Determining whether someone has Alzheimer’s disease usually requires an extended diagnostic process. The doctor takes the patient’s medical history, discusses symptoms, administers verbal and visual cognitive tests.
The patient may undergo a PET scan, an MRI or a 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.
All that could change dramatically if new standards proposed by a working group at the Alzheimer’s Association are widely adopted.
Its final recommendations, expected later this year, will accelerate the shift that has already taken place: from defining disease through symptoms and behavior to defining it biologically — with biomarkers, substances in the body indicating disease.
The draft guidelines, Revised Criteria for the Diagnosis and Staging of Alzheimer’s Disease, call for a simpler approach. That may mean a blood test to indicate the presence of amyloid. Such tests are now available in some clinics and doctors’ offices.
“A person with biomarker evidence of amyloid in the brain has the disease, whether they are symptomatic or not,” said Dr. Clifford R. Jack Jr., the chair of the working group and an Alzheimer’s researcher at the Mayo Clinic.
“The pathology exists for years before the onset of symptoms,” he added. “That’s science. Can’t be beat.”
He and his colleagues on the panel did not recommend testing people without symptoms of cognitive decline. But skeptics predict that will likely happen. If so, a large proportion will be positive for amyloid and therefore diagnosed with Alzheimer’s.
A 2015 Dutch study it is estimated that more than 10 percent of cognitively normal 50-year-olds will be positive, as will about 16 percent of 60-year-olds and 23 percent of 70-year-olds. Most of those individuals will never develop dementia.
A number of experts and interested parties remain unconvinced by the argument for unifying biomarkers, however. The American Geriatrics Society has called the proposed standard “premature” — and noted a high proportion of panel members with ties to the pharmaceutical and biotechnology industries, creating potential conflicts of interest.
“It’s jumping the gun for at least five to 10 years,” says Dr. Eric Widera, a geriatrician at the University of California, San Francisco, and the author of a critical review. editorial in The Journal of the American Geriatrics Society.
Some background: The panel undertook the effort just five years after the release of the final guidelines for the diagnosis, because “two major events really mandated revision,” said Dr. Jack.
First, the best of the amyloid blood tests have proven to be highly accurate, less invasive than spinal taps and less expensive than brain scans. In addition, aducanumab (brand name: Aduhelm) and lecanemab (Leqembi), two drugs that remove amyloid from the brain, have received regulatory approval, although not without intense controversy.
Studies have shown that the drugs have a modest but statistically significant ability to slow the progression of symptoms over 18 months in those with mild cognitive impairment or mild Alzheimer’s disease. (Drugmaker Biogen is withdrawing aducanumab, but other amyloid-lowering drugs are in the pipeline.)
Are those 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 can allow further treatment to prevent the memory loss, impaired judgment and eventually hopelessness caused by the disease. Doctors diagnose many diseases, including diabetes and cancer, with tests in asymptomatic people.
But how many of those with amyloid in the brain (most of whom will also have tau deposits) eventually develop dementia? “The answer, unfortunately, depends,” said Dr. Jack.
The Mayo Clinic Study of Aging followed nearly 5,000 cognitively normal adults in a Minnesota county for an average of 9.4 years. It found a high rate of dementia among those who carried the APOE4 gene, which is associated with an increased risk of Alzheimer’s.
For people age 65 and with high levels of amyloid, the estimated lifetime risk of dementia is as high as 74 percent for women and 62 percent for men.
But only 15 to 25 percent of people carry that gene, according to the National Institute on Aging. Among participants who did not, both men and women at 65 had an estimated lifetime risk of dementia of about 55 percent with high levels of amyloid and 36 percent with moderate levels.
“Because death rates are high in older people, many will die before they develop dementia,” said Dr. Jack.
said Dr. Jason Karlawish, a geriatrician and co-director of the Penn Memory Center in Philadelphia, that he considers amyloid “a risk factor, in the way that smoking is a risk factor for cancer.
“But I think the evidence remains inconclusive and convincing that amyloid alone determines Alzheimer’s disease.”
Two major studies of amyloid-lowering drugs in cognitively normal people, expected to be completed in 2027 and 2029, may provide such evidence if they are able to show that amyloid removal is inhibited, arrests or reverses cognitive decline in that age group.
So far, the proposed guidelines are “not ready for clinical practice,” said Dr. Karlawish.
As for the the working group, about one-third of the 22 members work at companies that develop drugs and diagnostics, their disclosures show. Almost another third disclosed research grants or contracts, consulting fees, honorariums or other payments from industry sources.
“They will directly benefit 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 an off-label drug regimen, despite no evidence to date that the drugs are effective in people without symptoms.
“These are not benign drugs,” added Dr. Widera. “These drugs are for life — like statins, but more expensive and more dangerous.” Aducanumab and lecanemab can cause brain bleeding and shrink the brain, side effects that are uncommon.
Criticized by Dr. Widera criticized the working group’s proposal for not addressing the harms of the new standard — including unnecessarily scaring people who are unlikely to develop dementia and potentially causing employment and insurance discrimination.
Dr. Jack, who has no reported conflict of interest, defended his working group. “Members are committed to accurately reflecting what current science says,” he said. “There is no consideration of commercial gain. Everyone is focused on what is best for patients.
Many studies have found, however, that industry payments and sponsorships, even with cheap food, has a measurable influence. They are related to being a doctor more likely to prescribe sponsored drugsand more favorable research results when manufacturers sponsor studies of drugs and medical devices.
many patient advocacy groupsincluding the Alzheimer’s Association, also has industry ties.
often, redefining diseases or changing guidelines means reducing limits and expanding classifications, sometimes called “diagnosis creep.” Thresholds for high blood pressure and high cholesterol are lower today than in years past, for example. New precursor conditions such as prediabetes are also expanding the number of people identified as having the disease.
With amyloid testing as a criterion, “there will be a new pandemic of Alzheimer’s disease,” predicts Dr. Widera. “There will be a big push for early detection.”
Some of that pushback may come from the patients themselves. “We are in an information age where people are interested in knowing 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 — smoking cessation, exercise, improving diet — that can still have a “protective effect,” he said.
“I personally would not choose to know if I have plaques in my brain,” he added. And he won’t prescribe amyloid drugs to asymptomatic patients, he said, until further research shows effectiveness in that group.
However, “we graduated from the notion 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 they’re doing . “I will, I will not refuse to offer them a trial.”
