Authored by Robin Seaton Jefferson via The Epoch Times,
In March, the U.S. Food and Drug Administration (FDA) issued a revised draft guidance to help drug companies develop medication to treat cases of early Alzheimer’s disease that “occur before the onset of overt dementia.”
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.”
The American Heart Association reports that death due to heart disease has declined by 60 percent since 1950 and that the number of people in the United States dying of a heart attack each year has dropped from one in two in the 1950s to one in 8.5 today. Mr. Tanzi said that is because doctors now treat their patients proactively for a disease that could otherwise kill them many years in the future.
As a geneticist who co-discovered three of the first Alzheimer’s disease genes, Mr. Tanzi replicated the cascades of cellular changes in Alzheimer’s in a petri dish so scientists could conduct tests as the disease developed and test drug efficacy. He said the problem is now that doctors don’t diagnose Alzheimer’s disease until the brain has already deteriorated to the point of dysfunction. Patients “need safe and affordable drugs to intervene with amyloid deposition as early as possible,” he added.
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.
“This would be most important for those with early-onset familial Alzheimer’s disease gene mutations, those with Down syndrome, and carriers of the APOE epsilon variant that increases risk for Alzheimer’s disease, where you know amyloid deposition is guaranteed or highly likely beginning early in life,” Mr. Tanzi added.
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.
An estimated 6 million Americans aged 65 and older live with Alzheimer’s and dementia, with the majority being over age 75. “The proposed changes will move what is a feared but far from universal disease of aging, Alzheimer’s dementia, to a largely silent, asymptomatic disease affecting a much larger population, as most people with positive amyloid biomarkers have no cognitive issues,” Dr. Widera wrote in his commentary, published in February in the Journal of the American Geriatrics Society.
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.
According to Fierce Biotech, a company that reports on the biotech industry, the FDA isn’t going as far as to say that amyloid reduction can be considered a primary endpoint—the main result measured at the end of a study to see whether a given treatment worked—in Alzheimer’s trials. However, the agency suggests that this biomarker can serve as a surrogate endpoint—an indicator that tells if a treatment works—to predict clinical benefit.
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.
For these reasons, the FDA is considering other approaches, including endpoints based on cognitive assessments or surrogate endpoints, which may allow for shorter trial durations in the earliest stages of disease, Fierce Biotech reported.
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 American Geriatrics Society (AGS) commented on the criteria expansion, expressing concerns that it would “place many older and multimorbid people at risk of overdiagnosis, which in turn could lead to initiation of treatments with as yet unproven clinical benefit, particularly in an asymptomatic population, and high potential for harm.”
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.
Authored by Robin Seaton Jefferson via The Epoch Times,
In March, the U.S. Food and Drug Administration (FDA) issued a revised draft guidance to help drug companies develop medication to treat cases of early Alzheimer’s disease that “occur before the onset of overt dementia.”
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.”
The American Heart Association reports that death due to heart disease has declined by 60 percent since 1950 and that the number of people in the United States dying of a heart attack each year has dropped from one in two in the 1950s to one in 8.5 today. Mr. Tanzi said that is because doctors now treat their patients proactively for a disease that could otherwise kill them many years in the future.
As a geneticist who co-discovered three of the first Alzheimer’s disease genes, Mr. Tanzi replicated the cascades of cellular changes in Alzheimer’s in a petri dish so scientists could conduct tests as the disease developed and test drug efficacy. He said the problem is now that doctors don’t diagnose Alzheimer’s disease until the brain has already deteriorated to the point of dysfunction. Patients “need safe and affordable drugs to intervene with amyloid deposition as early as possible,” he added.
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.
“This would be most important for those with early-onset familial Alzheimer’s disease gene mutations, those with Down syndrome, and carriers of the APOE epsilon variant that increases risk for Alzheimer’s disease, where you know amyloid deposition is guaranteed or highly likely beginning early in life,” Mr. Tanzi added.
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.
An estimated 6 million Americans aged 65 and older live with Alzheimer’s and dementia, with the majority being over age 75. “The proposed changes will move what is a feared but far from universal disease of aging, Alzheimer’s dementia, to a largely silent, asymptomatic disease affecting a much larger population, as most people with positive amyloid biomarkers have no cognitive issues,” Dr. Widera wrote in his commentary, published in February in the Journal of the American Geriatrics Society.
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.
According to Fierce Biotech, a company that reports on the biotech industry, the FDA isn’t going as far as to say that amyloid reduction can be considered a primary endpoint—the main result measured at the end of a study to see whether a given treatment worked—in Alzheimer’s trials. However, the agency suggests that this biomarker can serve as a surrogate endpoint—an indicator that tells if a treatment works—to predict clinical benefit.
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.
For these reasons, the FDA is considering other approaches, including endpoints based on cognitive assessments or surrogate endpoints, which may allow for shorter trial durations in the earliest stages of disease, Fierce Biotech reported.
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 American Geriatrics Society (AGS) commented on the criteria expansion, expressing concerns that it would “place many older and multimorbid people at risk of overdiagnosis, which in turn could lead to initiation of treatments with as yet unproven clinical benefit, particularly in an asymptomatic population, and high potential for harm.”
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.
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