. After 18 months, the group receiving placebo infusions had a mean CDR-SB score of 5.58 while those receiving lecanemab had a mean score of 4.14. This difference was highly statistically significant and clinically meaningful. In addition, cognitive testing and evaluations of activities of daily living showed statistically significant and clinically meaningful decreases in deterioration in the lecanemab group. Earlier studies of lecanemab indicated that the medication slowed progression of the illness by a year or more and fewer participants developed symptoms necessitating nursing home admission.

Although lecanemab slowed progression of the illness in the CLARITY AD trial, there were side effects. About 26 percent of individuals receiving lecanemab had infusion-related reactions compared to 7 percent of those receiving placebo. For the most part, these reactions were mild to moderate and occurred with the first dose. Some participants elected to take preventive medications prior to subsequent infusions. About 12 to 13 percent of participants developed edema or effusions in the brain visible with imaging; these are known as ARIA (amyloid-related imaging abnormalities). In general, ARIA was mild and mostly asymptomatic. Those with ARIA continued in the study, and the ARIA resolved within four months.

Analysis of data from an earlier lecanemab trial demonstrated that patients with milder symptoms experienced stronger benefits from the drug. Currently, blood tests are being developed that can help determine whether an individual has changes in the brain associated with AD prior to exhibiting clinical symptoms. Such blood tests may help predict when an individual may experience the onset of symptoms. It is likely that initiating anti-amyloid treatment before symptoms occur will be more effective at delaying the emergence and/or progression of symptoms.

Role of Abnormal Tau

As mentioned earlier, beta-amyloid is one of two proteins that accumulate in the brain with AD. Tau is the other. In addition to the development of drugs like lecanemab that reduce amyloid in the brain, drugs that attack abnormal tau are also in early stages of development. Accumulating tau may trigger both brain degeneration and clinical symptoms.

Is it possible that AD symptoms could be prevented or significantly delayed by initiating treatment a few years prior to symptom onset with a combination of medications that reverse amyloid accumulation and attack tau? Such a strategy is now being studied in a clinical trial with individuals who have a dominantly inherited form of AD.

If such an approach is successful, we may be getting close to preventing or substantially delaying the onset of AD. Similar to other disorders, there might be broad screening via blood tests of people when they reach age 50. If such tests reveal presymptomatic AD, preventive treatment(s) could begin. This could not only save individuals from a devastating illness but also save their families from the serious physical, financial, and emotional toll of caring for loved ones suffering from dementia.

This post was written by Eugene Rubin, MD, Ph.D., and Charles Zorumski, MD.