It's pretty clear at this point that the latest class of Alzheimer's drugs — for all of the headlines, excitement and controversy it's caused — has limited effectiveness and potentially serious side effects, prompting researchers to look elsewhere.

Why it matters: The fact that we've found drugs with any effectiveness against Alzheimer's is a huge deal, but the hunt for the holy grail is still on.

• Eli Lilly's drug donanemab could soon become the third anti-amyloid monoclonal antibody — which targets a buildup of proteins in the brain thought to contribute to Alzheimer's — to receive some kind of FDA approval, all in the past three years.
• "Donanemab and related drugs caused a splash. But I think that now we're kind of moving on," said Keith Vossel, director of the Mary S. Easton Center for Alzheimer's Research and Care at UCLA.
• "The clinical uptake of these drugs has been slower than expected [because of] the moderate benefit that is offered, so that gives scientists more motivation to find news ways to slow the disease course."

Driving the news: An FDA advisory committee voted unanimously earlier this month in support of donanemab, concluding that its benefits outweigh its risks.

• The FDA had called for an outside review earlier this year after some patients enrolled in a clinical trial experienced brain swelling, bleeding and other adverse events.
• But Leqembi, the Alzheimer's drug from Biogen and Eisai approved a year ago, offers a somewhat cautionary tale: Many patients are still deciding that the drug isn't worth it, for one reason or another, as evidenced by its muted commercial success after launch. Sales have been picking up this year, however.

That's not to say that donanemab won't make a difference to some patients, as clinical trial data show it can slow cognitive decline by about a third.

• That may be enough to make Eli Lilly billions of dollars.
• But some scientists remain skeptical that the drug's effects, while measurable in clinical trials, will be noticeable to patients.

Where it stands: As of January, there were 127 drugs being assessed in 164 clinical trials against Alzheimer's, according to a study published in an Alzheimer's-focused journal. Three-quarters aim to modify the disease versus treat its symptoms, and a quarter were in Phase 3.

• Less than a fifth of total drugs under development — and 22% of those in Phase 3 trials — target amyloid.
• By comparison, a third of the drugs in late-stage trials target chemical messengers in the brain known as neurotransmitters.
• The drugs in Phase 3 trials target 10 categories of biological processes, and there are two Phase 3 trials looking at preventing the disease altogether (more on that below!).

The bottom line: "I think we're probably seeing something that is very close to the maximum benefit from an anti-amyloid therapy," said Matthew Schrag, a Vanderbilt neurology professor and director of the Cerebral Amyloid Angiopathy Clinic.

• "This is not the beginning. This is decades of development and many, many, many, many failed trials have led to something that is just barely detectable. And what we're learning is beta amyloid is just one component of a very complicated disease."

Amyloid isn't the hottest target in the Alzheimer's drug development pipeline, despite its series of approvals. It's been eclipsed in number by those targeting neurotransmitter receptors and inflammation or immunity.

• "Finally, we've transitioned to other pathways based on the biology of aging. So we have inflammation as a very prominent target in the disease," said Howard Fillit, co-founder and chief science officer at the Alzheimer's Drug Discovery Foundation.

Yes, but: The "vast majority" of investments are still going toward beta-amyloid, Vanderbilt's Schrag said, and many of the drugs targeting neurotransmitters are aiming to treat symptoms, not the underlying disease.

• One alternative target getting a lot of attention is tau, another protein that some scientists suspect may play a greater role than amyloid in cognitive decline.
• GLP-1s are also part of this conversation, and Novo Nordisk is currently running clinical trials testing semaglutide — the active ingredient in Ozempic and Wegovy — against early Alzheimer's.

The big picture: Alzheimer's is only one kind of dementia, and patients can have more than one kind at once or can be misdiagnosed. These patients will only partially benefit from drugs targeting the biological roots of Alzheimer's, or won't benefit at all.

• "If you have somebody who has Lewy bodies and Lewy body dementia in addition to Alzheimer's disease, then we're only treating part of the pathology," Fillit said.

Future amyloid-targeting therapies may also look different than today's, and not everyone agrees that the current crop has been milked for all it's worth.

• "I don't think we're at the end of the story with these monoclonal antibodies," the Alzheimer's Drug Discovery Foundation's Fillit said.
• The next iteration may be administered as injections and at home, similar to insulin or fertility drugs.
• Beyond that, the later generations of anti-amyloid drugs could be taken orally, Fillit said.

One of the questions presented to the FDA advisory committee earlier this month — which it ultimately didn't vote on — was whether tau levels should be used to limit which patients get Eli Lilly's donanemab.

• Patients with lower tau levels responded better to donanemab than those with higher levels in clinical trials, but Lilly argued patients benefited regardless of tau levels.
• Some researchers are still skeptical that the benefits of these drugs outweigh their risks, especially for patients who may be particularly vulnerable to side effects. But determining who those patients are is proving difficult.
• "I think we don't completely understand the population that's at risk," Schrag said.

On the other hand, there are currently trials underway testing anti-amyloid drugs as preventatives — which could multiply the eligible patient population if ultimately successful.

• The theory behind the trials is that treating amyloid before the onset of cognitive decline will delay dementia.

Between the lines: Taking anti-amyloid therapies in their current form as preventatives would likely be a nonstarter for most patients, although successful clinical trial results would be "a proof of concept and very valuable," Fillit said.

• "I think what's going to be really important is the willingness of people to take a medication that is an intravenous source every two weeks to a month with pretty high rates of side effects," UCLA's Vossel said. "The question is whether that would get adopted in clinical practice for prevention."
• The cumulative expense would also be enormous. But pills may be a different story, as they're cheaper and easier for patients to access.

Reality check: Any drug — whether a preventative or a treatment — that targets amyloid will probably have limited effectiveness if amyloid is only part of what causes Alzheimer's.

The big picture: "The model we're looking at for prevention is kind of like we look at heart disease," Fillit said.

• Lifestyle intervention is important, "but when people have high cholesterol, we add a statin," he added.