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.

Mitral Valve Regurgitation

When I first flipped my lifestyle by joining the gym in December 2015, I began with the treadmill.  I was pretty aggressive, working my way quickly up to a speed of 4.2 MPH on an incline of 15 degrees.  It was challenging at first, but I got used to it.  More recently, I've noticed that I can't do that any more.  I usually start at 3.5 mph and 5 degrees, dropping to 3.0 mph after about 15 minutes -- when I begin to work up a good sweat.  I still go on for 55 minutes.

When I noticed that my stamina had gone down, I attributed it to the fact that I'm just older now.  I was 66 when I started, but I'm 73 now.  But is there more to the story?

In 2018 I saw a cardiologist about a heart murmur.  I had an echocardiogram to see what was going on. The radiologist report found my heart was sound overall, but noted, "Mild mitral regurgitation is present."  It all looked good enough, and I had no reason to go back and see the cardiologist again.

Fast forward to January 2023.  You will recall that I was hospitalized with sepsis, and they ran a lot of tests on me.  I still had that heart murmur, and they did another echocardiogram.  This one found more pronounced mitral valve regurgitation with prolapse, and they advised me to see a cardiologist when I was released.

So I saw a new cardiologist yesterday who discussed the mitral valve situation with me - a topic about which I knew very little.  He said there was no rush, but I will need to have that valve repaired or replaced (not sure which he said) sooner or later.  The problem is that the valve is leaking some blood from the left ventricle back into the left atrium.  This reduces the efficiency of the heart.  Loss of stamina is a symptom.

The doctor said that he had had the same condition.  He had his mitral valve replaced at a hospital in Spokane in 2015.  It was done by a robot, and I've watched a couple of YouTube videos about how the robot operates.  They don't break the sternum to get access to the heart anymore, they just send probes in by different methods.  A common result is to have a few dime-sized scars in the trunk where the probes went in.  They may repair the valve, or they may replace it.  Apparently it's not a permanent fix, and it must be repeated at 10-year intervals. 

Sustained aerobic exercise remains the strongest feature of The Dementia Toolkit.  I continue to be really happy with my memory and cognition as compared to 2015.  Hopefully we'll be able to address this, and my stamina will return.

Working on a new edition ... or a new book

We wrote earlier that recent tests indicate that I have normal pressure hydrocephalus, or NPH. NPH is sometimes misdiagnosed as Alzheimer's disease because of very similar impairment of memory and cognition, gait and balance problems, presentation in MRIs, and enlarged ventricles.  But it's also known for causing urinary incontinence.  Alzheimer's disease may show these things, but not urinary incontinence in the MCI stage.  NPH often appears alongside Alzheimer's disease in what's called mixed dementia. I've talked to several people who know about this stuff. Some think I likely have both, while others believe it's more likely that I only have NPH.

The Alzheimer's Association produced the 2023 edition of the Facts and Figures Report in March. I need to review it for you, but they devote a lot of ink to mixed dementia. Their bottom line is that most people dying with dementia are found on autopsy to have at least two different neurodegenerative diseases operating at the same time. So maybe NPH and Alzheimer's disease together.

But for my case, we just don't know. So I've been busy preparing a new edition of Beating the Dementia Monster that treats both diseases and describes uncertainty in my actual diagnosis. Or maybe it'll be a new book.  It will have to be a new book, if I find I need to change the title to say, "... How I stopped the advance of cognitive impairment from neurodegenerative disease," or "How I stopped the advance of cognitive impairment."  Won't be just a new edition if the title must change.

Regardless, applying the tools of The Dementia Toolkit made a huge difference in slowing and perhaps temporarily reversing the progress of my disease.  This points more to Alzheimer's disease than NPH.

I've made a lot of progress folding the NPH story into my narrative and something about the science there, but there's a lot unresolved in my mind. So it's hard to finish.  Stay tuned...

Is donanemab ready for prime time?

We've been writing about the promise of donanemab since 2021, although not so much lately.  Being a "mab," it's another monoclonal antibody that removes amyloid from the brain.  Like Aduhelm and Leqembi, it can cause "amyloid-related imaging abnormalities," or ARIA.  With ARIA come brain swelling and microhemorrhages - with occasional fatalities.  Nevertheless, these treatments are removing amyloid plaques from the brain and appear to be slowing the progress of Alzheimer's disease.  The jury is still out on their effectiveness, but signs are pointing in the right direction.

Today, Eli Lily announced completion of a major trial for donanemab showing that it may be the most effective of the "mabs" so far.  But again, there were two fatalities associated with the treatment and a third fatality that's not being blamed on it.  The trial lasted 18 months, and it involved 1,700 patients.  Eli Lily must get their results properly documented and submit them to the FDA.  They plan to apply to the FDA in June for approval of donanemab as a treatment for Alzheimer's disease.

When marketed, it will need a new proper name and a price tag.  Biogen is selling Leqembi for $26,500 per year, but Lilly has not announced either a price or a name for their new treatment.  We also don't know how long it will take the FDA to approve donanemab.