regular-article-logo Thursday, 23 May 2024

Test before symptoms

How new test criteria might impact Alzheimer’s diagnosis and treatment

Paula Span Published 10.04.24, 07:19 AM

Determining whether someone has Alzheimer’s disease usually requires an extended diagnostic process. A doctor takes a patient’s medical history, discusses symptoms, and 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, which are associated with Alzheimer’s disease.


But all of that could change if new criteria proposed by an Alzheimer’s Association working group are widely adopted.

Its final recommendations, expected later this year, will accelerate a shift that is already underway: from defining the disease by symptoms and behaviour to defining it biologically — with biomarkers, substances in the body that indicate disease.

The draft guidelines, Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease, call for a simpler approach. That could mean a blood test to indicate the presence of amyloid, which are already available in some clinics and doctors’ 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, the chair of the working group and an Alzheimer’s researcher at the Mayo Clinic in the US.

“The pathology exists for years before symptoms set in,” he added. “That’s the science. It’s irrefutable.”

He and his colleagues on the panel do not recommend testing people who have no symptoms of cognitive decline. But sceptics predict that’s likely to happen nonetheless. If so, a sizable proportion would test positive for amyloid and would therefore be diagnosed with Alzheimer’s.

A2015 Dutch study estimated that more than 10 per cent of cognitively normal 50-year-olds would test positive, as would almost 16 per cent of 60-year-olds and 23 per cent of 70-year-olds. Most of those individuals would, however, never develop dementia.

A number of experts and interested parties remain unpersuaded by the argument for turning to biomarkers alone. The American Geriatrics Society has called the proposed criteria “premature” — and has noted the high proportion of panel members with ties to the pharmaceutical and biotechnology industries, creating potential conflicts of interest.

“This is jumping the gun by at least five to 10 years,” said Dr Eric Widera, a geriatrician at the University of California, San Francisco, US, and the author of a sharply critical editorial in The Journal of the American Geriatrics Society.

Diagnosing Alzheimer’s before symptoms emerge could allow yet-to-be-developed treatments to prevent the memory loss, diminished judgement and eventual dependence the disease causes. 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 are also likely to have tau deposits) will eventually develop dementia? “The answer, unfortunately, is 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. It 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 per cent for women and 62 per cent for men.

But only 15 per cent to 25 per cent of people carry that gene, according to the US National Institute on Aging. Among participants who did not, both men and women at 65 had an estimated lifetime dementia risk of about 55 per cent with high amyloid levels and 36 per cent with moderate levels.

“Because death rates are high in older people, many will die before they develop dementia,” Dr Jack said.

Dr Jason Karlawish, a geriatrician and a co-director of the Penn Memory Center in Philadelphia, US, said he considers amyloid “a risk factor, in the way smoking is a risk factor for cancer,” adding, “but I think the evidence remains not yet clear and convincing that amyloid alone defines Alzheimer’s”.

Two major studies of amy- loid-reducing drugs in cognitively normal people, expected to conclude in 2027 and 2029, might provide such evidence if they are able to demonstrate that removing amyloid prevents, arrests or reverses cognitive decline in that age group.

For now, however, the proposed guidelines “are just not ready for clinical practice”,
Dr Karlawish said.

As for the working group, about one-third of the 22 members are employed by companies developing drugs and diagnostics, their disclosures show. Roughly another one-third disclose research grants or contracts, consulting fees, honorariums or other payments from industry sources.

“They will directly benefit from this change,” Dr Widera said. “These are not benign drugs,” he added. “You’ll be on these drugs for the rest of your life — like a statin, but a lot more expensive and dangerous.”

Aducanumab and lecanemab — approved drugs that remove amyloid from the brain — can cause brain bleeds and shrink brain volume, side effects that are not uncommon.


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