Determining whether someone has Alzheimer’s usually requires an extensive diagnostic process. A doctor takes a patient’s medical history, discusses symptoms, administers verbal and visual cognitive tests.
The patient may have a PET scan, MRI or spinal tap – tests that detect the presence of two proteins in the brain, amyloid plaques and tau tangles, both of which are associated with Alzheimer’s disease.
All that could change dramatically if new criteria proposed by an Alzheimer’s Association task force are widely adopted.
Its final recommendations, expected later this year, will accelerate a shift already underway: from defining disease based on symptoms and behavior to defining it purely biologically — with biomarkers, substances in the body that indicate disease.
The draft guidelines, Revised Criteria for the Diagnosis and Staging of Alzheimer’s Disease, call for a simpler approach. This could mean a blood test to indicate the presence of amyloid. Such tests are already available in some clinics and doctor’s offices.
“Someone who has evidence of an amyloid biomarker in the brain has the disease, whether they are symptomatic or not,” said Dr. Clifford R. Jack Jr., task force chair and Alzheimer researcher at Mayo Clinic.
“The pathology exists for years before symptoms appear,” he added. “This is science. Is undeniable.”
He and his colleagues on the panel do not recommend testing people who do not have symptoms of cognitive decline. However, skeptics predict that this is likely to happen. If so, a fairly large percentage would be positive for amyloid and therefore diagnosed with Alzheimer’s.
A 2015 Dutch study estimated that more than 10 percent of cognitively normal 50-year-olds would test positive, as would nearly 16 percent of 60-year-olds and 23 percent of 70-year-olds. Most of these people will never develop dementia.
However, several experts and stakeholders are not convinced by the argument to turn to biomarkers alone. The American Geriatrics Society called the proposed criteria “premature” — and noted the high percentage of panel members with ties to the pharmaceutical and biotech industries, creating potential conflicts of interest.
“That’s jumping the gun by at least five to 10 years,” said Dr. Eric Wintera, a geriatrician at the University of California, San Francisco, and author of a sharply critical article in The Journal of the American Geriatrics Society.
Some background: The panel took on the effort only five years after the last diagnostic guidelines were issued because “two big events really called for a revision,” Dr. Jack said.
First, the best of the amyloid blood tests have been shown to be highly accurate, less invasive than spinal taps, and far less expensive than brain scans. In addition, aducanumab (brand name: Aduhelm) and lecanemab (Leqembi), two drugs that remove amyloid from the brain, received regulatory approval, although not without intense controversy.
Studies showed that the drugs had a modest but statistically significant ability to slow the progression of symptoms over 18 months in people with mild cognitive impairment or mild Alzheimer’s disease. (Drug company Biogen is withdrawing aducanumab, but other amyloid-reducing drugs are in the works.)
Are these advances enough to justify the possibility of diagnosing healthy people with irreversible disease based on a blood test that detects amyloid? Some doctors are already making such requests.
Diagnosing Alzheimer’s before symptoms appear could allow yet-to-be-developed treatments to prevent the memory loss, impaired judgment and eventual dependence that the disease causes. Doctors diagnose many diseases, including diabetes and cancer, by testing asymptomatic people.
But how many of those with amyloid in the brain (most of whom will also have tau deposits) will eventually develop dementia? “The answer, unfortunately, is that it depends,” Dr. Jack said.
The Mayo Clinic Study of Aging followed nearly 5,000 cognitively normal older adults in one Minnesota county for an average of 9.4 years. He found high rates of dementia among those who carried the APOE4 gene, which is associated with an increased risk of Alzheimer’s.
For those who were 65 and had high levels of amyloid, the estimated lifetime risk of dementia reached 74 percent for women and 62 percent for men.
But only 15 to 25 percent of people carry this gene, according to the National Institute on Aging. Among participants who did not, both men and women at 65 had an estimated lifetime dementia risk of about 55 percent with high amyloid levels and 36 percent with moderate levels.
“Because death rates are high in the elderly, many will die before developing dementia,” Dr Jack said.
Dr. Jason Karlawish, a geriatrician and co-director of the Penn Memory Center in Philadelphia, said he considers amyloid “a risk factor, the way smoking is a risk factor for cancer.
“But I think the evidence is still not clear and convincing that amyloid alone defines Alzheimer’s disease.”
Two major studies of amyloid-reducing drugs in cognitively normal humans, expected to be completed in 2027 and 2029, may provide such evidence if they are able to demonstrate that amyloid removal prevents, halts or reverses cognitive decline in this population. age group.
For now, the proposed guidelines “simply aren’t ready for clinical practice,” Dr. Karlawish said.
As for the task force, about a third of its 22 members are employed by companies developing drugs and diagnostics, their disclosures show. About another third disclose research grants or contracts, consulting fees, honoraria, or other payments from industry sources.
“They will benefit directly from this change,” said Dr. Widera. He pointed to estimates that 40 million cognitively normal Americans could test positive for amyloid, be diagnosed with Alzheimer’s disease, and possibly start off-label drug regimens, even though there is no evidence to date that the drugs are effective in asymptomatic people.
“These are not benign drugs,” Dr. Widera added. “You’ll be taking these drugs for the rest of your life — like a statin, but much more expensive and much more dangerous.” Aducanumab and lecanemab can cause brain bleeding and shrink the brain volume, side effects that are not uncommon.
Dr. Widera further criticized the task force’s proposal for not discussing the harms of the new criteria — including needlessly scaring people unlikely to develop dementia and potentially causing employment and insurance discrimination.
Dr. Jack, who has no reported conflicts of interest, defended his work group. “Members are committed to accurately reflecting what current science says,” he said. “Commercial profit was not taken into account. Everyone was focused on what was best for the patients.”
Numerous studies have found, however, that industry payments and sponsorships, even for cheap meals, have a measurable influence. They are associated with doctors being more likely to prescribe promoted drugs and with more favorable research outcomes when manufacturers sponsor studies of drugs and medical devices.
Many patient advocacy groups, including the Alzheimer’s Association, also have ties to the industry.
Often, redefining diseases or revising guidelines means lowering thresholds and expanding classifications, sometimes called “diagnosis creep.” The thresholds for high blood pressure and high cholesterol are lower now than in years past, for example. New precursor conditions such as pre-diabetes are also expanding the number of people defined as having the disease.
Based on the amyloid test, “there will be a new pandemic of Alzheimer’s disease,” Dr. Widera predicted. “There will be a big push for early detection.”
Part of that push may come from the patients themselves. “We live in an information age where people are interested in learning more about their current and future health,” said Dr. Gil Rabinovici, a neurologist who directs the Alzheimer’s Disease Research Center at the University of California, San Francisco.
An early diagnosis of Alzheimer’s disease can prompt lifestyle changes — quitting smoking, exercising, improving diet — that could still have a “protective effect,” he said.
“I personally wouldn’t choose to find out if I had plaques in my brain,” he added. And he wouldn’t prescribe amyloid drugs to asymptomatic patients, he said, until further research showed efficacy in that cohort.
However, “we’ve graduated from the idea that the doctor determines who learns what,” he said, adding that after thorough counseling, “if I’m convinced I’m not going to harm them and I feel they understand the information I’m going to get, I’m not going to I refuse to offer them a trial.’
