Alzheimer’s disease: have we got the cause all wrong?

Studies with mice that mimic human Alzheimer’s disease have shown that memory loss occurs before plaques form in the brain. Other studies have suggested that it is the smaller fragments (“oligomers”) of beta-amyloid that are really toxic to nerve cells. And it has even been suggested that the formation of plaques is a way for the brain to round-up all these dangerous oligomers into one place for safety.

It’s very hard to tell without the full information from the aducanumab trial, but maybe the disease had progressed too far in the participants for the treatment to be effective. Perhaps the small beta-amyloid oligomers had already done their damage, setting the disease in motion before the participants were even recruited to the trial.

Alzheimer’s disease vs Alzheimer’s dementia

At a recent Alzheimer’s Research UK Conference, there was near universal agreement that it’s time to separate the concept of Alzheimer’s disease from the menace of dementia.

Alzheimer’s disease is defined as the build up of beta-amyloid plaques and tangles of another protein, tau, combined with some mild memory changes. Dementia is a symptom of this disease. Advances in brain imaging mean that doctors can now spot these indicators of Alzheimer’s disease much earlier (up to 25 years before dementia symptoms set in). An astonishingly under-reported fact is that progression to dementia is not a given. Not all people who show these clinical signs of Alzheimer’s disease will progress to dementia in their lifetimes.

We are only beginning to study the reasons that some people with Alzheimer’s disease avoid Alzheimer’s dementia. Age is the single biggest risk factor for this progression; the younger you are when beta-amyloid starts to build up in the brain, the more likely you are to suffer from dementia. Diet, education and head injuries may also play a role in this process, but to what extent we do not know.

Another major factor we are only just beginning to understand is genetics. Small variations in our genes seem to influence not only whether we will get a build up of beta-amyloid in the brain, but whether that accumulation leads to dementia symptoms.

The process of finding these so-called “risk genes”, however, is slow. Progress has mostly come from “big data” studies that track tiny changes in the two billion odd DNA bases of the human genome across tens of thousands of individuals and try to find patterns between these changes and rates of Alzheimer’s.

There are around 30 areas of the human genome that have been linked to the risk of developing Alzheimer’s dementia, although there are certainly more to be discovered.

Aducanumab: right treatment, wrong time?

As with treatments for many other human diseases, it might be that treatments such as aducanumab might only be effective if they are given early enough, before the disease has caused irreversible changes. A better understanding of the environmental and genetic factors behind Alzheimer’s disease combined with ever more sensitive brain imaging techniques will help doctors identify warning signs even earlier, before even minor memory loss occurs.

While screening and diagnosing people – before symptoms have set in – for an as-yet incurable disease, raises many ethical dilemmas, it might present a fresh window of opportunity to retest beta-amyloid drugs, such as aducanumab. Ultimately, we need to focus our research on understanding the early stages of the disease so that we can prevent Alzheimer’s disease before dementia takes hold.

Vicky Jones, Senior Lecturer in Cell Biology, University of Central Lancashire

This article is republished from The Conversation under a Creative Commons license. Read the original article.