Mayo racing to define what is, and isn’t, Alzheimer’s in hope of better treatments

Dr. David Jones was showing pictures of famous people to a patient as a standard cognitive test a few years ago when he stumped an elderly woman with an image of someone notoriously recognizable: Osama Bin Laden.

Turns out, the memory blackout went deeper. The woman could describe recent activities and historical events, but had no recall of 9/11 — not the mastermind behind it, the buildings destroyed or the airplanes that destroyed them.

The loss of such an intense, specific memory suggested something different at work to Jones, a neurologist, than Alzheimer’s disease which commonly causes memory loss and dementia in other patients.

And it led Jones and colleagues at Mayo Clinic in Rochester down a path that culminated late last month with a major discovery: a condition known as LANS that not only is distinct from Alzheimer’s, but offers a better prognosis than the dreaded, incurable disease.

“Until now, there has not been a specific medical diagnosis to point to, but now we can offer them some answers,” Jones said.

The discovery comes at a pivotal time. Recent studies found that as many as 25% of people diagnosed with Alzheimer’s actually had other conditions that were causing their dementia. But the misdiagnosis didn’t matter much because it didn’t change their limited treatment options.

The advent of new anti-Alzheimer’s drugs has changed that calculus and created the need for more precision. The treatments come with high costs and side-effect risks and should be reserved for patients who stand to benefit.

Diagnostic accuracy has improved in recent years with the use of brain scans and spinal fluid tests to see if patients have proteins that are biomarkers of Alzheimer’s. New blood tests for these biomarkers could make that diagnosis even easier and faster, and allow primary care doctors to make those judgments without the need for neurologists or other specialists.

But Jones said it won’t be good enough to simply rule out Alzheimer’s and tell people their dementia is caused by something else.

“They want to know, well, what is it?” he said. “What do I do about it? What are the genetic implications? What’s the future going to look like for me?”

The aging of the American population will only increase the pressure to provide answers.

Alzheimer’s afflicts 6.9 million Americans and accounts for at least 60% of the U.S. cases of dementia — an umbrella term for a variety of cognitive problems that can range from memory loss to disrupted thoughts to emotional disturbances. With more people living into their 80s, the Alzheimer’s Association estimates that the degenerative disease will afflict 12.7 million Americans by 2050.

It is unclear how many people have LANS, which is short for Limbic-predominant Amnestic Neurodegenerative Syndrome and refers to a disease of the limbic system that sits in the center of the brain and regulates certain emotions, memories, behaviors and motivations. Jones and colleagues figured out how to identify LANS by reviewing imaging scans and specimen samples from 218 people who died after being diagnosed with Alzheimer’s or a related condition.

LANS is distinct in its impact on semantic memory, blocking out very defined and precise events like 9/11, and appears to target older seniors. LANS inflicts no damage on the neocortex, the outer section of the brain, which was the smoking gun that allowed Mayo researchers to distinguish it.

Patients with Alzheimer’s by comparison have plaques and tangles in the neocortex that gum up the pathways by which the brain’s thinking cells, or neurons, communicate. New antibody infusions such as Lecanemab remove the excess of amyloid beta proteins that cause these harmful deposits in the brains of Alzheimer’s patients. But it appears the treatment would have no impact on LANS.

The distinction between the diseases won’t matter right now to primary care doctors, who at this point conduct basic cognitive tests to check for initial signs of dementia and order tests to identify other treatable causes such as vitamin deficiencies, infections or cardiovascular problems, said Terry Barclay, clinical director of neuropsychology for the HealthPartners Center for Memory and Aging in St. Paul.

Those doctors often turn to occupational therapists to conduct more detailed cognitive tests, and then to neurologists to conduct brain scans and other tests to diagnose Alzheimer’s.

Specialists will quickly update their practices to search for these “Alzheimer’s doppelgangers” in their patients, Barclay said: “It’s so important to identify these other conditions, because they have different underlying mechanisms.”

Mayo also recently collaborated with researchers at the University of Pennsylvania to identify a condition known by the acronym LATE. Brain scans showed that it caused dementia through an excess of another protein, TDP-43, that wasn’t always present in patients with Alzheimer’s.

Both LATE and LANS are so new that there hasn’t been time to tailor treatments. But that will happen now that their symptoms and physical characteristics have been discovered, said Dr. David Wolk, the co-director of the Penn Memory Center who led much of the research.

”If we don’t know how to define them, we cannot study them,” he said.

Jones said he has been working to eliminate a sense of “nihilism” in his profession that came from years of diagnosing patients without being able to offer any better treatments for their specific causes of dementia. He led a training session in Chicago this summer for neurologists who needed continuing education to maintain their licenses, and challenged them to identify the percentage of patients at risk for a misdiagnosis of Alzheimer’s that would merit extra brain scans and tests to get it right.

Jones said he recognizes that he has certain advantages at Mayo, which by its nature draws patients from across the world who are seeking answers and diagnoses that they didn’t get from their local doctors. He is hopeful that artificial intelligence can help other clinics increase their diagnostic activities by scanning patients’ records and test results and flagging those at greatest risk for cognitive problems.

Both Mayo and HealthPartners are studying the use of this technology in dementia screening.

Many patients aren’t going to end up with a simple either/or diagnosis of Alzheimer’s, said Joseph Gaugler, director for the Center for Healthy Aging and Innovation at the University of Minnesota School of Public Health. Autopsies have found that many patients had multiple causes of dementia, he said, and that was before many of these newer causes were discovered.

Gaugler urged doctors to improve their diagnoses, because patients and families are comforted when they know exactly what is causing dementia and can set more realistic expectations for their futures.

“It is important to many families to know what the cause is,” he said. “It can help them prepare.”