Alzheimer's ... or not?

It was in March of 2015 when my local neurologist gave me a diagnosis of "early stage senile dementia, likely of the Alzheimer's type."  I then went to the Brain Wellness Center at the University of Washington's Harborview Medical Center where, after three hours of testing and an MRI, they said I had mild cognitive impairment, or MCI.  As we said in Beating the Dementia Monster, MCI is the last step in the disease process before dementia, and it usually lasts about five years.  They did not, however, write in my diagnosis the cause of the MCI.  Alzheimer's disease is the most common of about thirty possible causes of MCI.  It was in discussions that they indicated my MRI and test results were consistent with Alzheimer's disease.

Since then, I've been tested annually there in Seattle, and I've had about six more MRIs.  Some of these MRIs were associated with various studies I participated in where I also received lots of intensive cognitive testing.  After making aggressive lifestyle changes at the end of 2015, I showed steady improvement until about 2019.  After that, my cognition seemed to largely stabilize.

The MRI results are interesting.  The volume of my lateral ventricles has consistently been measured at >99 percentile for men my age, indicating significant atrophy of my brain.  Much more than most men my age.  (Or, perhaps, hydrocephalus has been pushing the ventricle walls outward.)  But the volume of my hippocampus is another matter.  The MRI in 2015 measured it at the 33 percentile for men my age, and a subsequent MRI in 2017 found it to be less than the one percentile.  The radiologist report for an MRI in 2018 reported no change from 2017.  But then in 2021, an MRI measured my hippocampus volume at the 52 percentile.  

This does mot mean that my hippocampus was growing, since these numbers are normalized for men my age.  All of our brains are atrophying as we age, and our hippocampi are all shrinking.  But from this data, it's fair to conclude that my hippocampus was atrophying faster than other men into 2018, but much less rapidly than other men into 2021.  This follows my personal experience with subjective changes in my memory and cognition, and it seems to be a consequence of the radical lifestyle changes I made, beginning in 2015.

Since 2015 the technology for diagnosing Alzheimer's disease has been advancing.  The final diagnosis is still the autopsy, but newer techniques are narrowing the probabilities of an accurate diagnosis in life.  One of those techniques is analysis of cerebrospinal fluid from a lumbar puncture, which I had on April 11 of this year.  The sample was analyzed at Mayo Clinic, and the results were returned a few days later.  My read of the results is that they were somewhat inconclusive, but it was clear that something is not right in my brain.  They did not support an Alzheimer's diagnosis, but they did support hydrocephalus.  The report said the results needed to be assessed in the context of other clinical findings.

So I saw my local neurologist yesterday to review the results.  Her assessment is that I do not have Alzheimer's disease but rather normal pressure hydrocephalus, or NPH.  We've said before that NPH is often misdiagnosed as Alzheimer's disease, primarily because it also causes cognitive decline and enlarged ventricles in the brain.  (It is not, however, known to affect the volume of the hippocampus.)  About a quarter or more of people with NPH are found also to have Alzheimer's disease.

We acknowledged in Beating the Dementia Monster that my Alzheimer's diagnosis was not certain, but it seemed highly probable.  It now seems less probable.

The hippocampus volume is a bit enigmatic.  I asked my local neurologist what that might mean, since there's no reason to believe that it was caused by hydrocephalus.  She said she didn't know.  But my improved cognition, which seemed to track with hippocampus volume changes, is surely due to my lifestyle changes.  So it seems to me that whatever caused the atrophy of my hippocampus and my cognitive decline has been countered by my lifestyle changes.

I will discuss this further with my regular neurologist in Seattle in June.  I expect her to agree with my local neurologist that it's now much less likely that my neurological issues were caused by Alzheimer's disease.  But I'd also like to know what she thinks about the anomaly of my hippocampus volume changes.

Another Post-Amyloid Possibility?

We have been less than enthusiastic about all of the research attention going to "the amyloid hypothesis."  Other factors, like viruses, bacteria, and genetics cause and/or contribute to both the initiation and progress of Alzheimer's disease.  Some of these factors may turn out to be more productive targets of research.  There may be interventions that are more effective than simply removing beta amyloid from the brain, but that's where most of the attention has been.  

Our friend Laurie directed me to some very interesting new research that has popped up from MIT’s Picower Institute for Learning and Memory, published in the Proceedings of the National Academy of Sciences.  The research suggests that interfering with the activities of a certain enzyme in the brain, which is overactive in Alzheimer's disease, could actually reverse the effects of the disease.

The news is exciting, but we are very early on the path to development of an actual treatment from this research.  And the current research has been conducted with genetically modified mice.  The mice have been bred to have brains that behave much like human brains with Alzheimer's disease.  But as we've noted before, promising research with these mice has often led to disappointment.  That's because mice aren't people.

But it is still exciting.  Essentially, the researchers treated mice with a peptide that blocks the operation of a certain version of an enzyme leading to dramatic reductions in neurodegeneration and DNA damage in the brain.  The enzyme has been implicated in the tau tangles that we discussed in Beating the Dementia Monster and are typical of the progress of Alzheimer's disease.  After treatment, the mice showed improvements in their ability to perform certain tasks, like learning to navigate a maze.

What's a peptide?  What's an enzyme?  A peptide is a string of amino acids, usually strung together inside a cell to build a protein.  Chains of peptides are then shaped into proteins.  Which amino acids are in a given string (and therefore the protein) is specified by the corresponding gene in the DNA.  Some peptides, like beta amyloid, may not be long enough to form an actual protein.

An enzyme is a protein that, due to its size, shape, and arrangement of charges, catalyzes chemical reactions.  For example, the burning of carbon and hydrogen in your body (taken from the food you ate) takes place at much lower temperatures than in your fireplace, because the reactions are catalyzed by enzymes.  Enzymes do a lot of really important stuff in biochemistry, especially in the brain.

The enzyme in question here is called CDK5, and it regulates synaptic function.  Sometimes ... maybe not so well.  There have already been efforts to moderate the activity of CDK5 in Alzheimer's disease, but these efforts have not gone well.  The researchers believe that using a certain artificial peptide, rather than the drugs that were tried earlier, is producing much more promising results.  The special peptide was engineered by the researchers with 12 amino acids in the chain.

So will this turn out to be a whole new path to a truly effective treatment?  It certainly has the potential. 

Cleaning out the amyloid ... more controversy

While there are a lot of yellow lights flashing, the main drive in research on a pharmacological treatment for Alzheimer's disease -- the magic bullet drug -- has focused on removing amyloid plaques from the brain.  Aduhelm, Leqembi, and other prospective amyloid cleaners get nearly all of the attention and a lot of the funding.  But there remain questions about their effectiveness, their safety, and their cost.  A new study, published in the journal Neurology, has further energized the questions.

The research, "Accelerated Brain Volume Loss Caused by Anti-β-Amyloid Drugs: A Systematic Review and Meta-analysis," abstract available here, correlated data from different brain imaging studies.  It found that these amyloid removal treatments led to brain volume loss.  Is that a good thing or a bad thing?  Is the brain losing tissue because it's getting better, or are the treatments introducing new problems?

The volume loss is associated with a phenomenon called "amyloid-related imaging abnormalities," or ARIA.  ARIA include the microhemorrhaging in patients using the monoclonal antibody treatments, like Leqembi, that are suspected to be involved in the deaths of a few patients.  And so there is reason for concern.  

This has led to controversy.  Is it possible ARIA is really evidence that the treatments are working?  Or are they actually accelerating neurodegeneration?  I'm not equipped to answer that question, but there seem to be strong opinions on both sides.  Nevertheless, there's unanimous agreement that more study is necessary.  And this all just underscores how little we understand about these things.

You can read more here.

Answering my biggest question...

What is my biggest question? It's, "Do I really have Alzheimer's disease, or is there some other explanation for my roller-coaster experience?"

Certainly the first neurologist who examined me in 2015 was confident it was Alzheimer's disease.  When I was referred to the highly reputable Brain Wellness Center at the University of Washington's Harborview Medical Center, they established that I was cognitively impaired, and my MRIs were consistent with Alzheimer's disease.  In fact, my MRI results in 2017 were consistent with someone in memory care.  And my condition responded to lifestyle changes consistent with the widely respected FINGER study.  

As we discussed in Beating the Dementia Monster, the final diagnosis of Alzheimer's disease is in the autopsy.  Not being in a rush to get to that step, my diagnosis carried an element of doubt.  Something was causing my cognitive decline, but was it Alzheimer's disease?  Or maybe something else, like normal pressure hydrocephalus?

Since 2015, the technology for diagnosing Alzheimer's disease in a living patient has advanced quite a bit.  Most notably, checking for beta amyloid polypeptides and certain species of tau protein in cerebrospinal fluid has become an accepted tool, as have PET scans for both beta amyloid and tau.  We anticipate that reliable blood tests may become available in the next year or so.

While it's still cutting edge, I asked my local neurologist about a test of my cerebrospinal fluid.  She thought this was a good idea, but she referred me to have it done at Harborview rather than a local facility.  That's what I decided to do.

And that was today.  

We came to Seattle and made our way to Harborview.  There I met a new (to me) neurologist recommended by my neurologist back home.  He administered a lumbar puncture, taking 20 ml of spinal fluid (quite painlessly).  He said we would likely have results next week.  The sample was to be sent overnight to Mayo Clinic for analysis to be analyzed for both beta amyloid and tau.  The neurologist cautioned that some results are strongly confirmatory (either positive or negative), but they can also be ambiguous.  After the procedure, we returned to our son's apartment, and we will return home tomorrow to await the results.

While waiting for the results, the neurologist suggested some reading.  He recommended the Mayo Clinic web site where they discuss the test and its interpretation.  So I looked it up and found it very interesting.  Maybe you will too.  Click here.

I will update you when I have results.

More about Alzheimer's disease as an autoimmune disease

We wrote recently about new thinking with regard to what causes Alzheimer's disease to begin and to progress.  The post was based on the work of one team from Washington University, St. Louis, but they are not alone.  My friend Teale recently shared with me a story from ScienceAlert.com written by a researcher from the Krembil Brain Institute, part of the University Health Network in Toronto.  Their new hypothesis was published here in Alzheimer's and Dementia; the journal of the Alzheimer's Association. 

Their research suggests there is a similarity between certain fat molecules in brain cells and fat molecules in some bacteria.  Instead of attacking the bacteria, the brain's unique immune system confuses the molecules and attacks neurons, not bacteria.  This may spark the activation and dormancy cycle we discussed in the previous post.  And consistent with what we said in Beating the Dementia Monster, these researchers propose that beta amyloid is actually a normal product of the immune system, and its function is to protect the neurons.  So getting rid of beta amyloid may be a bad strategy.  This, of course, challenges the idea that we can fight Alzheimer's disease by removing amyloid plaques, the principle behind why Aduhelm and Leqembi should work. 

I would speculate that this abnormal immune response may be encouraged by conditions in the brain, such as susceptibility to inflammation and oxidation.  These, in turn, are influenced by genetic makeup, diet, exercise, and other lifestyle characteristics.  And where brain cells have been attacked by the autoimmune response, the generation of BDNF during exercise and intermittent fasting strengthens and replenishes them.

As we've said before, what this really tells us is that Alzheimer's is an incredibly complex disease.  We just don't understand it very well at all.

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.