Predicting Alzheimers & Dementia (and minimizing risk)

[AnUser]

Risk of Afib as well, is there any trial showing short term benefits of supplementation on cognition anyway? MR study of Omega-3 index?

It feels heavily marketed. But I might be wrong.

Nowhere near as convinced as for lipids, BP, etc.

[DrFraser]

So a few things - there is plenty of literature out there on DHA and depression - essentially showing no link and many psychiatrists actually using Omega 3 fatty acids for mood disorders (of which I’m not convinced has evidence). However, there is a relationship between having a high fish diet and decreased mood disorders. However, there will always be individuals who get adverse effects with these, but on a population basis, it seems to promote better mental health).

The Afib stuff is far from clear - especially at typical doses of EPA+DHA at ~1000 mg/day. If the relationship exists at all, it is dose related, and there is an approximate 30% symptomatic vascular disease reduction with optimization of Omega 3’s.

Now in regard to the defective transport into the brain @adssx with those with ApoE4’s - this is why I’ve now gone over to the NatureBell Product that is krill based and loaded with phospholipids, which significantly gets around that issue. A double dose (4 capsules) is required to get up the 1000 mg of EPA/DHA. This supplies 800 mg of phospholipids.

@Beth My best assessment on HSV-1 is that it is likely doing low grade damage to the brain and causing neuroinflammation. So suppressing that would be the rational. This is a separate issue than treating an episode where it comes down the nerve to cause a visible outbreak.

This is what Vera-Health says on this:
Recent studies suggest that valacyclovir and acyclovir, both antiviral medications, may have a role in reducing the risk of Alzheimer’s disease (AD). The VALAD trial is investigating the use of valacyclovir in patients with mild AD who are seropositive for HSV1 or HSV2. This trial hypothesizes that valacyclovir could slow cognitive and functional decline by reducing amyloid and tau accumulation in the brain 2.

Further supporting this, a study found that valacyclovir and acyclovir could reverse transposable element dysregulation in HHV-positive AD brains, potentially reducing tau-associated neuropathology 3. Additionally, a systematic review and meta-analysis demonstrated that antiherpetic medications, including valacyclovir and acyclovir, significantly reduced the risk of dementia, particularly in individuals with severe herpesvirus infections 4.

Moreover, computational docking studies and animal models have shown that valacyclovir may improve neurobehavioral markers and reduce neuroinflammation, suggesting a potential disease-modifying effect in AD 5.

The mechanism by which these antivirals may exert their effects involves inhibiting HSV1, which has been implicated in AD pathogenesis, particularly in individuals carrying the APOE-ε4 allele. HSV1 reactivation in the brain can lead to amyloid beta and tau formation, contributing to AD pathology 6.

In summary, current evidence suggests that valacyclovir and acyclovir may decrease the risk of Alzheimer’s dementia by targeting HSV1-related mechanisms. However, further clinical trials are needed to confirm these findings and establish definitive treatment guidelines. These drugs are primarily used for treating herpes infections by interfering with DNA polymerase to inhibit DNA replication (ASHP).

[Beth]

WOW, thanks for that and I had no idea.

I’ll reach out to your personally on this, but for everyone’s benefit…

If one gets cold sores, does it mean you have HSV1 or does one still need to test to confirm … meaning, is it always the cause?

(it looks like I’m going to be consuming 1000 calories a day in pills!!!)

[medaura]

ApoE4 brings an impairment to the transporters of DHA into the brain. To circumvent the problem a phospholipid form is called for. I get mine from Nordic Naturals, the only problem being the dosage needed is much higher as a percentage of the product is phospholipid. If anything the implication from the data is that apoE4 people need MORE DHA than others so the seeming non response is from dose insufficiency. However I’ve seen that to have a protective effect a high omega 3 index needs to go hand in hand with high Vit 12 and Vit D levels. Otherwise the benefits are largely mooted.

[CronosTempi]

@DrFraser

ApoE4’s - this is why I’ve now gone over to the NatureBell Product that is krill based and loaded with phospholipids, which significantly gets around that issue. A double dose (4 capsules) is required to get up the 1000 mg of EPA/DHA. This supplies 800 mg of phospholipids.

FWIW, Rhonda Patrick (who has ApoE4) stated in a podcast with Huberman, that she’s personally has given up on krill oil because 100% of commercially available product that she has come across is significantly rancid, which turns supplementation with it from a positive to a health negative.

I read somewhere that when it comes to fish oil, the human nose is pretty sensitive detecting rancidity, because rancidity has such dire health effects that we have evolved to have a strong aversion to it and good ability to detect it. So unless masking agents are used (and I’ve seen fish oil with lemon scent added!), you should be able to tell if a given oil “passes the smell test”.

[DrFraser]

The naturebell isn’t, I routinely cut open a capsule with each bottle of omega 3 products I start and assess.
So interesting claim, but not an issue with my latest bottle.

On the HSV question prior - generally best to get an IgG level for HSV1/2 to confirm. This is an inexpensive blood test.

[Deborah_Hall]

Wondering if a woman* (*c’est moi) who went through early menopause (age 42) but took estradiol and progesterone from that time to age 70 would be protected from negative effects of early menopause.

[adssx]

@DrFraser

Now in regard to the defective transport into the brain @adssx with those with ApoE4’s - this is why I’ve now gone over to the NatureBell Product that is krill based and loaded with phospholipids, which significantly gets around that issue.

@medaura

ApoE4 brings an impairment to the transporters of DHA into the brain. To circumvent the problem a phospholipid form is called for.

Unfortunately, @medaura @DrFraser , I’m afraid this is totally wrong: neither lysophosphatidylcholine-bound omega-3 fatty acids nor krill oil increase brain DHA in APOE4 mice:

• Parkinson's disease - #643 by adssx
• Parkinson's disease - #640 by adssx

I emailed these papers to Rhonda Patrick and she never got back to me. The archetype of the bullshit health influencer.

[adssx]

@DrFraser

So a few things - there is plenty of literature out there on DHA and depression - essentially showing no link and many psychiatrists actually using Omega 3 fatty acids for mood disorders (of which I’m not convinced has evidence).

No. The largest trial, VITAL-DEP, n=18,353 with 465 mg EPA + 375 mg DHA (so 55% EPA and 45% DHA) over a median treatment duration of 5.3 years (!!!) found that “Depression risk was significantly higher comparing omega-3 (651 events, 13.9 per 1000 person-years) with placebo (583 events, 12.3 per 1000 person-years; hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P = .03).”: Effect of Long-term Supplementation With Marine Omega-3 Fatty Acids vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial 2021

Is there a single better trial that found that omega 3 could lower depression? Most trials are small, short, and of low quality. VITAL-DEP is the definite answer to the question: EPA + DHA CAUSES depression.

Meta-reviews and analyses only found that EPA only or EPA > 60% could lower depression: Omega 3 makes me depressed: why? - #39 by adssx

So EPA alone improves depression while EPA + DHA makes it worse. Conclusion: DHA causes depression?

[jjrap1]

Being ApoE3/4, I’ll definitely be getting the AD panel, however I wonder if there is any test that either tests directly for FN1, or is strongly associated with the existence of the protective FN1 variant:

Predicting Alzheimers & Dementia (and minimizing risk)

Scientists Find Gene Variant Giving Up to 70% Protection Against Alzheimer’s A newly discovered variant in the FN1 gene, which is responsible for making thefibronectin protein, reduces the likelihood of developing Alzheimer’s by up to 70 percent. This finding could lead to more effective treatments for the disease. Led by a team from Columbia University, researchers looked closely at a particular group of people: those with another gene variant called APOEe4 who had never developed Alzheimer’s. Considering APOEe4 significantly increasesthe risk of getting the disease, they suspected there might be a counterbalance. Sure enough, genome sequencing of 10,763 individuals across two groups of people, revealed the protective effects of a specific FN1 variant in people with APOEe4. The FN1 variant seems to be helping to regulate the amount of fibronectin in the brain. The researchers estimate that hundreds of thousands of people with the APOEe4 allele in the US alone have this protect…

[59vw]

@Neo

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

Keep in mind that the shingles vaccine is designed to prevent a previous VZV infection (chicken pox) from resurfacing as a dermatomal eruption (shingles). Most children in the US (and I’m guessing in most developed countries) these days don’t ever get chickenpox like many of us did. They get a vaccine (varivax) that prevents the initial VZV infection so it is pointless for them to ever get the shingrix vaccine.

It will be interesting to see if the incidence of AD goes down significantly when these individuals reach 60 ish and older.

[DeStrider]

Many of my colleagues here in Hong Kong have been getting shingles recently. They said it’s a horrible experience and they had wished they had gotten the vaccine. Some have claimed long term detrimental effects from shingles!

[59vw]

Not sure if your post is in response to mine. Just so there is no misunderstanding you should definitely get the shingrix vaccine if you had chicken pox as a child. I was just stating that it doesn’t make sense if you had the varivax vaccine as a child and never got chickenpox. If you never got chickenpox as a child then you should get the varivax vaccine now.

[BeatTheOdds]

@59vw

shingrix

I am 43 in the UK and had chickenpox as a child. I’m also ApoE4/4. The SHINGRIX vaccine is expensive for me at nearly £500. The NHS only gives this vaccine free when we turn 65 or at 50 if with severe immunosuppression. My take is this is probably money well spent in my position.

Upon further research, it seems most if not all pharmacies won’t vaccinate me until I’m 50.

[DeStrider]

Taurine associated with a 26% lower risk of dementia.

- YouTube

[adssx]

@DeStrider

Taurine associated with a 26% lower risk of dementia.

https://www.youtube.com/shorts/XXyzhbNKuOo?si=cpG0Fu4vPbggcSAb

Based on: Association of amine biomarkers with incident dementia and Alzheimer’s disease in the Framingham Study 2018

Ninety-three participants developed incident dementia (mean follow-up=15.6±5.2 years). Higher plasma anthranilic acid levels were associated with greater risk of dementia (HR=1.40; 95%CI=[1.15–1.70]; p=8.08×10–4). Glutamic acid (HR=1.38; 95%CI=[1.11–1.72]), taurine (HR=0.74; 95%CI=[0.60–0.92]) and hypoxanthine (HR=0.74; 95%CI=[0.60–0.92]) levels also showed suggestive associations with dementia risk.
We identified four biologically plausible, candidate plasma biomarkers for dementia. Association of anthranilic acid implicates the kynurenine pathway, which modulates glutamate excitotoxicity. The associations with hypoxanthine and taurine strengthen evidence that uric acid and taurine may be neuroprotective.

(not sure you want high uric acid though btw)

[DrFraser]

So … I’ll gently disagree. This is a great example of statistical significance, not being the same as clinical significance. So the delta here is 1.6 per 1000 person years. So 1 person in 625/year more likely to have depression? So that person can stop. Not clinically meaningful (unless you are the 1:625).

It is impossible from this data to understand the actual % of the population studied who had depression, but in the US ongoing rate is reported at 8.8% currently, but some estimates are much higher. Yet this dataset has a 1.23-1.39% in a given year. So representative? I don’t know.

Overall, saying DHA causes depression has a result of 1 excess case/year per 625 individuals. Those individuals simply cease. But the 624 who it makes no difference continue.

I cannot see any clinical relevance of this, except to make sure to be aware that if I have a patient on DHA (which will be virtually 100% of my patients) and they have new onset depression - consider the possibility that cessation of DHA might be sensible.

[adssx]

You might be right, as there was no significant difference in PHQ-8:

Still:

1. That’s the best trial we have for omega 3 and mental health and it shows that EPA + DHA increases the risk of depression, this might not be significant but in any case we cannot say that omega 3 help with mood disorders.
2. Meta-reviews show that only EPA-dominant formulations improve depression. So if EPA alone is antidepressant but EPA + DHA is not, then surely DHA has some negative impact?
3. When I posted that DHA made me depressed, several other people chimed in: Omega 3 makes me depressed: why?

I think the problem is even worse in APOE4 people: Parkinson's disease - #639 by adssx

1. Supplemental DHA does not go into their brain
2. High serum DHA is associated with a HIGHER risk of dementia

So I would not give DHA to:

• People with a personal or family history of depression or mood disorders and/or
• APOE4 carriers

[amuser]

E3/E4 here, and I haven’t noticed anything from fish oil supplementation. Lucky, I guess.

[DrFraser]

I think this is complicated. It is interesting that Dr. Dayspring is not on top of this controversy.

He want’s omega 3 index of 10% in those with ApoE4’s. Does it matter if not getting into the brain? Might it be harmful?

Do phospholipids bypass this pathway of the DHA transporter?

There is clearly an age related issue also in the literature, younger people even with apoE4/E4 transport DHA well into their brain, whereas older individuals don’t.

We don’t know, if you start at age 50 years with solid supplementation, if it continues to get absorbed well.

Also ApoE3/E4 or E2/E4 how bad is their absorption to the brain? An E4/E4 is more concerning, but that is only 4-6% of cases of ApoE4 carrying individuals.

For the majority, I’m favoring early use, but ones that have phospholipids or through fish consumption.

I do give DHA to patients irrespective of family history or personal history of mental health disorders, and for the time being those with ApoE4’s. I’m waiting to be convinced that this isn’t sensible, and change my approach.