Now Alzheimer's disease is an autoimmune disease? That's a switch!

In the few years that I've spent trying to understand Alzheimer's, one thing has impressed me above all else.  We just don't understand this disease.

Sure, we know that the Alzheimer's brain loses cells and atrophies.  Problems with tau protein cause the microtubules to collapse into tangles.  And we see amyloid plaques accumulate in ways that might impede memory and cognition.  Maybe they too can kill neurons.  Certainly what we notice most about the disease is what happens to people as the disease progresses--the deterioration of their memories, cognition, and even personhood.  That's what we notice, but are those effects central to the disease's dynamic?

We've written before about grave questions with our understanding about how these things happen.  There seem to be several genes involved in many (but not all) cases.  Do these genes cause the disease, or do they just create conditions in the brain that are fertile for the disease?  There is other evidence implicating a role in the disease for the herpes virus, and that seems to be an avenue to pursue.  But there is also evidence that a bacterium causing gum disease plays some kind of role.  Maybe the amyloid plaques are simply the body's defensive action to protect the brain from an invasion of bacteria?  There are many hypotheses.  Some fit together, while others suggest multiple, entirely different mechanisms of the disease.

So now there's another hypothesis.  Alzheimer's is actually an autoimmune disease, and we should be barking up that tree.  Where did that idea come from?

The idea comes from research published in Nature, one of the most prestigious scientific journals.  It was "Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy."  The research was conducted by a team led by Dr. David Holtzman of Washington University, St. Louis.

In Beating the Dementia Monster, we provided a rather simplistic explanation of the brain's immune system.  We said that the brain was isolated from the body's main immune system by the blood-brain barrier, and used its own immune cells, called microglia, to fight off any invading pathogens that succeed in crossing the blood-brain barrier.  It doesn't use T-cells or B-cells.

Or does it?  Dr. Holtzman's team found T-cells and evidence of T-cell activity in the brains of mice bred to imitate Alzheimer's disease.  They further found that they could halt brain atrophy by removing the T-cells.  The thought is that the T-cells are constantly being activated to respond to an antigen and are subsequently exhausted.  But there's a cycle in which the exhausted cells lay dormant for a while and are then reactivated.  But they're not that dormant, and the "dormant" cells can cause injury to surrounding cells.  

And why are they constantly being reactivated?  They weren't sure, but this seems to be where the autoimmune part comes in.

As we've said so many times before, mice are not people, and something we see in mice may not apply to people.  But in samples of brain tissue from people with different stages of Alzheimer's disease, the researchers found higher levels of T-cell presence in the more advanced stages.

So what does this all mean for Alzheimer's disease research?  As a minimum, it gives us a new avenue to pursue for understanding the disease.  But it also may be about to turn everything we think we know about the disease on its head.

Leqembi / lecanemab / BAN2401 approved by the VA

In Beating the Dementia Monster, we discussed the promise of the monoclonal antibody treatment BAN2401.  Since then, it has become more widely known generically as lecanemab, and then commercially as Leqembi.  When administered to patients with early stage Alzheimer's disease, it appears to be more effective than Aduhelm.  Aduhelm is generally priced at $28,200 per year, while Leqembi is priced at $26,500 per year.  Aduhelm is administered intravenously every four weeks, while Leqembi is received intravenously every two weeks.  Both require regular MRIs to check for brain swelling and microhemorrhaging.  We mentioned before that three patients died during the lecanemab trials, although there is dispute over cause of death for at least two of these cases.

I recently received an email from James, one of the subscribers to this blog, noting that the Veterans Administration has now approved Leqembi for some veterans with early stage Alzheimer's disease.  The news was reported in this article from Military.com.   The article acknowledges that drug trials so far have found that, like Aduhelm, Leqembi effectively removes amyloid plaques, but testing to determine how well it improves memory and cognition is still in progress.  Trials for both treatments are incomplete, but, so far, there are better results with Leqembi than with Aduhelm. 

Looking more broadly at the pharmacological approach to treating Alzheimer's disease, the question still remains whether treating amyloid plaques is addressing the actual disease mechanism or a just a symptom.  Removing the plaques doesn't cure the disease, although it improves memory and cognition.  As we discussed before, some researchers propose that the plaques are actually a defense mechanism against the real culprit(s), certain microbes that have entered the brain.  As we discussed in Beating the Dementia Monster, these may be the herpes virus or the p. gingivalis bacteria. 

Ooops .... Flashing lights or not?

In 2020 we wrote about research at MIT showing that exposure to light flickering 40 time per second can influence the appearance or progress of Alzheimer's disease.  But is that still true?  Maybe not.

One of the principles of scientific research is that others should be able to replicate your results.  We wrote earlier about seminal research on amyloid pathology that no one bothered to seriously try replicating.  Some tried, but they blamed the disparity in their results on their own methodology.  Or they didn't pursue the disparities, because of the momentum that the original research had in the scientific world.  A decade or two later, the original research turned out to be a fraud.  While there's no suggestion of fraud around the flickering light research, other researchers are failing to replicate their results.

A recent article in ALZForum reported on research at New York University’s Langone Medical Center.  While the research found a small effect from the light, it was nothing like that published earlier from MIT.  

Why not?

As you can imagine, there is a lot of discussion around that question.  Does it mean that flashing light won't influence the progress of Alzheimer's disease?  Were there differences in how the research was conducted in the two laboratories?

I don't know, but my earlier enthusiasm for this as a path to a meaningful treatment has waned.

New neurons from old...

In Beating the Dementia Monster we discussed one way in which stem cells in the hippocampus can be prompted to form new neurons.  This is by generation of the brain-derived neurotrophic factor through aerobic exercise and intermittent fasting.  This, I believe, has been the mechanism by which I have, at least temporarily, stopped the progress of my disease.

But my friend Teale sent me an article from SciTechDaily about another way in which stem cells in the hippocampus can be prompted to form new neurons.  The article was based on research published in the journal, ScienceAdvances.  To me, it was very interesting and points to significant possibilities ... some day.  While the researchers were optimistic about possibilities, they are a long way from developing from this research a method for reversing a neurodegenerative disease, like Alzheimer's disease.

To us nerds, the research is a bit fascinating, although the eyes of many will glaze over when I get into it.  Especially since it doesn't seem to point to any near-term therapies.  And it was based on research using mice whose genome -- their DNA -- had been "edited."  Aside from the fact that they were not normal mice, we've said before that mice are not people.  Research that found something promising with mice very often turns out to be meaningless when applied to us humans.  So you may not want to read further.

The essence of the research was to focus on stem cells that are dormant.  Apparently, stem cells become more and more dormant as we age, and it gets harder to have them form new neurons.  What the researchers stumbled on entirely by accident is that some proteins involved in the processing of energy in the cell also help regulate the stem cells.  Part of that regulation is to dampen "neurogenesis" from the stem cells -- the formation of new neurons.  So between the edited genome and and injection of some chemicals, the researchers perturbed the chemical energy cycle in a manner that caused the proteins involved with processing energy to reduce suppression of the stem cells.  This gives us more new neurons.

If you've taken a biology class in the past 15 years, you know that the mitochondria are "the powerhouse of the cell."  (They didn't know this stuff back when Baby Boomers were in school.)  It's here that nutrients are metabolized in a couple of complex cycles to produce the chemical ATP.  The ATP is distributed throughout the cell as a form of fuel.  An intermediate product in the process is a chemical called pyruvate, and it is transported by a protein called "the mitochondrial pyruvate carrier" or MPC.  The researchers said that MPC plays an unexpected role in regulating stem cell behavior. Therefore, manipulating the energy production process will manipulate either the amount or the behavior (not sure which) of the MPC and therefore manipulate the generation of new neurons from stem cells.

Having taught cell biology some years ago these findings are fascinating.  Your mileage may vary.

Music is powerful ... but why?

We've written in the past about research on music and dementia.  Music has the power to dig deeply into the memory of someone with dementia to recall long-forgotten experiences involving music.  These memories are usually pleasant, and the individual is uplifted, at least while listening.  

As with other memories, people with Alzheimer's disease can often recall childhood memories, even though they can't remember an event a day earlier.  More likely, they will recall much earlier events and experiences if it had an emotional dimension.  Music, of course, stimulates emotion.

My friend Mike sent me a link to this interesting article on music and dementia.  In explaining the longevity of music in the brain and its influence on people with dementia, the article clarified several terms you will hear in discussions of memory and the brain.  Here's my summary.

Implicit memory is a form of long-term memory involving the unconscious ability to remember a habit or routine.  Procedural memory is a type of implicit memory.  An example might be how to get dressed.  

Explicit memory, also long-term memory, involves the intentional recollection of factual information, experiences, and concepts.  

Then there's episodic memory, a form of explicit memory.  It's the long-term recollection of everyday events, such as birthdays.  Memories in this category are formulated in the hippocampus but are encoded more durably in other parts of the brain.  You will recall that the first part of the Alzheimer's brain to fall is usually the hippocampus.  But procedural memory is executed elsewhere in the brain, so it's not as vulnerable to the early stages of Alzheimer's disease.

So how does all of this play out?  According to the researchers interviewed for the article, episodic memory recalls hearing music long ago and the emotions surrounding that event.  With the associated emotions, recalling the event transports the mind back in time to the experience.  If you want to sing, on the other hand, that requires procedural memory.  

Short term memories arising in the hippocampus will be lost long before any implicit or explicit memories.

The 2014 film, Alive Inside, remains one of my favorite ways of understanding how music can enrich the lives of those with dementia.