Predicting Alzheimers & Dementia (and minimizing risk)

[DrFraser]

I think the problem with these drugs include up to 20% intracranial hemorrhage rate, and I’m not entirely convinced that all AD is the same. Will what works in Knight Family Dementia - which is young onset AD work on standard AD or AD due to senescence or ApoE?

We have evidence of other items that will get us 50% rate reduction that don’t involve these risks or costs, which will inevitably be high.

I’m not jumping on this yet. More data, including in individuals with ApoE4’s with MCI would be welcome.

[Neo]

@DrFraser

problem with these drugs include up to 20% intracranial hemorrhage rate

Thx for perspective

I spoke to a scientist very close this and who thought that those risks were largely driven by how much the drugs had to clear

So the risks are large when intervening late

But may be much smaller if done earlier and perhaps hardly at all if done preventably

Will be interesting to learn more as more data comes in

[DrFraser]

This is a fair perspective - the more diseased your brain, the more likely you are to hemorrhage.

The problem has been the cost of these agents, and then secondarily identifying which individuals are at highest risk (and also if having a whole host of bad lifestyle choices - should society bare these costs?).

We need to understand who will benefit (and who will be harmed) by these interventions. There must be a computation of cost per additional year of quality of life - the system cannot sustain giving every last item to every individual. This will result in patients at risk being denied (as I see daily on many of my prescriptions) and then there is the option to pay for it or not. By necessity, we’ll see the affluent get these therapies and the poor get denied.

This however isn’t a new concept in our healthcare system.

[Neo]

@DrFraser @AnUser Also in this week’s 经济学人, just out:

Do viruses trigger Alzheimer’s?

[DrFraser]

More and more I’m checking people for HSV-1 particularly and also oral p. gingivalis as being big risk factors. VZV (chickenpox virus/shingles) may also add risk. I do have some patients on long term valacyclovir who are at risk.

[Neo]

@DrFraser

VZV (chickenpox virus/shingles) may also add risk. I do have some patients on long term valacyclovir who are at risk.

Exactly, from the article

Researchers at Tufts University, working with Professor Itzhaki, have probed why such reactivation occurs. In 2022 they found that infection with a second pathogen, the shingles virus, could awaken the dormant HSV1 and trigger the accumulation of plaques and tangles. This may explain why shingles vaccination appears to be protective against dementia.

In another study published in January, the Tufts researchers also showed that a traumatic brain injury—a known risk factor for Alzheimer’s—could also rouse HSV1 and start the aggregation of proteins in brain cells grown in a dish.

If viruses are a trigger, though, then vaccination or antiviral drugs could prevent future cases. Such treatments could also slow or halt the progression of Alzheimer’s in those who already have the disease. None of this requires major breakthroughs. Antivirals for the cold-sore pathogen already exist and are off-patent. And the shingles vaccine is now routinely offered to elderly people in many countries.

One study published in 2018 found that for older people in Taiwan who had cold sores, taking an antiviral cut the risk of dementia by 90%. Several subsequent analyses of medical data from other countries found more modest protective effects of antivirals, typically between 25 and 50%.

The first double-blinded randomised clinical trial to test the effectiveness of antivirals against dementia is now under way. A group of researchers mostly based at Columbia University are testing whether valacyclovir, an antiviral used against HSV1, can slow down cognitive decline in people with early stage Alzheimer’s. Between 2018 and 2024, the researchers recruited 120 patients and treated half with the antiviral. They expect to publish their findings later this year. @adssx have you heard anything on about how the trial might have gone?

@DrFraser

1. Do you consider valacyclovir is people who never have any cold sores or other signs of HSV1 activation if they ever had antibodies in their blood?

2. At what age might one consider the shingles vaccine if the goal is to minimize dementia risks?

3. Did you ever write one of your blog posts on this topic? Could perhaps be a really interesting and powerful one

[DrFraser]

Antibody positivity is sufficient.

I think all interventions to prevent/delay neurocognitive decline need to start at an age >=20 years from when one might expect to reach a typical age of having a diagnosis of the disease. For example, individuals with ApoE4/E4 - we start seeing them get dementia in early 60’s, 50% by age 71 years. So I’d think starting an ApoE4/E4 on specific plans at age 40 years would be sensible.

I do need to write this up - it is on my list to look at chronic infections (including HSV).

[Barnabas]

Is it straightforward to test for HSV-1 antibodies?

[DrFraser]

Blood test - when I order it ~$125 if doing NAA (for actual particles in circulation) or $41 for antibodies (IgG) to HSV 1 and 2.

More detailed response as requested from @Barnabas - generally I would just look for IgG antibodies as this shows that you have past infection. Given that you will suppress, but no eliminate HSV or VZV once you have it - that is sufficient (and cheaper).

Also, on FidaLabUS.com they now have this test for the common AD genes:
At Home Tests for Individuals - FIDALAB
Assesses an individual’s genetic predisposition to Alzheimer’s (excluding APOE gene)

Test For
Eleven genetic variations of eight genes (TREM2, PICALM, SORL1, PSEN1, PSEN2, APP, EPHA1, and MS4A6A) associated with Alzheimer’s

Collection Method
Buccal Swab or Oral Rinse

Your Benefit
Know your genetic risks for Alzheimer’s

They have arranged a discount (I don’t make anything from this) - use this code: FRASER: 10% off for your patients It’s $150, but with discount $135. People with ApoE4’s, and I guess other people should be aware of this option.

[Barnabas]

That response demands a follow up question. What would make you go in one versus the other direction?

[L_H]

I’ve just posted this on a different forum. it’s association only but it does encourage me to keep eating lots of fish to support brain vascular health

Sardines and Portuguese Longevity

An association study only it makes me want to continue eating sardines… Study population average age is 71 “Researchers found that among people who ate no fish, 31% had markers of severe underlying vascular brain disease, compared to 23% of those who ate three servings a week, and 18% of those who ate four or more servings of fish per week. This association between lower fish consumption and greater severity of markers of vascular brain disease was independent of any differences in brain volumes and other variables like age and sex.” https://www.neurology.org/doi/10.1212/WNL.0000000000012916 https://www.aan.com/PressRoom/Home/PressRelease/4933

[dicarlo2]

Is there a drawback to using valacyclovir prophylactically/long term to help the immune system suppress various viral infections? Given that it works for chickenpox/shingles, it seems like it could be prudent to take it even in the case of no HSV infection.

[adssx]

@Neo

@adssx @DrFraser - any thoughts these seems like it could be big if translated to general prevention?

I’m very skeptical about these drugs for the moment so I’ll wait and see…

[adssx]

@Neo

At what age might one consider the shingles vaccine if the goal is to minimize dementia risks?

The earlier the better? It’s approved in all adults but most countries only give it from age 50 or 65: Vaccines for longevity - #25 by adssx

A friend of mine in his 20s had a lot of outbreaks, got the shingles vax and no more outbreaks.

Pneumococcal also seems good: Vaccines for longevity - #144 by adssx

[RapAdmin]

Earlier menopause and poor synaptic health could raise Alzheimer’s risk: Study

Research suggests earlier menopause and poor synaptic health together...

[DrFraser]

I guess this would be one more reason to use rapamycin - as prolonging time to menopause might have significant benefits.

[John_Hemming]

I would say [aging mechanism] = [development mechanism]

If you slow development you slow aging.

[DeStrider]

@adssx @DrFraser based on your extensive research which currently available intervention do you think is the best to prevent Alzheimer’s before it develops?

[RapAdmin]

Is Dementia Incidence Still Dropping? Birth Cohort Data Say Yes.

As the baby boom generation reaches its hopefully golden years, scientists have been projecting a doubling of dementia cases in the U.S. by 2050, alarming health care agencies, the public, and health economists. Now, a new editorial argues this “tsunami” could be more of a gentle wave. In the March 12 JAMA, Eric Stallard, Svetlana Ukraintseva, and Murali Doraiswamy at Duke University, Durham, North Carolina, explain that tsunami predictions assume that dementia prevalence in each age range remains constant over time. That is not the case, they say.

Their analysis of three large population studies found that age-adjusted prevalence has dropped by a whopping two-thirds over the last 40 years. In other words, every successive birth cohort has a lower risk of dementia than did its predecessor. Extrapolated forward, these rates would predict only a 25 percent bump in dementia cases by 2050. This would challenge conventional wisdom. “I feel a bit like Copernicus,” Stallard quipped.

Other scientists agreed this analysis is reasonable, and said it highlights the potential for people and societies to modify dementia risk through health and lifestyle interventions.

https://www.alzforum.org/news/research-news/dementia-incidence-still-dropping-birth-cohort-data-say-yes

[adssx]

Lecanemab: what would you do?

I would look at: Blood pressure: if not optimal, telmisartan (up to 80 mg if tolerated). Glucose (HbA1c and HOMA-IR): if not optimal, dapagliflozin 10 mg or empagliflozin 25 mg Lithium orotate (1 to 10 mg?). Serum B12: if in the lower “normal”, methylcobalamin sublingual. Theracurmin (high absorption curcumin). If he has bladder issues due to prostate enlargement: terazosin 5 mg. If ApoB > 100 mg/dL: ezetimibe 10 mg. Vitamin K2 MK7 1,000 ug If difficulties falling asleep: Melatonin 3 mg 3 hours before sleep (not “at bedtime”). If waking up during the night: melatonin 3 mg (crashed and dissolved below the tongue) when waking up (to help fall back asleep). Omega 3 (mostly EPA) might help as he’s not APOE4.

You can add to this list: amlodipine (if BP still too high with telmisartan 80 mg), selegiline low dose (especially if depressed), vaccines, GLP-1RAs (if overweight or obese), vitamin D (if deficient, otherwise probably useless). Rapamycin looks great but it’s unclear what is best for neuroprotection: 1 mg/day or larger intermittent dose?