A proposed new method in testing for and diagnosing Alzheimer’s disease has pitted physician against physician, researcher against researcher, and even has the Alzheimer’s Association and the American Geriatrics Society at odds. Allegations of undue influence and conflicts of interest are also in the swirl.

The trigger for it all are new criteria proposed by an Alzheimer’s Association (AA) working group that call for diagnosing Alzheimer’s on the basis of a simple blood test, including even when the subject for the test shows no obvious symptoms of Alzheimer’s or similar cognitive loss. Formal adoption of the criteria is expected sometime in 2024.

Key arguments made in favor of such testing are:

1) the working theory that the earlier the disease is detected, the better are the chances its progression can be slowed

2) the emergence — and in some cases the Food & Drug Administration’s approval — of drugs that appear capable of slowing disease progression, at least temporarily, when it is diagnosed in its earlier stages and

3) the fact that a blood test is far simpler, less invasive, and less expensive than diagnostic processes that exist today, which usually involve a doctor taking a medical history, discussing symptoms, administering verbal and visual cognitive tests, and perhaps having the patient undergo a PET scan, an MRI, or a spinal tap.

Blood Test Looks for “Biomarkers”

Those tests (PET, MRI, tap) are designed to detect the presence of two proteins in the brain, amyloid plaques and tau tangles, that are both associated with Alzheimer’s. These are often referred to as “biomarkers.” The new vigorously debated proposal would use the blood test to look for the presence of these biomarkers in a more streamlined and more affordable way. Such tests are reportedly already available in some clinics and physicians’ offices.

“Someone who has biomarker evidence of amyloid in the brain has the disease, whether they’re symptomatic or not,” said Dr. Clifford R. Jack, Jr., as quoted by The New York Times (NYT). He is the chair of the AA working group and an Alzheimer’s researcher at the Mayo Clinic. “The pathology exists for years before symptom onset,” he added. “That’s the science. It’s irrefutable.”

Others say, essentially, not so fast. Because there are other serious considerations to take into account.

Those with Normal Cognition May Be Termed “Positive” for Alzheimer’s In New Test

When the Los Angeles Times (LAT) reported on the controversy, the paper said that under the AA proposal, tens of millions of Americans with normal cognition would test positive for abnormal levels of amyloid or tau, the two proteins the tests look for, but studies suggest the majority of them may never be diagnosed with dementia. “A 60-year-old man who tests positive, for example, is estimated to have a 23% risk of developing dementia in his lifetime,” the LAT stated.

According to news accounts, under the AA proposal, people with no memory problems who test positive for abnormal levels of amyloid or tau proteins would be classified as Stage 1 Alzheimer’s. They would move to Stage 2 if they begin to experience difficulties such as depression, anxiety, or apathy (symptoms that can be unrelated to Alzheimer’s) even if the patient’s cognition is unchanged. Stage 3 would be for those with mild cognitive impairment, while Stages 4 through 6 would describe patients with mild, moderate, or severe dementia.

The LA Times quoted Dr. Andrea Bozoki, a University of North Carolina neurologist, as saying, “I’m troubled by this. You are taking a bunch of people who may never develop dementia or even cognitive impairment and you’re calling them Stage 1. That doesn’t seem to fit.”

The New York Times similarly pointed to a 2015 Dutch study which estimated that more than 10 percent of cognitively normal 50-year-olds would test positive, as would almost 16 percent of 60-year-olds and 23 percent of 70-year-olds. But most of those individuals would never develop dementia.

American Geriatrics Society Calls Proposal Premature

The American Geriatrics Society has reportedly called the AA proposed criteria “premature.” The NYT quoted Dr. Eric Widera, a geriatrician at the University of California, San Francisco, as saying, “This is jumping the gun by at least five to 10 years.” Dr. Widera sharply criticized the proposal in an editorial in The Journal of the American Geriatrics Society. He also chided the AA working group for not adequately discussing possible harms of using the new testing criteria. Harms that he said include needlessly terrifying people unlikely to develop dementia and potentially causing discrimination in employment and insurance if an Alzheimer’s “condition” is revealed even if it is not definitive.

The LAT quoted Dr. Madhav Thambisetty, a senior researcher at the National Institute of Aging, as saying, “I think this is untested, uncharted territory. I’m not at that stage where I would be able to make a diagnosis of Alzheimer’s disease in somebody who’s cognitively normal based on the presence of a single biomarker. This is an ethically gray area.”

Are there Discrimination Risks with the New Test?

He too noted the proposed plan does not address the serious bioethical concerns that come with testing healthy people for signs of Alzheimer’s. The LAT observed that studies have found that people with no memory problems who learn they are positive for abnormal levels of amyloid or tau proteins can suffer from depression, anxiety, and thoughts of suicide. And the paper agreed that a positive test can lead to discrimination by employers and by companies offering life, disability, and long-term care insurance.

“That risk is so real,” the LAT said, “that people with no memory complaints who volunteer for an ongoing clinical trial that requires an amyloid test are advised to consider getting any insurance they’ve been contemplating before taking the test.” Dr. Widera asked at one point: “If somebody tests positive for amyloid and they are an airplane pilot, do they have to disclose that to the airlines?”

The Costs and Side Effects of Alzheimer’s Drugs

There is also the matter of the financial toll and potential side effects of drugs designed to treat Alzheimer’s disease, especially if larger numbers of people seek them out when told the biomarkers showed up on their blood test. The FDA has required such drugs to carry warnings that they can cause potentially fatal bleeding or swelling in the brain. Thus far, drugs that have been used for Alzheimer’s have tallied in at a cost of roughly $26,000 per year.

“These are not benign drugs,” Dr. Widera was quoted as saying. “You’ll be on these drugs for the rest of your life — like a statin, but a lot more expensive and a lot more dangerous.” Two drugs — aducanumab (Aduhelm) and lecanemab (Leqembi) — have been shown to have potential to cause brain bleeds and change brain volume, side effects that showed up for some subjects in clinical trials. (Note: Drugmaker Biogen has announced it will stop marketing aducanumab, partly due to lackluster adoption of the drug by physicians. The hesitancy is said to be owed at least in part to lingering concerns about the effectiveness and safety of the drug. Biogen, in partnership with drugmaker Eisai, will continue to promote lecanemab.)

“Redefining” Alzheimer’s Disease

According to the LAT, while a study of lecanemab’s effects on asymptomatic people has begun, there is currently no evidence that giving it to people without cognitive impairment can reduce the risk of dementia or delay the onset of Alzheimer’s symptoms. Also, although it’s theorized that finding amyloid early and removing it might avoid irreversible brain damage, “so far researchers have failed to demonstrate that a build-up of amyloid causes dementia — or that removing it alleviates symptoms.”

“They are redefining what it means to have Alzheimer’s,” Dr. Widera went on to say. “You no longer need to have cognitive impairment to have this disease. You just need the positive blood test. That could lead doctors to prescribe the new drugs to people without memory problems.” He added that with amyloid testing as the criterion, “there will be a new pandemic of Alzheimer’s disease. There will be a big push for early detection.”

AA Says Early Detection of Alzheimer’s Is Key Driver for Blood Testing

In further support for what the AA is pursuing with blood testing, the Association noted that a plan to create a new class of “symptom-free” Alzheimer’s patients actually began to form more than a decade ago and was included in proposals to update diagnostic criteria for the disease in 2011 and 2018. Among the reasons for doing so was that diagnosing Alzheimer’s before symptoms appear could allow yet-to-be-developed treatments to emerge to prevent the memory loss, diminished judgment, and eventual dependence the disease causes. This is analogous to how doctors diagnose many diseases, including diabetes and cancer, with tests in asymptomatic people.

And there remains the conviction, borne out by some clinical evidence, that the earlier Alzheimer’s can be treated, the more effective that treatment can be. The AA’s Marie Carrillo emphasizes that, “In order to prevent dementia, we need to detect and treat the disease before symptoms appear. The purpose of this initiative is to advance the science of early detection and treatment.”

Neurologist Sees Both Sides as Potentially Valid

The NYT article also quoted Dr. Gil Rabinovici, a neurologist who directs the Alzheimer’s Disease Research Center at the University of California, San Francisco, as stating that a push for pre-symptomatic testing may come from patients themselves. “We are in an information age where people are interested in knowing more about their current and future health,” he told the paper. And “an early diagnosis of Alzheimer’s disease might prompt lifestyle changes — quitting smoking, exercising, improving diet — that could still have ‘a protective effect.’”  

He added that he would not prescribe amyloid drugs to patients without symptoms until further research showed effectiveness in that patient group. But, he went on to note, people have bypassed the notion that only the doctor determines who can or should learn information about their health status and risks. So Dr. Rabinovici said that, along with extensive counseling, “If I’m convinced I’m not going to harm them and I feel they understand the information they’re going to get, I’m not going to decline to offer them a test” [meaning a blood test for Alzheimer’s biomarkers.]

Another geriatrician out of Philadelphia was quoted as saying he does consider amyloid a risk factor for Alzheimer’s “in the way smoking is a risk factor for cancer.” But he added, “I think the evidence remains not yet clear and convincing that amyloid alone defines Alzheimer’s disease.” And Dr. Jack, who was mentioned earlier and who leads the AA panel, has also been quoted thus: “Should you diagnose Alzheimer’s disease in asymptomatic persons? The answer is no.”