I'm speaking in Florida, May 14

I've been invited by the good people at Tapestry Hospice to come speak to their staff about my experience with Alzheimer's disease.  This will be at their upcoming spring conference in Miramar Beach, Florida.  

Tapestry Hospice is headquartered in Calhoun Georgia.  They read Beating the Dementia Monster, and they watched this video of an earlier presentation that I made back before the dawn of the Age of Covid.  They are especially interested in the great difference that lifestyle changes can make in the progress of the disease.   

Except for one Zoom talk, this is the first chance I've had to speak since the covid restrictions began.  So Amy and I are really looking forward to it.  They have consented to allowing me to video the talk, and I hope to make it available after we get home.

Re-thinking beta amyloid -- again

A case of dementia can be called Alzheimer's disease when the presence of "sticky" amyloid plaques and neurofibrillary tangles is observed in the brain.  Forget the tangles for now, but the sticky amyloid molecules clump onto brain cells, apparently killing them.  This is the generally operational hypothesis, and it is the basis for the strategy of using monoclonal antibodies to remove the plaques from the brain.  It is the mode of operation for treatment with aducanumab, donanemab, and others.  

But we said in Beating the Dementia Monster that not everyone agrees on the actual role of the plaques in the disease.  What if the plaques are actually a form of protection for the cells?  Wouldn't that mean that removing them is a big mistake?

On April 14, Nature Immunology published research suggesting something like that.  The research involved removing certain genes from mice to manipulate which proteins are constructed in the brain.  Pretty much everything that happens with respect to metabolism in the brain is executed by proteins, and removing different proteins from the picture help explain what they were there to do in the first place.  

In Beating the Dementia Monster, we explained that microglia are cells that constitute the brain's immune system.  The brain has special needs with respect to immunity, so it gets its own system, isolated from the body's normal immune system.  The microglia then run the brain's immune system, and they appear to play a role in Alzheimer's disease.

By knocking out different genes in mice (and thus preventing their corresponding proteins from being constructed), the researchers found that certain proteins participate with microglia in compacting amyloid into plaques.  So maybe the amyloid is only sticky after being treated by the microglia.  Without this treatment, the amyloid molecules continue as wisps along blood vessels to some, so far unexplained, end.  One hypothesis is that the microglia are acting as trash compactors to gather and store the amyloid in a less toxic form.

(Recall our previous cautions that mice are not people, and what works with mice may not work with people.) 

If so, this is a true game-changer.  It would upend much of the direction of the search for an effective treatment for Alzheimer's disease, since so much focus has been on the importance of removing the plaques.  While the plaques may figure in killing the cells, we would first need to recognize their benevolent purpose.

We have developed several treatments that remove amyloid plaques from the brain, but their outcomes with respect to improved cognition have been disappointing.  There has been great pressure on the FDA to approve aducanumab as a treatment for Alzheimer's disease, but we discussed earlier that the FDA's advisory council has recommended that it not be approved, at least not yet.  Those promoting aducanumab have increased pressure on the FDA (for example), but the advisory council recently doubled down on their conclusion that the antibody's effectiveness has not been demonstrated.

You can find a more in-depth discussion here.

Cabbage, brussels sprouts, broccoli anyone?

The MIND diet we discussed last time has a warm spot for cruciferous vegetables, like kale, cauliflower, bok choy, and others.  They get their name from the cruciform shape of their flowers.  They are interesting to us, because a chemical called sulforaphane is produced when they are cooked.  What's so great about sulforaphane?  It just may be able to remove beta amyloid and aberrant tau protein from the Alzheimer's brain.  At least it seems to in mice.

We regularly encounter Alzheimer's research using mice with very promising results.  However, we've also emphasized that mice are not people, and enthusiasm over research results with mice often don't live up to their promise when the same tests are conducted with humans.

The mice used in research have their genetic code modified such that their brains produce the beta amyloid and tau proteins that appear in human patients with Alzheimer's disease.  We call these "transgenic mice."  Apparently as a consequence, the mice also experience cognitive decline.  We also find that removing the amyloid plaques and performing other activities that affect the presence of amyloids and tau proteins can influence their cognition.  We expect this in the case of Alzheimer's disease, but the mice do not actually get Alzheimer's disease.  Only humans get Alzheimer's disease.  So Alzheimer's research with mice is always suspect.

My friend Jim sent me two journal articles on research with mice and sulforaphane.  One was from the January 2018 issue of the Journal of Alzheimer's Disease, and the other was from the June 2018 issue of Molecular Nutrition and Food Research.  In both cases, treatment with sulforaphane was associated with clearing the abnormal amyloids and tau proteins.  The mice were transgenic to imitate Alzheimer's disease, but their cognition remained consistent with non-transgenic mice as they aged.

How did the sulforaphane pull this off?  Recall that the main thrust of the MIND diet is to control the twin apocalyptic horsemen of Alzheimer's disease, inflammation and oxidation.  And sulforaphane goes after both of them.  Which is probably why Dr. Martha Clare Morris's research found such a prominent place for broccoli and other cruciferous vegetables in the MIND diet.

So eat your vegetables.    

Whither the MIND Diet?

In Beating the Dementia Monster, we proclaimed the MIND diet to be the ultimate diet for brain health, and we blogged about it repeatedly.  However, we also said that the research jury was still out.  We went to press with the second edition of the book while covid-19 was hitting, and we repeated the existing claim that study results would be ready in April 2021.  I've been waiting eagerly ever since.

So it's now April 2021.  Where are the results?

I don't know if this was the original plan and I misunderstood what I read, but we now don't anticipate seeing results until June -- if then.  (I feel like a 5-year old on Christmas Eve, unable to get to sleep.  What's two months?)  Here is where the status of the research is tracked by the NIH,  You'll see that they mark April for "Estimated primary completion date" of the study, while June is the "Estimated study completion date."  

"Primary completion date" means "The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure."  Recall that most studies include both primary and secondary outcomes, primary being the outcome we're most interested in.  "Study completion date" means "The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit)."  So study completion date is about getting all of the data, but not necessarily having reduced it and interpreted it.

For this study, the primary outcomes relate to changes in cognition measured through neuropsychological testing.  The secondary outcomes relate to physiological changes in the brain observed through imaging.  The secondary outcomes are mainly total brain volume and hippocampal volume, but there are some other factors as well.

So will they report the results as soon as they've finished slicing and dicing the data?  Or will they keep it under wraps until some big conference that will give them a spotlight?  

Pretty much the biggest conference of the year is the Alzheimer's Association International Conference held each year in Amsterdam, and that will be in July.  Last year's conference was virtual due to covid, but they're planning a hybrid conference this year.  I attended last year and got a lot out of it.

A concern I have is whether covid disrupted the protocol and could bring the results into question.

When will we hear the actual results?  Will they be leaked ahead of the formal announcement?  We'll see.  I'm guessing the formal release will be at Amsterdam, but we'll know the results before hand.

Covid devastation

I've had a lot of stuff going on, and, until recently, there wasn't much to talk about.  Suddenly I have a whole load to talk about, but I'm having trouble getting to it.

Yesterday I was on a conference call with a committee organizing a conference on dementia, and someone working in an elder care facility remarked that all of the facilities have experienced a spike of families seeking admission for someone newly diagnosed with dementia.  This is a consequence of the pandemic and the extreme isolation that many seniors have experienced.  

As we discussed in Beating the Dementia Monster, social connection plays an important role in the onset and prevention of dementia.  A little less than a year ago, I wrote about a friend who had died in a memory care facility, and I attributed it the isolation brought on by covid precautions.  The increase in neurological issues among those isolated by the pandemic has caught the attention of researchers, and you can read some of what they are saying here. 

Donanemab's "mixed" results

On April 7, we wrote about recent research results with Eli Lilly's monoclonal antibody, donanemab.  In an article in the New England Journal of Medicine, researchers had characterized the results in terms of primary and secondary outcomes.  After 72 weeks, researchers were finding positive results on the primary outcomes, but the secondary outcomes were "mixed."  I did not have access to the actual article, only the abstract, and I wondered what was going on with the secondary outcomes.

So Dr. Freeman, who reviewed the manuscript of Beating the Dementia Monster for me, shared his paper copy of the NEJM with me, and I was able to read the article in its entirety.  (I didn't read the whole thing, just the important stuff.)  And so I found out about the mixed results in secondary outcomes.

The first thing that struck me in the secondary outcomes was that there was no improvement in hippocampus volume or volume of the ventricles when compared to the placebo.  The biomarkers used to diagnose my Alzheimer's disease were my shrinking hippocampus and my expanding ventricles.  (Expanding ventricles are a proxy for volume loss of the whole brain.)  Also there was no meaningful difference in tau protein loading with respect to placebo and non-placebo participants.  We discuss the significance of tau in Beating the Dementia Monster.  These results make me wonder to what extent donanemab is able to address the actual disease process.

The mini mental status exam (MMSE) was one of four other secondary outcomes based on cognitive testing.  You will recall that I was initially diagnosed with Alzheimer's disease based on my poor MMSE score.  The MMSE is a fairly simple test, but it is often considered sensitive enough to be used to measure changes in cognition in research.  Nevertheless, more comprehensive tests are considered more reliable.  As with the other three secondary test measures, subjects showed some improvement, but not as much as the primary outcome -- the iADRS score we discussed in the April 7 post. 

These results are relatively positive, and they seem to be mostly in keeping with Eli Lilly's expectations.  However, we should hope that further testing will find better cognitive improvement, as well as improvement in biomarkers.  

This was a phase 2 trial, which means it had a smaller number of subjects (257 patients, about 1/2 receiving the placebo).  It is likely to go to phase 3, which will have a broader base of participants.  It is not unusual to have different results in a later trial.

 

Biogen ... or Eli Lilly?

The news about Alzheimer's disease drug trials has been dominated by Biogen's monoclonal antibody, aducanumab.  But it's not the only show in town, as we discussed back in January.   There has been increasing anticipation regarding that other monoclonal antibody, donanemab, which has continued to show promise in clinical trials and may be more effective.  As we've discussed before, there is skepticism regarding the effectiveness of aducanumab, and the FDA won't say anything about approving it until summer.  

In March, the New England Journal of Medicine published this article regarding the status of the donanemab trials.  They are in the second of the three phases of the trial, and the team conducting the trial (called Trailblazer) is reporting positive early results.  They are very optimistic about the ability of the donanemab to remove amyloid plaques and they are meeting their primary objective.  The primary objective is "a change from baseline in the Integrated Alzheimer's Disease Rating Scale (iADRS) Score."  iADRS is a composite tool that combines scores from a couple of other rating scales.  It is said to demonstrate acceptable psychometric properties and to be effective in capturing both disease progression and separation of placebo and active drug effect.  

However, results for the secondary objectives were "mixed."  Secondary objectives consisted of results of other cognitive assessments (including the mini mental status exam we discuss in Beating the Dementia Monster), as well as reduction in amyloid plaques, reduction in tau protein loading, and change in brain volume.  It's not clear to me which of these has been "mixed."

They reported, "In patients with early Alzheimer’s disease, donanemab resulted in a better composite score for cognition and for the ability to perform activities of daily living than placebo at 76 weeks, although results for secondary outcomes were mixed.  Longer and larger trials are necessary to study the efficacy and safety of donanemab in Alzheimer’s disease."

Just like aducanumab, donanemab will not "cure" Alzheimer's disease.  It will, at best, slow its progress.  It's not a pill, but requires intravenous infusions every four weeks.  But slowing the progress of Alzheimer's disease could still give someone several more years of enjoyable living, and testing these treatments is helping us to further understand this incredibly complex disease.