Possible dementia breakthrough drug may delay degeneration

Dr Mac Gardner explains how the recent discovery of a drug that can help in Alzheimer’s is a notable advance, but not the end of the story.

Dementia is a horrible word, and many people, especially older people, know why.

There are a number of diseases, chief among which being Alzheimer’s, that lead to a progressive loss in thinking and understanding, the hollowing out of a person’s self, and that mostly come on in older age.

Those who observe, rather than those actually affected, can, in a sense, suffer more knowingly.

An awful experience is to see a loved family member, a spouse or a parent gradually lose the essence of their being, to fail to recognise their family, to become cantankerous and eventually to decay away in a dementia facility, drooling and doubly incontinent, death providing a blessed release.

But in the early days, often before anyone has tumbled to the diagnosis, the effects can be minimal: what’s known as "mild cognitive impairment".

I have previously (9.3.23) written in these columns about the need for access to physician-assisted dying in the case of dementia, for those who have signed an advance directive and for whom death would be greatly preferable to life.

In that piece, I wrote " ... therapeutic prevention with medication, much less reversion to normality, is, as yet, no more attainable than the pot of gold at the end of the rainbow".

I need now to rewrite that bit.

The Journal of the American Medical Association doesn’t usually annotate an article as "breaking" news: but in the issue of 17.7.23, there was indeed a paper so headlined, accompanied by as many as four editorials.

This was an extraordinary piece of work, coming out of the United States but with multi-national collaboration, describing the effects of a drug called donanemab, which had been tested among 1736 patients with early symptomatic Alzheimer’s/mild cognitive impairment.

This was a very stringent piece of science, and in the jargon, a "randomised, double-blind, parallel, multicentre, placebo-controlled trial". Which is to say, we can put considerable faith in the validity of the findings.

This is what donanemab did.

Those with Alzheimer-related mild cognitive impairment, or should I say most of them, showed a degree of deceleration in their disease progress.

In other words, it is buying them time, precious time.

Not all benefited. The drug had the side effect, in some, of causing brain swelling, which could worsen disease.

And the outcome was dependent upon certain key factors: related firstly, to the nature of two important molecules that accumulate in the brain in Alzheimer’s, amyloid and tau; and secondly, according to a person’s particular combination of a gene called APOE.

And, of course, the question remains: is this as far as it will go? That is, is it buying time for a couple of years or so before the disease inexorably progresses? So is it not a cure, just a temporary relief?

Undoubtedly, these research groups will continue to follow up with the treated patients, to see how they go.

Let’s return to amyloid (more fully, beta-amyloid).

This is a protein that can build up in the brain, leading eventually to Alzheimer’s dementia, but starting many years, indeed decades, before overt symptoms arise.

The long list of previous failures in Alzheimer’s treatment mostly targeted amyloid, seeking to remove it from the brain with antibodies directed against it; this time, donanemab seems to have done the trick.

But then there’s also tau. This is a different protein that clogs up brain cells, and it is uncertain if tau accumulation follows amyloid or happens independently, in parallel.

So dealing with amyloid may still be leaving the field clear for tau to do its damage. And so donanemab might only offer a period of respite.

In order to understand the picture, the many collaborating clinics had access to PET scanning.

This was necessary in order to determine the true nature of the diagnosis, since PET scanning can demonstrate the presence of amyloid and tau.

Perhaps, in the fullness of time, when we have PET at our new hospital, we may be able to offer treatment to those showing possible signs of early Alzheimer’s, always assuming they can be identified in time.

As a neurologist who himself had that diagnosis wrote: "For people with more severe Alzheimer disease, the horses are out of the barn, but the earliest stage, probably even before there are significant cognitive impairments, looks like the sweet spot for management".

But in the meantime, the option of assisted dying for advanced dementia, when the horses are well and truly out of the barn, should surely remain.

 - University of Otago graduate Mac Gardner is a retired medical geneticist.