Is It Too Soon to Diagnose Alzheimer’s in People With No Symptoms?

That’s in large part because the medications that reduce levels of amyloid in the brain — Leqembi (lecanemab) and Kisunla (donanemab) — have only shown benefits in people with mild cognitive impairment (MCI) or mild-stage dementia, and their potential side effects can be serious. To date, “we have zero evidence … that treating people with just amyloid in their brain leads to any positive outcome,” says Eric Widera, M.D., professor of medicine and clinician-educator in geriatric medicine at the University of California, San Francisco (UCSF). Those studies, called AHEAD and TRAILBLAZER-ALZ 3, described below, are happening now.

Widera is a member of the International Working Group, or IWG, researchers from 17 countries who published a 2024 paper in JAMA Neurology cautioning against diagnosing people with Alzheimer’s disease based solely on biology without signs of dementia. The IWG and others warn that the availability of blood tests can cause undue worry for people who test positive without getting appropriate counseling on how to interpret the results.

“They’ll be confused because they’ll know they don’t have Alzheimer’s dementia … but they’ll start to notice every problem with their memory,” says Deborah Blacker, M.D., geriatric psychiatrist and epidemiologist at Massachusetts General Hospital. In reality, not every memory blip is cause for concern; some are due to inattentiveness (you lost your keys because you were distracted when you walked in the door), or lack of sleep or even certain medications.

Importantly, most people with amyloid in their brain make it through life free of dementia. Having tau in the brain increases risk, but not to 100 percent. In a 2018 computer modeling study that estimated probabilities of disease progression based on amyloid status and other factors such as age and national death rates, fewer than 1 in 4 cognitively normal 75-year-old women who test positive for amyloid go on to develop Alzheimer’s dementia during their lifetime. For men at the same age, that figure is 1 in 5. It’s been known for decades that many who die with normal cognition have “a head full of amyloid,” Blacker says. For a 75-year-old woman with both amyloid and tau in her brain, the lifetime risk of Alzheimer’s dementia is closer to 1 in 3.

“There’s a lot that needs to go wrong for something as important as cognition to fail,” adds Fanny Elahi, M.D., a neurologist-scientist at the Icahn School of Medicine at Mount Sinai in New York City. “We actually are very resilient.”

Test results may cause unnecessary alarm

When people hear “Alzheimer’s disease,” most imagine the dreadful condition that robs a person’s memory and thinking skills — not an abnormal test result. A blood test measures biology, Elahi says. “It doesn’t equate to dementia. It doesn’t mean [those testing positive] are ‘doomed.’ ” Still, the psychological impact of biomarker tests on people with no apparent impairment is murky. Some worry that disclosing test results may invite possible discrimination in employment, housing and insurance.

But since “we know there is biology that contributes to Alzheimer’s-related dementia,” she adds, a test tells someone they are at higher risk for dementia. What the test cannot measure is when someone might develop a life-altering disease — or whether they will at all.

While a positive test doesn’t signify Alzheimer’s-related dementia, “a negative test doesn’t mean you won’t develop a different neurodegenerative disorder,” Daniel Press, a cognitive neurologist at Beth Israel Deaconess Medical Center in Boston, wrote in an email. “I guess my main advice would be to talk it through with an expert before getting [a test].”

Some scientists liken the Alzheimer’s blood test to a PSA test, which detects a protein whose high levels could signal prostate cancer, yet often isn’t cause for alarm. Since many prostate tumors grow slowly, “more people die with prostate cancer than from it,” Blacker says.

Similarly, Elahi perceives the buildup of amyloid — as well as tau — as a lifelong continuum. “Everyone who lives is on that continuum,” she says. The big unknown is how long it will take these proteins to reach a tipping point and trigger dementia. For one person it could happen when they’re 50 years old, for another at age 90, and for another never, Elahi says.

A major benefit of identifying people at early stages of disease is that this is when they’re most likely to respond to treatments being tested in clinical research studies — and while there’s still time to make lifestyle changes.

There is accumulating research suggesting that everyday actions — such as ongoing exercise, healthy eating and managing stress — can reduce a person’s risk of dementia.

If a test result will move a person to change their lifestyle, there’s benefit, Elahi says. But if it causes someone to become depressed and lose hope, that’s not helpful. The psychological impacts are important. As is how the test results are used. “This, I think, is true for every diagnostic test that has ever become available. Interpretation … and communication of what that result means is everything,” she says.

The AHEAD study aims to address the question of whether the disease-slowing drug Leqembi might work for people with no symptoms. The National Institutes of Health and Eisai, one of the drug’s developers, are funding the research. Enrollment closed in September 2024, with more than 1,600 people ages 55 to 80, who are amyloid-positive but show no signs of cognitive decline, randomly assigned to receive infusions of either Leqembi or a placebo once every two to four weeks for four years. Results are expected by late 2028 or early 2029. A similar study, TRAILBLAZER-ALZ 3, is testing Kisunla in people with “preclinical Alzheimer’s,” described as no cognitive decline but signs of amyloid and tau in their brain.