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The AHEAD study: Treating Alzheimer’s disease before symptoms appear

November 9, 2023

Research suggests that amyloid clumps, a hallmark feature in Alzheimer’s disease (AD), begin to accumulate decades before an individual displays symptoms of AD. Lecanemab, an FDA-approved anti-myeloid medication, has been shown to reduce the rate of disease progression and slow cognitive and functional decline in adults with AD. Now, in the landmark AHEAD study, researchers are testing the effect of lecanemab in individuals who have no evidence of cognitive decline but in whom biomarkers indicate the presence of amyloid in the brain, suggestive of preclinical AD. (AHEAD, 2023)

Halting preclinical AD in its tracks

Reisa Sperling, MD, a neurologist at Brigham and Women’s Hospital in Boston and a professor of neurology at Harvard Medical School, is co-principal investigator of the international study.

On a recent episode of Fierce Pharma’s podcast, “The Top Line,” Sperling explained the goal of the study. “We started the AHEAD study because we felt that probably our best opportunity to intervene with something that’s going after the buildup of amyloid in the brain is when it’s at its earliest stage,” said Sperling. “We know in that period of ten to 15 years before people have Alzheimer’s dementia, there are changes in their thinking and memory, but they are very subtle. We thought being able to intervene at that point by trying to reduce amyloid as soon as possible might have an even better chance of preventing dementia one day altogether.” (The Top Line, 2023)

The AHEAD study consists of two sister trials, A-3 and A-45. The A-3 arm is the first ever trial aimed at stopping what may be the earliest signs of AD. Individuals aged 55-80 years who have evidence of amyloid plaque buildup in their brains but who don’t yet have symptoms of AD are eligible to participate and will receive an intravenous infusion of leacanemab once every four weeks for four years. The A-45 arm is for similarly aged participants who have evidence of elevated amyloid levels. These individuals will receive a more frequent infusion of lacanemab up front (once every two weeks for about two years) and then once every four weeks for the remainder of the study. (AHEAD, 2023)

Researchers are incorporating innovative features such as screening with biomarkers in blood, novel PET imaging agents, sensitive cognitive outcome scales, dosing tailored to the level of amyloid in the brain, and recruitment approaches to ensure diverse representation.

Worldwide, 100 sites are participating in the trial, which is funded by the National Institutes of Health (NIH) in partnership with the pharmaceutical company Eisai. The trials are conducted by the NIH-funded Alzheimer’s Clinical Trial Consortium, a network of leading academic Alzheimer’s research centers. (AHEAD, 2023; Brigham Clinical, 2023)

AHEAD follows another large trial, known as A4, in which Sperling was also involved. The findings, published in September in The New England Journal of Medicine, showed that the drug solanezumab did not slow AD progression, but the study did demonstrate the success of a new test used to detect very early memory changes in clinically “normal” individuals. A4 also showed that Tau-PET brain imaging technology, previously used in the Harvard Aging Brain Study, can be used to detect tau tangles, another pathologic sign of AD. (Sperling, 2023; Brigham Clinical, 2023)

What’s next?

Enrollment for AHEAD is still open, and Sperling says that researchers are working on plans for possible interim analyses of the biomarkers and PET scans collected in the study. She and her colleagues are also in the early planning phases of the A2 study. In this study, she hopes to follow individuals who are not yet amyloid positive on a PET scan but who have evidence of early brain changes detectable through blood tests. Participants would receive an anti-amyloid antibody or active amyloid vaccine to prevent amyloid from accumulating in the hopes of slowing disease progression. (Brigham Clinical, 2023)

Sources:

(2023, October 16). Brigham Clinical & Research News. What’s next for Alzheimer’s disease: clinical trials show the promise of intervening early. https://bwhclinicalandresearchnews.org/2023/10/16/whats-next-for-alzheimers-disease-clinical-trials-show-the-promise-of-intervening-early/

(2023, November 3). The Top Line. Exploring the promise of earlier Alzheimer’s treatment. https://www.fiercepharma.com/pharma/top-line-ahead-study

AHEAD study. https://www.aheadstudy.org/about/

Sperling RA; A4 Study Team; et al. (2023, September 21). N Engl J Med. Trial of Solanezumab in Preclinical Alzheimer's Disease. https://pubmed.ncbi.nlm.nih.gov/37458272/