Wildfires and Dementia

It's wildfire season here in the Pacific Northwest.  There were recent reports of as many as 200 fires burning, but we've actually had relatively minimal smoke where we live in south central Washington State.  Not like 2017.  That was bad.  After being unexpectedly stranded on the East Coast last week for four days (due to that computer hiccup you heard about), we flew home above the smoke.  I could see it out the window of the airplane.  It was there.

We wrote previously about how air pollution promotes Alzheimer's disease.  Tiny particles in the air can pass along the path of the olfactory nerve into the brain, bypassing the blood-brain barrier.  The particles then promote the disease.  Therefore, we find higher incidences of Alzheimer's disease among people who live near freeways.  Car exhaust includes many of these particles, classified as PM2.5.

But what's worse than car exhaust?  Apparently, it's wildfire smoke.  According to new research presented at the Alzheimer's Association International Conference (currently in progress in Philadelphia), the PM2.5 particles from wildfire smoke are significantly more likely to cause dementia than particles from other sources.

So what did the researchers do?  They reviewed and analyzed health records of more than 1.2 million customers of Kaiser Permanente in southern California, 60 years or older between 2009-2019.  None of them had been diagnosed with dementia at the beginning of the study.  They estimated total PM2.5 exposure from various sources, including satellite-derived aerosol properties and Environmental Protection Agency monitoring.  They used air quality monitoring data, satellite imagery, and machine learning techniques to separate wildfire and non-wildfire exposure to PM2.5 particulates.  The researchers determined each study participant’s exposure to both sources of PM2.5 according to where they lived. They compared that information to subsequent diagnoses of dementia in participants’ health records. 

So what did they find?  The researchers observed a 21% increase in the odds of dementia diagnosis for every increase of 1 microgram of particulate matter per cubic meter ( µg/m3) of air in a three-year average wildfire PM2.5 exposure.  They determined that the study population had a 3% increased risk of dementia diagnosis for every increase of 3 µg/m3 in the three-year average of non-wildfire PM2.5 exposure.  

If I'm reading this right, and the relationships are linear, that implies that a 1 micro-gram per cubic meter increase in PM2.5 particulates from wildfire smoke increases your risk of dementia by by a factor of 21 times over other sources!  That's a huge difference!

From the Alzheimer's Association press release: “Previous research has found that exposure to PM2.5 is associated with dementia, but in light of our large, long-term study, its apparent the risk from exposure due to wildfire smoke is an even bigger concern,” said Holly Elser, M.D., Ph.D., the study’s first author and a neurology resident at the Hospital of the University of Pennsylvania, Philadelphia. “Air pollution produced by wildfires now accounts for more than 70% of total PM2.5 exposure on poor air quality days in California. This is a real problem.” 

Why would this be?  The press release further quotes Dr. Elsner:  "[In wildfire smoke], PM2.5 are produced at higher temperatures, contain a greater concentration of toxic chemicals and, on average, are smaller in diameter than PM2.5 from other sources."  She said more research needs to be done to determine the exact mechanisms.

So ... check the air filters in you home system.  Mine has a bluetooth signal to my cell phone to tell me when it's time to change a filter.  An Air Quality Index (AQI) number of 100 or higher means the air is unhealthy to breathe. To reduce their risk when the AQI is 100 or higher, it's recommended that people stay inside when possible and close the windows.  (Fires or no fires, our AQI here today is 23.  The sun is shining brightly, and the sky is very blue.)

Confirming my suspicions...

As we wrote back in May, Dr. Dean Ornish has been completing some extensive research on lifestyle and Alzheimer's disease.  He is supplying something that has been relatively lacking in this area -- "randomized clinical controlled trials" where lifestyle is changed, and the results with respect to dementia are measured.  (And, of course, compare that to a similar population where you didn't change lifestyle.)  In other words, if members of a group are shown to have Alzheimer's disease, and you change their lifestyle, will the trajectory of the disease change in a meaningful way compared to others?

At the time we published Beating the Dementia Monster, we relied on longitudinal studies to make our case from research.  A longitudinal study would evaluate a population and compare the incidence of the disease with the lifestyles of the people.  This produced interesting results strongly supporting my claim regarding why I had improved, but these studies did not provide the more conclusive evidence of a randomized clinical controlled trial -- change the lifestyle and measure the results.

So Dr. Ornish and his team just published the results of their study in the journal, Alzheimer's Research and Therapy.  It is "Effects of intensive lifestyle changes on the progression of mild cognitive impairment or early dementia due to Alzheimer’s disease: a randomized, controlled clinical trial," dated June 7, 2024.  (Click here for an easier read.)  It concluded, "Comprehensive lifestyle changes may significantly improve cognition and function after 20 weeks in many patients with MCI or early dementia due to AD."  This is exactly what we expected to find, but there was another gem in it that was important to me.

Seven or so years after I implemented the Dementia Toolkit, I finally had a chance to get a PET scan of my brain to measure the metabolism of glucose and a spinal tap to measure amyloids in my spinal fluid.  The only biomarker I had to this point were my MRIs showing brain atrophy beyond what was normal for my age.  These additional tests would be more conclusive.  But the PET scan showed normal metabolism of glucose in my brain, and the spinal tap results were ambiguous with respect to Alzheimer's disease.  That could suggest that I don't have Alzheimer's disease.

I asked my neurologist whether the lifestyle changes could actually influence my brain chemistry and the results of these tests, but she didn't know.  My logic regarding the PET scan is that, if the lifestyle changes resulted in normal brain function, they must be forcing normal metabolism of glucose in the brain.  That's what the PET scan would then show.  But I'm not a doctor.

The gem I found in the research is that lifestyle changes resulted in movement of the spinal tap results of test subjects to near normal values.  This strongly suggests that the brain chemistry of the test subjects moved close to normal.  They didn't say anything about PET scans, apparently because covid restrictions affected their ability to conduct some tests.  Nevertheless, this tells me that my PET scan and spinal tap were not valid tools for establishing whether or not I have Alzheimer's disease.  My MRIs are the best evidence, and they strongly support the Alzheimer's diagnosis.

Not another mab ... and maybe it works

Monoclonal antibodies, with their brain swelling and microhemorrhaging, may not remain the only game in town for treating Alzheimer's disease.  (Think Aduhelm, Leqembi, and Kisunla.)  In a June press release, Annovis Bio announced completion of an apparently successful phase 2/3 trial of a new medication, buntanetap.  Rather than use antibodies to eat up amyloid plaques, this medication modulates production of the polypeptides that make up the plaques.  In addition to a reduction in the appearance of plaques, researchers noted a reduction in tau tangles.  (We discuss the relationship between amyloid plaques and tau tangles in Beating the Dementia Monster.)

Part of the good news here is that the medication was delivered orally over a relatively short period of time.  Not being a monoclonal antibody, there was no brain swelling or microhemorrhaging -- ARIA.

The trial included 353 patients, ages 55 to 85.  They were randomly assigned to receive buntanetap at one of three doses, or a placebo, on top of their standard of care for 12 weeks (roughly three months).  Compared with a placebo, cognitive function was significantly improved in patients treated with 15 mg buntanetap and in those treated with the higher dose.  

In patients treated with 30 mg buntanetap, response to treatment correlated with higher cognitive test scores at the beginning of the trial.  In other words, the higher the initial test scores, indicating less cognitive impairment, the greater the improvement in cognitive function.

When 23&Me tests you for susceptibility to Alzheimer's disease, they look for the presence of the ApoE4 gene in your genome.  (We discuss this in Beating the Dementia Monster.)  This gene makes it more likely that you will develop Alzheimer's, but (like me) you don't need the gene to get it.  And having the gene doesn't guarantee that you will develop the disease.  But having the gene does influence how well the monoclonal antibodies will work for you, and having the gene also increases your risk for brain swelling and microhemorrhaging.  But not so with buntanetap.  ApoE4 status doesn't appear to influence the side effects or how well the medication works.

Buntanetap also shows promise for treatment of Parkinson's disease, at least if started in the early stages.

So there was a reduction in amyloid plaques and tau tangles (not sure how they measured that...), and patients' cognitive test scores improved enough to get the researchers excited.  But how much did they improve?  Caregivers apparently didn't notice anyone getting better.  That's kind of important.

Annovis Bio is now preparing for a phase 3 clinical trial.  A successful trial will pave the way for FDA approval.  In the first two trials, the researchers learned a lot about effective dosing and about how to administer the drug.  Perhaps a refined treatment protocol will produce results that even caregivers will recognize.

Welcome Kisunla

We reported previously that the FDA's advisory panel had recommended approval of the monoclonal antibody treatment donanemab.  This followed the successful completion of all three phases of the clinical trial.  This week, the FDA took the advice of the panel and approved donanemab for treatment of some early stage cases of Alzheimer's disease.  Eli Lilly will market donanemab as Kisunla.  

During the clinical trial, test subjects received 700 mg injections of donanemab every 4 weeks for the first 3 doses, and then 1400 mg every 4 weeks (or placebo) for a total of up to 72 weeks.  They demonstrated a statistically significant reduction in clinical decline compared to placebo at Week 76.  At the outset of the study, the study population had a mean age of 73 years, with a range of 59 to 86 years.  Fifty-seven percent of patients were female, 91% were White, 6% were Asian, 4% were Hispanic or Latino, and 2% were Black or African American. 

According to Lilly, “Kisunla slowed cognitive and functional decline by up to 35% compared to placebo at 18 months in its pivotal Phase 3 study and reduced participants’ risk of progressing to the next clinical stage of disease by up to 39%.”

About half of patients (47%) achieved sufficient amyloid-beta clearance to be able to stop treatment after a year, and 69% met that mark by 1.5 years.  Eli Lilly plans to charge about $700 per vial, but I'm not sure how much is in a vial.  Is that one initial dose -- 700 mg?

As a monoclonal antibody for removing amyloid plaques, Kisunla brings the same side effects and risk factors as the other "mabs."  The ones of most concern are some brain swelling and microhemorrhages.  The understanding is that, for most people, the risk is worth the benefit.  These effects are referred to as "amyloid-related imaging abnormalities," or ARIAs.  Treatments must be monitored with periodic brain MRIs.

This is, of course, good news.  Nevertheless, we remember that, when the mabs remove amyloid plaques, they are treating symptoms.  Hopefully we will be seeing treatments that go to the actual core disease itself -- whatever that is.