Should Alzheimer's be diagnosed without symptoms? Proposal to use blood tests causes excitement among scientists

Should Alzheimer's be diagnosed without symptoms? Proposal to use blood tests causes excitement among scientists

A controversy has arisen among researchers over the attempt Blood tests and brain scans to diagnose Alzheimer's disease instead of the cognitive tests that have been used for decades.

Proponents of this change argue that new biomarker tests can detect Alzheimer's at a very early stage — the best time to apply treatments to prevent the disease from returning. But critics point out that this well-intentioned initiative could lead to people being diagnosed on a single test even if they don't show symptoms of cognitive decline — and may never develop any.

"There is a risk that asymptomatic people will experience incomprehension and stress if we tell them they have Alzheimer's. But in most cases, nothing will happen in their lives," says Nicolas Villain, a neurologist at Sorbonne University in Paris, who wrote a paper published Nov. 1 in JAMA Neurology 1 wrote down and criticized the new diagnostic criteria.

Plaques and tangles

The brains of people with Alzheimer's have two key characteristics: Plaques of sticky amyloid-β proteins and tangles of tau proteins. The neurodegeneration associated with the development of these plaques and tangles is irreversible, which is why researchers are seeking treatments to help healthy people completely avert this damage.

In recent years, companies have started To market drugs that slow cognitive decline in Alzheimer's disease by removing amyloid from the brain, and scientists have highly accurate assays for both amyloid and tau proteins perfected.

"It is this combination of the possibility of widespread, clinically available accurate diagnosis with the possibility of doing something about the disease that led us to update the criteria," says Clifford Jack, a clinical Alzheimer's and dementia research specialist at the Mayo Clinic in Rochester, Minnesota, who co-led the effort to revise the diagnostic criteria. Jack and his colleagues on a working group at the Alzheimer's Association, a nonprofit research and advocacy group in Chicago, Illinois, released their guidelines in June 2 in the journal Alzheimer’s & Dementia.

The criteria state that a single abnormal result in a core set of biomarker-based tests is enough to diagnose Alzheimer's. These tests include Measurements of amyloid and tau protein levels in the blood or cerebrospinal fluid, as well as positron emission tomography (PET), which helps quantify amyloid plaques.

Devastating diagnosis

But Villain and his colleagues point out in their critique that a large proportion of people diagnosed this way would never develop cognitive symptoms: A 65-year-old man who is amyloid biomarker positive has a lifetime risk of about 22% for developing Alzheimer's dementia, which is only about 1.7 times higher than the risk for a similar person who is is amyloid biomarker negative.

Critics also argue that people who test positive for a single biomarker and are cognitively unimpaired should be informed that they are at risk for the disease but should not receive an official Alzheimer's diagnosis. A person without symptoms who either tests positive in multiple biomarker tests or has a gene variant that significantly increases the risk of developing Alzheimer's dementia, could be classified as a “presymptomatic” Alzheimer’s diagnosis, the critics write.

Jack acknowledges that biomarker testing makes it possible to diagnose asymptomatic individuals with the disease — but the guidelines state that biologically based diagnoses are intended to "support but not replace" clinical assessments. And the working group doesn't recommend Alzheimer's biomarker testing for healthy people, so a hypothetical positive diagnosis for someone without symptoms shouldn't happen, he says.

Still, the new criteria could expand eligibility for clinical trials that could help develop treatments for asymptomatic people, Jack said. “The reality is that every person who ultimately becomes demented due to Alzheimer's has been asymptomatic with the disease for a period of time,” he says. “In the future, medicine needs to focus on how to prevent the onset of symptoms, because by the time someone becomes symptomatic, extensive irreversible damage has already occurred.”

Nothing on the shelf

Currently, medications for biomarker-positive, asymptomatic individuals are lacking except in clinical trials, says Andrea Bozoki, a cognitive neurologist at the University of North Carolina School of Medicine at Chapel Hill who co-authored the JAMA Neurology review. This would leave such individuals with the psychological pain of having a diagnosis of a terminal illness but no treatment options, she says.

The new drugs that slow the cognitive decline caused by the disease, are approved in the United States only for people who already have mild cognitive impairment.

Bozoki fears the new criteria will encourage healthy people who fear they are at risk or who have a family history of the disease to see a doctor who will order a biomarker test for them. If they are diagnosed, she says, they could be prescribed the new Alzheimer's drugs. These have not been shown to be effective in asymptomatic groups, cost tens of thousands of dollars per year and carry the risk of cerebral hemorrhage and fatal seizures.

That will make it even more important that researchers and doctors ensure they properly communicate risks and uncertainties as Alzheimer's tests and drugs become more accessible, said Winston Chiong, a neurologist and ethicist at the University of California, San Francisco, who was not involved in any of the working groups.

1. Dubois, B. et al. JAMA Neurol. https://doi.org/10.1001/jamaneurol.2024.3770 (2024).

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2. Jack, C.R. et al. Alzheimer. Dementia. https://doi.org/10.1002/alz.13859 (2024).

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