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Alzheimer’s researchers are (finally) shifting their focus away from amyloid plaques

Writer Kristina Fiore points out that the amyloid cascade hypothesis has so far “bombed” in clinical trials. Drugs meant to disrupt amyloid buildup have not improved cognition.

There has been a longstanding belief that the primary cause of Alzheimer’s disease is the accumulation of beta-amyloid, that clump together in the brain to form plaques.
National institute on Aging

Moving the behemoth of medical research in a new direction can take a long, long time.

Even after a considerable amount of good evidence suggests that an old idea needs to be seriously rethought — or dismissed — many in the scientific community tend to resist turning their focus elsewhere. Instead, they dig in their research heels in what is often a last-gasp attempt to prove the old theory correct.

That seems to be the case with the amyloid cascade hypothesis of Alzheimer’s disease. That’s the longstanding belief that the primary cause of this devastating brain disease is the accumulation of pieces of protein, called beta-amyloid, that clump together in the brain to form plaques. Those plaques then set off a series (cascade) of events that lead to the memory loss and other cognitive symptoms of Alzheimer’s. 

But there are (and have been for quite a while) big problems with that hypothesis — problems that are (finally) leading Alzheimer’s researchers to broaden their research focus.

A more complicated picture

Reporter Kristina Fiore describes this paradigm shift in a terrific series of articles published this week in MedPage Today. Here’s an excerpt: 

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Over the past 30 years, billions have been spent putting the amyloid hypothesis in Alzheimer’s disease to the test.

After several failed attempts at targeting pathways involved in the accumulation of this protein in the brain, researchers are acknowledging that there’s probably more to the Alzheimer’s picture — that it may be something else, or some other combination of factors, that causes the neurodegeneration that leads to the disease’s characteristic cognitive impairment.

“There is no question in 2015 that amyloid is not the ‘proximate’ cause of cognitive impairment,” David Knopman, MD, of the Mayo Clinic, told MedPage Today. “Instead, both by amyloid-dependent and amyloid-independent pathways, neurodegenerative changes such as synapse loss and neuronal death are the ‘proximate’ causes of cognitive impairment.”

“Therefore,” he continued, “exploration of therapeutic targets and therapeutic strategies directed against neurodegeneration should be an important component of the quest to treat Alzheimer’s disease.”

It’s not that amyloid has no role in Alzheimer’s. It’s clearly a culprit in genetic forms of the disease, and is present in the brains of the majority of patients with non-familial, or sporadic, forms. But that doesn’t mean it’s causative in all cases.

Some researchers — particularly those involved in the development of anti-amyloid drugs — continue to support expensive tests of therapies founded on the amyloid hypothesis. They suggest that if they target amyloid earlier, before symptoms appear or when they’re in extremely early stages, disease progression might be improved and prevention may even be possible.

Others are moving on to other pathways that don’t involve amyloid, including tau phosphorylation, lipid metabolism, and inflammation.

A broader set of factors

As Fiore points out, the amyloid cascade hypothesis has so far “bombed” in clinical trials. Drugs meant to disrupt the buildup of the amyloid have not improved cognition.

“Other factors that have thrown a curveball at the amyloid hypothesis include the finding that about 20% of patients who have certain biomarkers consistent with Alzheimer’s … don’t have evidence of amyloid plaques on brain scans,” Fiore writes. 

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“The converse is also true — a quarter to a third of patients have amyloid accumulation in their brains, but no symptoms at all,” she adds. “This has been termed ‘preclinical Alzheimer’s’ but the course of progression, if there is one, isn’t yet evident.”

A different strategy

In a video accompanying Fiore’s articles, Karl Herrup, a neuroscientist at the Hong Kong University of Science and Technology, argues that it’s time for researchers seeking treatments for Alzheimer’s to move on to targets other than beta-amyloid.

“In my opinion, the simple linear model that goes directly from amyloid to dementia has to be rejected,” he says. “And the reason is that it has been tested in the clinic and in mouse models and proven to be untrue. For example, if the hypothesis were true, you would think that if you took healthy people and put amyloid into their brains, they would get Alzheimer’s disease. And, in fact, the evidence suggests that they do not.”

Furthermore, doing the reverse — taking amyloid out of the brains of individuals with Alzheimer’s disease — has been shown to have no significant effect on the symptoms or progression of the disease, he adds.

“We need to stop using amyloid to define Alzheimer’s disease,” Herrup concludes. It plays a role in the disease, he says, “but so do lots of other things.”

“We need to look at all the cause of Alzheimer’s disease,” he adds, “if we’re going to make progress against this truly dementing illness.”

You’ll find Fiore’s articles on the MedPage Today website. You can watch Herrup speak — along with Dr. Rachelle Doody, a neurologist at Baylor College of Medicine, who believes that beta-amyloid should remain the main target of Alzheimer’s research — here.