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Early Brain Changes Seen in Late-Onset Alzheimer's

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By Anette Breindl
Science Editor

At one level, a new study published today is hardly a surprise: it shows that the processing of amyloid precursor protein (APP) is one of the major pathways changed in individuals with Alzheimer's disease.

But because of how the work was done, it shows how that processing is altered in sporadic, late-onset Alzheimer's rather than the early onset inherited form of the disease – which may offer clues to how to target such cases. Late-onset disease accounts for most Alzheimer's cases, but comparatively little is known about how it starts, and progresses.

"We have a lot of tools for studying the rare familial variants," Asa Abeliovich told BioWorld Today. But "it's been a challenge to understand common, sporadic Alzheimer's disease" that actually accounts for most cases.

Abeliovich is at Columbia University and the senior author of the paper detailing the findings, which was published in the July 25, 2013, issue of Nature.

Aside from the fact that early onset and late-onset Alzheimer's disease may be different in critical ways, current research on Alzheimer's disease in humans has another frequent weakness – namely, that it looks at only the later stages of the disease.

"If you stick to just looking at brain tissue from people who died of Alzheimer's disease, it is extraordinarily difficult to find a smoking gun – because at that point, the disease has been going on for years . . . and most of these changes are due to the disease, rather than what initially caused the disease."

In their work, Abeliovich and his team reanalyzed existing data from postmortem brains of individuals who had not had Alzheimer's disease. Their goal was to compare gene expression patterns of those who would have been likely to develop Alzheimer's disease, versus those who would have been less so.

To divide their subjects into high- and low-risk groups they looked at which variant of the APOE4 gene they carried. The high risk form of APOE, APOE4, "stands out in all of biology and all of medicine," Abeliovich explained, because it is both frequent in the overall population – a quarter of all individuals has at least one high-risk copy – and because its effects are, compared to most risk variants, simply enormous. Having even one high-risk copy triples a person's chance of Alzheimer's disease, while two copies increase that chance tenfold.

In their work, the researchers first compared the gene expression signatures of APOE4 carriers with patients suffering from late-onset Alzheimer's disease. That analysis yielded a few hundred genes whose expression profiles were similar in the two groups.

The team next essentially put the genes in order, using computational techniques to determine which ones were the first to become Alzheimer's like in their expression in the high-risk subjects and set off the changes that culminate, years or decades later, in outright disease.

One scientific result confirmed what other studies have repeatedly shown: namely, that the misprocessing of amyloid precursor protein is a key event in the disease. (See BioWorld Today, July 12, 2012.)

That finding has not yet led to any successful drugs – indeed, it has led to more than a dozen failed trials, most recently of Eli Lilly and Co.'s LY2886721. (See BioWorld Today, June 19, 2013.)

But Abeliovich noted that his team's insights into the details of APP processing differ from earlier findings – and indeed, that they show different points of intervention in APP processing – because the results show how APP is processed by humans at high risk for late-onset Alzheimer's, not by animals genetically engineered to develop early onset disease.

Several of the genes identified by Abeliovich and his team had not been implicated as being related to APP processing, including one, SV2A that is targeted by the approved anti-epileptic drug Keppra (levetiracetam, UCB SA).

Abeliovich stressed that his team's approach is not in any way a guarantee of success, nor is it clear that earlier attempts to target APP have failed because they were based on flawed animal models.

"I would never say that that's why the trials failed -- there are many reasons why trials may not show efficacy," he said. "But we do hope that this will be different."