In what could be viewed as an exciting but controversial period in Alzheimer’s disease drug development, those longing for a cure could be excused for being somewhat confused about the state of treatment.
The last decade has brought hopeful advances in medication, including approval of immunotherapy that could slow the rate of neurocognitive decline. But experts told the Deseret News that too few doctors are willing or well-trained to treat Alzheimer’s patients. And government-funded programs and many insurers won’t cover the cost of diagnostic tests or some promising treatments.
On Friday, the Food and Drug Administration declined to grant accelerated approval to donanemab; drug company Eli Lilly said it will seek traditional approval later this year. The FDA wants the clinical trial to proceed until 100 or more people use the drug for at least 12 months, but many, as planned, stopped taking the drug sooner because the study target — removal of beta-amyloid plaque that’s heavily implicated in Alzheimer’s formation — was reached quickly.
Two weeks ago, another amyloid-targeting drug, lecanemab, which manufacturers Eisai and Biogen will sell as Leqembi, won coveted accelerated approval. Despite this, Medicare will not yet pay for the drug because of an earlier ruling.
And the accelerated FDA approval in 2021 of Biogen’s aducanumab, sold as Aduhelm, recently drew harsh criticism. A congressional investigation cited “irregularities” in the approval process.
Meanwhile, more than 6 million Americans are coping with Alzheimer’s, a neurodegenerative brain disease that has long been deemed incurable and in some minds remains wholly untreatable.
That hope-crushing narrative simply isn’t true, experts told the Deseret News this week.
Several medications for Alzheimer’s disease have received FDA approval and are covered by insurers, but their benefits are modest and they don’t slow progression of the disease. Still, medications can help and the pace of new discoveries is speeding up.
Dr. Norman L. Foster, a neurologist and expert on Alzheimer’s clinical and imaging research, said even learning what doesn’t work is vital.
But the path to finding — and accessing — new Alzheimer’s treatments that act to slow the disease remains a rocky one.
Tangled signals
People with Alzheimer’s develop sticky clumps of the protein beta-amyloid in their brains between the nerve cells. As it builds up, it forms “plaques.”
Researchers found a couple of decades ago that a mouse-model version of Alzheimer’s disease could be treated by immunotherapy to remove those plaques from their brains, said Foster, an emeritus professor of neurology at the University of Utah. Removing beta-amyloid from the brain is the principle behind several of the drugs that have been or are being developed, including aducanumab, lecanemab and donanemab.
The plaque kicks off the process, but isn’t directly responsible for Alzheimer’s symptoms, Foster said. Tau tangles are. Amyloid accumulates outside the nerve cells and changes those cells’ environment so they develop neurofibrillary tangles inside the nerves, interfering with neuronal function. The belief is if you remove the plaque, you can prevent or slow development of the tangles.
The interplay of amyloid plaque and tau tangles has been confirmed by imaging and during microscopic examination of the brains of folks who died with Alzheimer’s. Foster said there is intriguing evidence from brain imaging that these newer medications, designed to attack amyloid, may also decrease tangles.
Plaque is detectable well before symptoms appear — even 10-15 years earlier — raising the possibility of Alzheimer’s dementia prevention. Those with symptoms have both plaques and tangles, creating a clinical diagnosis of Alzheimer’s disease. The fact amyloid accumulation does not itself cause cognitive problems “does not mean that removal of amyloid does not affect Alzheimer’s disease or does not affect cognition,” said Foster.
Aducanumab, lecanemab and donanemab remove the plaque, making it possible to slow development of tau tangles, though it won’t get rid of existing tangles or undo their damage. Those receiving the drugs aren’t expected to improve, just worsening to slow, so they are given only to those with mild symptoms. Early diagnosis and treatment is crucial.
The right diagnosis
There are 26 different dementia causes, and while 80% of those living with dementia have Alzheimer’s disease, not all do. Additionally, some have a combination of dementing illnesses, said Jeremy Cunningham, public policy director for the Utah Alzheimer’s Association.
Even if someone with Alzheimer’s has such a combination, treating the amyloid build-up might be important, which is why experts try hard to get people into research studies and get a proper — and accurate — diagnosis early, he said.
Cunningham laments there aren’t enough geriatricians or other skilled professionals treating the disease. Communities that have an Alzheimer’s research center are lucky, he said.
The correct diagnosis is crucial for a clinical trial to be meaningful. Foster said some trials may have shown little effect partly because the would-be Alzheimer’s treatment was being used on a high proportion of people who did not, in fact, have Alzheimer’s. “Relying solely on clinical opinions about a diagnosis is inadequate,” he said, noting that special scans that definitively show plaques and tangles on the brain are often not available outside of clinical trials.
“If you’re trying to find a treatment for Alzheimer’s disease, you have to treat Alzheimer’s disease and not just dementia syndrome,” Foster said. “One of the problems we have with the (older) approved cholinesterase inhibitors and why we have physicians and maybe the general community so unhappy with results is that they’re often given indiscriminately.”
As many as a third of people in earlier studies did not have evidence of Alzheimer’s pathology on amyloid Positron Emission Tomography (PET) scans, Foster said. Discovering that studies needed to be better targeted was a big step forward.
So was figuring out that “you need to have an antibody that removes amyloid plaque from the brain to have a benefit that impacts the disease.”
Four designer antibodies have been shown to do that, including the FDA-approved aducanumab and lecanemab. The latter, given as an infusion every two weeks, slowed cognitive decline by 27% over 18 months, winning FDA’s accelerated green light.
Gantenerumab, by Roche, removed some plaque but failed to show clinical improvement of symptoms. Roche ended its clinical trials, but is pursuing a similar drug.
Early studies of Donanemab, the one turned down for fast track but working toward approval, have been promising.
Treatment trials
Because immunotherapies like aducanumab and lecanemab change disease biology, “there are a number of different studies — phase 2 and 3 studies — that show it makes a difference in cognition and function,” Foster said.
He believes one fact is unassailable: “Alzheimer’s disease, often spoken of as untreatable, is a medically treatable, pharmacologically treatable condition.” But he adds there’s more to treatment than simply giving a drug.
You need the right diagnosis and treatment that matches. You need enough doctors who know how to treat a disease — and in the case of Alzheimer’s, they must be willing to deal with sometimes-difficult patients because of personality and neurocognitive change. Education and support for families, regular physical exercise and social activities are important parts of treatment. Treating other medical conditions and mood and sleep that worsen symptoms are also critical.
It doesn’t help, Foster said, that FDA labels don’t suggest when to treat patients with Alzheimer’s disease. And the new lecanemab instruction says to verify a person has the disease, but doesn’t specify how.
It gets even more complicated. Despite progress on the drug front, some — including Foster and Cunningham — say care for Alzheimer’s needs fundamental change.
Not willing to pay
CMS — the Centers for Medicare and Medicaid Services — and insurers who follow its lead have opted not to cover the cost of a diagnostic test for Alzheimer’s. They’ve also said no to paying for immunological treatment thus far, though lecanemab awaits a decision. Foster describes it as “kind of an interagency battle,” because the FDA approved aducanumab and lecanemab “in response to both need and evidence they make a difference,” but left it to CMS to decide how they would be used.
CMS could say, for instance, that it would pay for the treatment if a PET scan showed evidence of amyloid plaque. It hasn’t done that.
“CMS has, remarkably, been unwilling to provide physicians with sufficient guidance about how to do this — and they have been unwilling to provide diagnostics or treatments for Alzheimer’s disease,” said Foster.
Cunningham calls denial of coverage “unprecedented and troubling.”
“They haven’t really given a reason,” he said, noting CMS is being asked to revisit the decision.
The class of drugs is not so unique that the agency doesn’t know what to do — or so expensive that it won’t. Immunotherapy for multiple sclerosis is covered though it costs more than $50,000 a year. Lecanemab’s cost is expected to be in line with aducanumab, somewhere below $29,000 a year. The MS drug also had to show it changed the biomarker for MS that showed plaques on the brain, so there are striking similarities — except in what CMS is willing so far to do, Foster said.
Other barriers
Physicians and healthcare systems can also be roadblocks, Foster said, noting some have gotten comfortable saying there’s no reason to diagnose Alzheimer’s disease because nothing can be done about it.
“That’s false!” said Foster. “It’s not a person-oriented response. You should be asking, ‘What can I do for this patient in front of me?’ But if you decide you can’t diagnose and you can’t treat, you can wash your hands” of responsibility, he added.
That would be harder to do if Medicare and insurers paid for aducanumab or lecanemab treatment. Alzheimer’s immunotherapy appears so far to be a no-coverage carve-out. And some healthcare systems said they won’t give aducanumab.
“I’ve never heard of that before — never heard of a chemotherapy that healthcare systems decided as a policy they would not give. It’s unbelievable,” said Foster, who noted some question efficacy and others may be unwilling to build the infrastructure to provide such care.
Time lag is another challenge. When the plaques are removed from the brain, it takes time for any cognitive improvement. And cells with tangles and lost function don’t regenerate. So the best treatment or hope for prevention likely occurs early in the disease process.
But if you don’t have symptoms, it’s hard to show there’s improvement in clinical trials, Foster said.
Still, despite setbacks, drug manufacturers seem less likely to abandon the disease than they were even a few years ago. Foster said one drug that failed its clinical trial is being tested to see if the dose can be increased where it’s needed right by the plaques with fewer side effects. They’re trying to get the drug to cross the brain-blood barrier.
Getting help early
Several years ago, the FDA changed Alzheimer’s disease classifications. Stage 1 is brain pathology (plaques) without symptoms, while stage 2 is mild cognitive impairment due to that pathology. Stage 3 is mild Alzheimer’s disease dementia; stage 4 is moderate and stage 5 is severe.
The ability to find the amyloid plaques on the brain with a scan has made it easier to confirm and stage the disease. Such scans outside of clinical studies are hard to come by and very expensive.
Foster recommends getting a baseline neurocognitive evaluation in your 60s. Anyone with symptoms should seek evaluation regardless of age.
Despite the problems he sees, Foster is optimistic the medical community’s somewhat hands-off approach to Alzheimer’s will change. “I think the pressure will build up. As there’s more and more evidence, what has to happen probably is that the medical community has to be convinced about the effectiveness of treatment.”
He predicts a slow process.
Meanwhile, he said, the best way for people with Alzheimer’s to receive treatment is to enroll in a clinical trial. They can help move science forward and also access what seems promising. “The data is going to be very important, not just for approval but for marketing and other things,” he said.
That’s easier to do in some parts of the country, depending on who’s treating Alzheimer’s disease or researching promising drugs. Some places are what he calls a “dementia care desert.”
Participating in research lets people take some control of what their end-of-life issues look like, too, Cunningham said.
Raising voices
Cunningham describes Utah politicians as proactive on Alzheimer’s. “Our state is thankfully doing some wonderful things,” he said. “We have a state Alzheimer’s plan. We have a billing code for annual visits for that 5-minute test so doctors can be paid to do it. We have an Alzheimer's center at Utah State University and a geriatric clinic at the University of Utah.”
Like Foster, Cunningham thinks the future of medicine development will be bright, with researchers perhaps finding a combination of therapies to treat Alzheimer’s. Getting early diagnosis and care could mean a better prognosis, he said. It could allow more time to make plans and spend time with family, too.
“There’s no silver bullet and it’s not going to all be repaired. But if you are diagnosed early enough and slow the progression ... Think about where we were with HIV in the 1980s or cancer in the 1970s,” he said.
People can take steps to help themselves. Choices that are good for the heart are good for the brain. Controlling high blood pressure — keeping the systolic number under 135 — cuts risk drastically. Good dental hygiene and nutrition are important. So are keeping physically and mentally active and socially engaged. Sleep matters. Heart disease, high blood pressure, obesity, chronic pain and arthritis all offer risks.
“These are things any one of us can do,” said Cunningham.
There’s something else Cunningham thinks those concerned about Alzheimer’s should do: “We need their voices. We need people to go in and ask for a simple cognitive test during yearly physicals. We need more gerontologists,” he said.
“But just look how far we have advanced in the last five to 10 years. Part of that is good research funding — but also people willing to say, ‘I am going to face my fears and get involved in a clinical study. I’m going to be one of those individuals.’ People who are warriors.”