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Expert Working Group Lowers Expectations for Alzheimer's Drug Impacts

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An expert work group has reframed what is clinically meaningful to slow Alzheimer's disease progression during clinical trials, including treatment impact over time and the need for combination therapies.

Alzheimer's & Dementia: The Journal of the Alzheimer's Association has published the group's findings and recommendations:

  • Slowing progression of disease — rather than halting it, which may come eventually — has measurable and meaningful benefits for patients and their families, especially in early Alzheimer’s when cognition and memory are fully or mostly intact.
  • A statistically significant benefit in an 18-month clinical trial may signify and lead to an even more meaningful change when projected over succeeding years. 
  • It is unlikely any single intervention on dementia-related brain changes will have a large clinical effect on its own. For greater impact, combination therapies will be needed, just as they treat elevated blood pressure and cancer today.

The Alzheimer's disease process attacks the brain years, even decades, before a person develops problems with memory and thinking. But clinical trials for disease-modifying therapies in the symptomatic stage typically last about 18 months. Looking at results of drug trials, the work group convened by the Alzheimer’s Association considered how patients, families and the scientific community assess what is meaningful when it comes to slowing Alzheimer's disease progression. 

"Slowing brain deterioration even four to six months in the early stages of Alzheimer’s disease may lead to preservation of function for patients that can be very meaningful to patients and their families," says Ronald Petersen, M.D., Ph.D., Mayo Clinic neurologist, a work group member and lead author of the journal article. "The longer someone is able to delay loss of independence and to continue to participate in daily activities, the more meaningful these results become."

Complex disease process

Changes in the brain from Alzheimer's disease do not happen in isolation. Someone who is cognitively impaired typically has other neurodegeneration processes occurring at the same time.

Over the course of an 18-month clinical trial, "the observed clinical impact of a single intervention is reasonably expected to be quite modest," the authors write. However, if therapy is continued longer and its effectiveness is sustained, cumulative benefits will become more apparent.

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The work group notes that just as high blood pressure and cancer are treated with multiple medications, so too will multiple therapeutic interventions be needed to address complex brain changes and related memory and thinking problems.

"The work group recognized that we need to modify expectations of a single intervention on a complex set of neurodegenerative processes, but recent progress with newly approved Alzheimer's drugs is a tremendous first step," Dr. Petersen says.

About clinical meaningfulness

A 2021 article from the Alzheimer’s Association Research Roundtable referenced the Food and Drug Administration description of clinical meaningfulness as when "the treatment has a positive and significant effect on how an individual feels, functions, or survives."

Interpretation of clinical meaningfulness will be part of discussions clinicians will have with patients and their families when they are considering potential benefits, risks and challenges of disease-modifying therapies newly approved to treat Alzheimer's disease.

"It's a shared decision-making process when patients and families talk with their doctors about any potential treatment," Dr. Petersen says. "As we discuss the clinical meaningfulness of slowing the Alzheimer's disease progression, realistic expectations of benefits and risks must be conveyed."

Reference: Petersen RC, Aisen PS, Andrews JS, et al. Expectations and clinical meaningfulness of randomized controlled trials. Alzheimer’s & Dementia. 2023. doi: 10.1002/alz.12959

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