Diversity in clinical trials needs work

On May 11, Rep. Lisa Blunt Rochester, Democrat of Delaware, introduced H.R.3035, "to amend the Public Health Service Act to improve the diversity of participants in research on Alzheimer's disease, and for other purposes."  The bill has 23 cosponsors, five Republican and 18 Democrats.  On introduction, the bill was promptly endorsed by the Alzheimer's Association.

I don't know if this is too blunt of an instrument, but initiative is required to improve the diversity of test subjects in Alzheimer's research.  It's well established that African Americans and Hispanics develop Alzheimer's disease at significantly higher rates that Americans of European ancestry, but test subjects in drug trials and other studies have been far too heavily weighted with people like me -- of European ancestry.

There are several reasons why it's important to improve the diversity of the pool of study participants.  The one most troubling to me is that different "flavors" of the disease manifest themselves differently in different populations.  For example, the gene most commonly identified as a risk factor for Alzheimer's disease is the APOE4 gene.  (We discussed this gene and its protein in Beating the Dementia Monster.)  That's an important factor for us of European ancestry where it's been studied, but it's not at all clear that the association is the same in minority populations ... or if the character of the disease is identical in different populations.  I did see one study (which I've lost track of) that found the APOE4 gene to be a significantly lesser factor in development of Alzheimer's disease among African Americans.

While Alzheimer's disease is more prevalent among African Americans, it's actually rare in the population of Nigeria.  But at the same time, Nigerians have the highest observed frequency of APOE4 in the world.  What's going on there?  And does it have any relevance to people of African ancestry living in Europe and the Americas?  This points to more weaknesses in our understanding of the disease, and it merits study focusing on how it manifests in diverse populations.  

So we should remember that the disease sometimes unfolds differently depending on how it appears to have begun.  Some studies associate development of Alzheimer's disease with poor lifestyle choices, especially when young -- poor diet, smoking, lack of exercise, etc.  Then, as we discussed in Beating the Dementia Monster, there are three genes primarily associated with development of young onset Alzheimer's disease and can be considered to cause it outright.  Some studies find distinct differences in how rapidly the disease advances and other characteristics that appear to hinge in part on which conditions appear to be involved in developing the disease in the first place.  My point here is that we have what I call flavors of the disease, and they work differently in different populations.

That the disease begins and unfolds differently in different populations underscores weaknesses in our understanding of the disease and we need more study.  More study means more minority participants. 

Consume stinky stuff to improve cognition

In the second edition of Beating the Dementia Monster, we were cool to the role of dietary supplements in improving cognition in Alzheimer's disease.  However, we noted that some interesting research was in progress on something called spermidine.  Spermidine is a chemical found in the ribosomes of living tissue that contributes to a variety of metabolic functions.  

Ribosomes are an example of a type of structure in the cell called organelles in which proteins are constructed.  Organelles are to the cell what organs are to the body.  Messenger RNA brings design information from DNA to the ribosome, where a polypeptide chains of amino acids is assembled to be shaped into a functional protein.  

Spermidine contributes to maintaining the correct electric charge on membranes, and helps control the pH and volume of fluids between cells.  It does this by synchronizing an array of biological processes.  (Or that's what the Wikipedia says.) 

Spermidine is considered to be an agent of longevity in mammals, because it can, among other things, reduce inflammation and discourage oxidation.  And, of course, inflammation and oxidation play major roles in Alzheimer's disease.

So where do you find spermidine?  Well, it was first isolated in semen, but it can also be found in rotting flesh ... as well as other stuff that's gone bad, such as fermented beans.  But a properly constructed Mediterranean diet will have plenty of spermidine.  Aged cheddar cheese, broccoli, and wheat germ are recognized sources of spermidine.

The question is, can taking spermidine as a supplement improve cognition, perhaps by battling the Alzheimer's disease process?  Maybe, but we don't know yet.

Over the past several years research with fruit flies and mice have suggested that it can, although not strongly.  But what about in people?

An Austrian study, called the Bruneck Prospective Study, evaluated the lifestyles and eating habits of 829 subjects in five-year increments from 1995 through 2010, with followup in 2015.  The study explicitly inferred the amount of spermidine in people's diets and compared that to mortality.  While not a direct objective of the study, the researchers tested cognition of participants at each milestone.

The first finding was that people with spermidine in their diets statistically lived longer, although its not clear that all confounding factors were controlled.  The study also produced a rich database with which the influence of spermidine on cognition could be assessed.  Those who evaluated the data concluded that those with higher spermidine content in their diets were less likely to become cognitively impaired in succeeding years.  

Another study correlated spermidine dietary intake with changes in hippocampus volume and thickness of the cortex.  The study relied on the Mediterranean diet as a source of spermidine.  Since the MIND diet is derived from the Mediterranean diet, it's likely that results would be similar with the MIND diet.  Perhaps the results of the MIND Diet Trial in June will support this correlation.

But what about spermidine supplements?  There are certainly a lot of them on the market.  At this point, there is interest in the prospect that spermidine supplementation will have the same effect as consuming a diet high in spermidine, but there are no completed studies with sufficient credibility to support the idea.  However, there is one study that had promising results with a small cohort of test subjects, and it formed the basis for a larger study.  That study, called the SmartAge study, and a phase 2B is now in progress.  

What will if find?  We'll need to wait and see.  The difficulty is that results with animal models found a positive but disappointingly mild influence of spermidine on cognition.  Will humans fare better? 

Spoke in Florida

Yesterday, I spoke at the Tapestry Hospice Spring Conference.  They've treated us like royalty, and we're grateful to them.  About 40 staff and management were in attendance.  They purchased 100 copies of my book and distributed them to all attendees.  I believe that those not distributed today will go to other employees not present.

I've had a terrible challenge with insomnia for months, with only occasional reprieves.  Thursday night was not a reprieve, and it showed in my delivery.  However, my message seems to have been compelling enough that they received it enthusiastically, and they asked me to consider addressing two other conferences later this year.  (They won't be in Florida...)  With the additional challenge of jet lag to my insomnia, I want to see if efforts of my doctors to improve my sleep show any positive return before I decide on future engagements.

We did video the presentation, and I'd like to upload it to the Dementia Monster YouTube channel.  But I made a number of errors in setting up the camera, and it will take some editing to produce something worthy of sharing.  It may be that only the audio is salvageable.  They also videoed the presentation, and I may need to ask to blend their production with mine.  Or maybe it would be best to simply ask them if I can use their work outright.

We will be here a few more days enjoying sand and sun.  They've asked me to do some group photos Sunday morning.  The temperature is on the cool side, but the beach is absolutely beautiful. 

If not monclonal antibodies, how about stem cells?

No little attention in Alzheimer's research has focused on monoclonal antibodies to remove amyloid plaques from the brain.  According to the amyloid hypothesis, amyloid plaques accumulate on brain cells, interfering with their function and killing them.  These treatments to remove the plaques include aducanumab and donanemab, but the jury is still out on their effectiveness.  So now a stem cell treatment is gaining new attention following positive results from its phase I trial. 

The treatment is called Lomacell-B, and was it developed by a company named Longeveron in Miami, Florida.  It has been found safe in earlier trials for use as a treatment for other conditions, both in children and the elderly.   It has just completed its phase I trial for use with mild Alzheimer's disease, and the results are quite promising.  The primary purpose of a phase I trial is to demonstrate safety, but they also look for effectiveness of the treatment.  Phase I trials usually involve few participants, and the results are subject to misleading statistical vagaries. 

This treatment uses stem cells derived from bone marrow of young, healthy donors.  For the trial, it was administered in a single infusion, and results were measured over a year.  There were three groups of test subjects: one receiving a high dose, one receiving a low dose, and one receiving a placebo. 

Longeveron announced the results of the phase I tests on April 13 in this press release.  We have come to expect that attention on a new Alzheimer's disease treatment will cause the sponsoring company's stock to jump, but that hasn't happened with Longeveron.   I don't know why, but there are a lot of factors that go into pricing a stock, and this company is tiny.  It doesn't help that they've been losing money year over year for a while.

As with the monoclonal antibodies, Lomacell-B is not a cure, but it does appear to slow the progress of Alzheimer's disease in its earlier stages.  Longeveron is claiming that it appears to reduce Alzheimer's disease-associated brain inflammation, improve the function of blood vessels in the brain, reduce brain damage due to disease progression, and promote regenerative responses.  

I couldn't help noticing that these are similar to the effects we expect from the brain-derived neurotrophic factor (BDNF) generated during aerobic exercise.  We discussed this in Beating the Dementia Monster, noting that BDNF is understood to prompt stem cells in the hippocampus to form new neurons.

Longeveron hopes to launch a phase II study later this year. 

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.