# New Dementia Trial Results

There\'s a new [clinical trial
result](https://www.medrxiv.org/content/10.1101/2021.05.10.21256982v1.full)
showing that [Bredesen\'s
approach](http://www.bayesianinvestor.com/blog/index.php/2017/10/19/the-end-of-alzheimers/)
is able to at least partially cure common forms of Alzheimer-like
dementia. (Press release
[here](https://www.apollohealthco.com/finally-clinical-trial-demonstrates-reversal-of-cognitive-decline/)).
It has not received as much attention as it deserves.

The 9 month study seemed a bit less impressive than what I\'d hoped for,
but the outcomes still support the claim that common forms of dementia
are partly curable.

Out of 25 patients, 21 or 19 improved their cognition compared to the
start of the trial, depending on which measure I look at, and 2 or 3
declined.

Side effects included occasional improvements in hypertension and
diabetes, enough to allow patients to stop taking medications for those
conditions.

### 1.

Compared to [my prediction in
2017](http://www.bayesianinvestor.com/blog/index.php/2017/10/19/the-end-of-alzheimers/),
the trial happened a bit later than I expected, but achieved much higher
patient compliance than I expected. If I had predicted the study size,
I\'d have likely said something way too optimistic (a thousand?).

[The trial
registration](https://clinicaltrials.gov/ct2/show/NCT03883633) reports
an actual enrollment of 30 patients, whereas the paper reports 28 were
recruited, 3 of whom dropped out within 3 months. I don\'t see any
explanation for that difference. For comparison, it looks like
[Biogen\'s phase 3
trials](https://investors.biogen.com/static-files/8e58afa4-ba37-4250-9a78-2ecfb63b1dcb)
had completion rates of less than 60%.

The pandemic started in the middle of the trial, impairing compliance.
Exercise seems likely to have been reduced. Two patients showed reversal
of their improvement that was attributed to sheltering in moldy homes.
The pandemic reportedly hurt patients\' diets. I\'m unsure what to make
of that. Restaurant closures would have reduced access to food that
tempts people to cheat - my diet better resembles Bredesen\'s when I\'m
cooking at home. But the effect would likely be the opposite for those
who don\'t cook, as I\'m guessing they\'d eat more junk food.

### 2.

The study does not report
[ADAS-Cog](https://alzres.biomedcentral.com/articles/10.1186/alzrt48)
results. ADAS-Cog seems to be the usual measure for clinical trials. It
may be inappropriate for milder impairment due to [ceiling
effects](https://en.wikipedia.org/wiki/Ceiling_effect_(statistics)) -
I\'m unclear whether that\'s a reason for them to have avoided it.

They used several measures that seem to be fairly common tests of
cognition, and they pre-registered those, so it doesn\'t look like they
ran a lot of tests and selected those that favored the protocol.

### 3.

Their criteria for excluding people includes statin use, unless eligible
to discontinue. Yet they
[report](https://www.apollohealthco.com/facebook-live-clinical-trial-discussion/)
one patient discontinuing statin use after the treatment apparently
improved the patient\'s lipids (I\'m not 100% clear on whether that
patient was in the trial).

Did they exclude many statin users, and if so did that cause them to
have a more treatable population than most other dementia trials?
Bredesen is pretty concerned that statins cause dementia. The evidence
on this topic seems pretty weak. I\'ll guess that if statins were a big
enough cause of dementia to impact this trial in an important way,
someone would have managed to report better evidence than I\'ve found.
But I\'m still avoiding my doctor\'s advice to use a statin, partly due
to Bredesen\'s opinion.

### 4.

The trial didn\'t directly verify that patients had Alzheimer\'s. They
claim that if the treatment was only working on non-Alzheimer\'s forms
of dementia, then the 12 patients with an Apoe4 allele would likely have
done poorly, which was not the case. That\'s not a very rigorous
argument, but it would be fairly hard to accidentally produce the
indicated results without improving the health of some Alzheimer\'s
patients.

I\'ve minimized my use of the term Alzheimer\'s here, due to uncertainty
about whether it means much. Some authorities treat amyloid beta as [a
defining
feature](https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/expert-answers/defining-alzheimers-disease/faq-20436675)
of Alzheimer\'s, yet amyloid beta has been largely demonstrated to have
little causal influence on dementia.

The FDA has panicked recently over the failure of the amyloid beta
industry, and is trying to provide hope for that industry by allowing it
to market a drug (Biogen\'s Aduhelm) that reduces amyloid beta, as if
that treated a disease. Maybe Aduhelm is better than nothing, but the
[FDA
announcement](https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug)
seems to include a number of false statements that appear designed to
suppress awareness of better alternatives.

### 5.

This trial makes me slightly more optimistic about Bredesen\'s protocol,
mainly due to the evidence that they were able to get better compliance
than I expected. That evidence is somewhat tempered by the small size,
which likely means that only the most eager patients ended up in the
trial.

We ought to have a higher prior for Bredesen\'s lifestyle protocol than
for some novel drug, partly due to the evidence from [other
cultures](http://www.bayesianinvestor.com/blog/index.php/2017/10/19/the-end-of-alzheimers/#note4)
which suggests that most dementia is due to modern lifestyles. That
evidence has been neglected due to not fitting the High Modernist notion
of what qualifies as evidence.

In addition, Bredesen\'s protocol is composed of parts that look
reasonable to adopt even in the absence of effects on dementia. It looks
like the reluctance to adopt most of those parts comes from issues such
as price (much less than Aduhelm), hassle, and/or the fact that the
evidence for effectiveness is confusing. How does that compare to, say,
the CDC\'s reluctance to advocate mask use in March 2020?

### 6.

Two other recent trials showed drug-based promise for dementia.

[Cassava Science\'s trial
results](https://www.cassavasciences.com/news-releases/news-release-details/cassava-sciences-simufilam-improves-cognition-and-behavior):
cognition improved 10% over 6 months. I bought stock in Cassava due to
that announcement.

[Annovis Bio has
reported](https://www.biospace.com/article/annovis-bio-announces-positive-phase-2-data-anvs401-improves-cognition-in-alzheimer-s-disease-patients-cognition-improved-3-3-points-on-adas-cog11/)
a 30% improvement in cognition in 25 days, in 14 patients. I\'m still
wondering what to make of that announcement. Note that their comparison
to Biogen in their press release is confusingly favorable to Biogen,
which reported an improvement relative to placebo, but those patients
still declined. Whereas Annovis, Cassava, and the Bredesen trials show
improvement relative to baseline.

I\'ve seen three promising clinical trial results for dementia in the
last 6 months. Can anyone show me prior dementia trial results that had
similar promise but failed at a later stage?