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The FDA issued guidance to drug companies developing medication to treat Alzheimer’s before symptoms begin to show. Will this lead to overdiagnosis?
One theory about Alzheimer’s is that amyloid pathology can occur decades before symptoms appear, and to stop the disease, doctors may need to address this underlying pathology well before that happens. Some say that will label people as having a disease they may never develop; others say it’s the only way to stop it in those who will come to have it.
Treat Dementia Like Heart Disease
Rudolph E. Tanzi, who has a doctorate in neurology and is a professor of neurology at Harvard Medical School and the director of its Genetics and Aging Research Unit, said that to stop dementia and Alzheimer’s, doctors must treat it the way they currently treat heart disease.
“Just like we keep track of cholesterol and alter lifestyle and take safe drugs to lower cholesterol levels in order to avoid heart disease, we will need to do the same for Alzheimer’s disease,” Mr. Tanzi told The Epoch Times. “The FDA guidance is a step in that direction.”
Mr. Tanzi said that although the guidance is correct to advise treating early-stage Alzheimer’s patients, scientists will still someday need to prevent the buildup of abnormal amyloid deposits as soon as they begin in the brain before damage occurs.
Is Amyloid Positivity Enough to Redefine Alzheimer’s Disease?
But there is still no solid proof that any drugs, even if they reduce amyloid, will decrease dementia fates in the future, said Dr. Eric Widera, a professor of clinical medicine in the Division of Geriatrics at the University of California–San Fransisco. He also questions the risks of some drugs with serious side effects, such as brain bleeding and death.
There is a trend to redefine Alzheimer’s disease based on whether someone is amyloid positive on a test, “independent of whether an individual has any symptoms of cognitive impairment, or whether they will develop them in the future,” Dr. Widera said.
He explained that while scientists do have “pretty good evidence that in individuals with mild cognitive impairment and mild dementia,” two drugs, donanemab and lecanemab, “have an exceptional ability to remove amyloid.” However, he argues that this ability has only a “subtle effect” on the rate of decline in cognition.
“This is pretty clear evidence that suggests amyloid is likely not the only factor that contributes to Alzheimer’s disease progression and that we have a lot yet to learn about how to stop or reverse the disease,” he said.
The changes proposed will have effects that are “far from subtle” and will be marketed as “a new Alzheimer’s epidemic,” said Dr. Widera.
What Can Be Done?
For his part, Mr. Tanzi agrees that much more must be done. “We will need blood tests that tell us not only when amyloid is already doing its damage in the brain, but also tests that can tell us when to treat so as to prevent amyloid deposition in the brain in the first place.”
Mr. Tanzi said Alzheimer’s is only “beatable” when predicted early, based on family history and genetics; detected early, based on blood biomarkers and imaging; and intervened upon early, using safe and affordable drugs.
“The approved amyloid drugs, like Leqembi [lecanemab], are not approved for prevention, but only for treatment in the mildest cases of Alzheimer’s disease. That is good to do, but still too late.” He added that lecanemab “is too costly, at over $60,000 per year, including the necessary MRIs to detect brain swelling and hemorrhage.”
He said that is one of the focuses at the McCance Center for Brain Health, where he is currently fundraising for an Alzheimer’s disease clinical trial initiative to test combinations of repurposed safe and affordable drugs and natural products to lower amyloid levels in the brain, as a safer and more affordable alternative to amyloid immunotherapy like lecanemab.
“The hope is that combinations of safe and affordable repurposed drugs can someday be used in tens of millions of Americans to prevent Alzheimer’s disease,” he added.
What Will the Guidance Do?
As a draft, the document will “serve as a focus for continued discussions” for the treatment of early Alzheimer’s disease, the draft states. However, when finalized, the document “will represent FDA’s current thinking regarding the selection of subjects with early [Alzheimer’s disease] for enrollment in clinical trials and the selection of endpoints for clinical trials in this population.”
With its proposed guidelines, the FDA is focusing more on amyloid. It considers the reduction of brain amyloid, found by positron emission tomography (PET scans), to be a surrogate endpoint that is “reasonably likely to predict clinical benefit” and that clinical trials showing an effect on that surrogate endpoint can be the basis for accelerated approval, including for drugs intended to treat Alzheimer’s.
Alzheimer’s researchers currently use both cognitive and functional measures as co-primary endpoints, resulting in a two-year or less average clinical trial duration in the symptomatic stages of the condition. But it could take longer to establish clinically meaningful treatment effects among patients with early Alzheimer’s due to limited or nonexistent cognitive and functional deficits seen early on. Plus, tools often used to measure functional impairment in patients in the later stages of Alzheimer’s may not be able to identify subtle changes in early-stage disease.
Possibility of Overdiagnosis
In a draft document published in October 2023, the Alzheimer’s Association Workgroup suggested expanding the criteria for Alzheimer’s diagnosis and basing diagnosis on core biomarkers such as amyloid rather than clinical syndromes.
The AGS said the document fails to pay sufficient attention to the potential impact of an Alzheimer’s diagnosis on patient identity or any social and fiscal consequences.
“The reality is that many biomarker-positive individuals never develop cognitive impairment … and most people diagnosed with dementia will die with, not of, dementia,” the AGS wrote.
“At this juncture, a cognitively normal 50-year-old would have a 1 in 10 chance of testing positive for amyloid … and then carry an [Alzheimer’s disease] diagnosis in their health records,” the organization wrote.
The AGS added that this “distracts from the broader aim of ensuring high quality health care for individuals who already have cognitive impairment or dementia.”
Citing the “potential influence of financial ties between key stakeholders who make decisions on definitions and diagnostic thresholds,” the AGS said transparency is critical, and any conflict of interest should be disclosed.
The Epoch Times contacted the FDA and the Alzheimer’s Association Workgroup but did not receive a reply.