Another possible path to a cure ... or at least a better treatment

A couple of weeks ago several of you reached out to me with articles regarding a study of a possible new path to understanding of Alzheimer's disease.  I'm on the AMA's mailing list for new items of interest in the world of neurology, and I heard from them as well.  What was that all about?

In Beating the Dementia Monster, we discussed "young onset Alzheimer's disease" (or "familial Alzheimer's disease"), which begins to afflict people in their 50s or even younger.  Unlike the much more common "old onset Alzheimer's disease," it's far more driven by genetics, notably specific variants of three genes.  These are genes describing variants of the proteins presenilin-1, presenilin-2, and the amyloid precursor protein.  Like the genes for the APOE4 protein variant, they increase your risk for developing Alzheimer's disease.  But unlike the APOE4 gene, they almost always - but not quite always - guarantee that you will develop the disease.

There are three variants of the APOE gene that play in Alzheimer's susceptibility.  The common APOE1 gene appears to be neutral, the APOE4 gene promotes it, and the APOE3 gene seems to be protective.

There may only 300 families in the whole world that carry the bad variants of the preseniin-1, presenelin-2, and APP genes.  People carrying these genes form a rich study population, since the disease becomes so predictable, and people develop it before they develop other age-related co-comorbidities.  The comorbidities confuse the data and make people with the much more common "old onset" Alzheimer's disease (or "sporadic Alzheimer's disease") much harder to study.  People with the APOE4 gene variant are often the ones with old onset Alzheimer's disease, but that form of the disease is less commonly driven by genetics.  So for several decades, neurology researchers have been flocking to the South American nation of Columbia to study one particular family there that has been willing to subject themselves to the researchers.

The news has been driven by new findings from COLBOS (COLombia-BOSton), a collaborative project between the Universidad de Antioquia, Colombia and Massachusetts General Hospital, Boston.  What's interesting is the finding that, on autopsy, there were a few (one or two) people who carried the presenelin-1 gene but did not appear to develop dementia (unless it was driven by other causes).  These people seem to have been protected by the presence of the H3447R gene for the Reelin protein.

So what does the relatively rare H3447R Reelin protein do?  On autopsy, people with this gene variant had plenty of beta amyloid in their brains, but much less degenerated tau protein tangles.  (We discuss the role of beta amyloid and tau protein in Alzheimer's disease in Beating the Dementia Monster.) The going hypothesis is that the Reelin protein calms the activity in the brain that promotes the degeneration of tau protein that was causing cell death.  This may be a lead to finding a new approach to treating the disease.

It appears to me (and some researchers) that the removal of beta amyloid from the brain using monoclonal antibodies (like Aduhelm and Leqembi) is treating symptoms.  Yes, the beta amyloid is probably killing brain cells, but that may be a sideshow in the underlying disease, not part of its basic mechanism.  Stopping tau degeneration may, then, be getting closer to the actual disease mechanism itself.