#201

@DrFraser this may be of interest.

There are a few theories on what contributes to and causes AD. The Tau thing, genetics, and oral microbiome. One microbe of interest is Porphyromonas gingivalis

The oral microbiome is getting a lot of attention and a “new” drug is now in Phase II/III trials.

The GAIN trial (NCT03823404) is a Phase II/III double-blind, placebo-controlled clinical trial evaluating the safety and clinical activity of atuzaginstat (COR388), a novel bacterial virulence inhibitor, in patients with mild-moderate Alzheimer’s disease (AD).

COR388 is not super new, I’ve found research on this going back to 2017 and it is available as a research chemical.

Here is a good article on this

More importantly, the study explains the theory, results and how it all ties into the APOE effects related to Porphyromonas gingivalis

Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors

https://www.science.org/doi/10.1126/sciadv.aau3333

Now I need to read the protocol used in the study and see what the dosing is and check into getting some Atuzaginstat/COR388.

From my quick review on the weekend, it seems to me that early use of this drug should be tremendously beneficial not only for AD but also for CVD.

3 Likes
#202

I go for aging causing splicing problems as highlighted on the other thread.

#203

Yes - one of my YouTube Videos goes over pediodontal care and links to a discounted oral microbiome test that includes evaluation for P. gingivalis. I agree, an important item.

4 Likes
#204

Dementia Risk Mitigation

42% of people aged 55 years old will have dementia before death:

This article is very interesting. This article indicates that in the near future, adults currently over age 55 years, lifetime risk of dementia will be 42%. Frequencies of ApoE alleles are as follows:
ApoE4/E4 2-3%, Heterozygous for ApoE4 (e.g. one E2 or E3) is 22%, and 59% have ApoE3/E3.
So 25% of people have and ApoE4 (or 2) and yes, more risk of dementia. Currently 40-65% of patients with AD have at least one copy of an ApoE4.

Genetic factors to examine:

ApoE status - Through FIDALabUS.com with Code FRASER25 they will allow self ordered ApoE genotype for $50

Through FIDALabUS.com they will be offering the following gene analysis for $150. Your other option is more difficulty, which is to get your genome sequenced (such as through dnacomplete.com, get.sequencing.com) and upload your genome to Promethease.com. Genes/SNPs to look for include:

PSEN1 – strongly associated with early onset AD

PSEN2 – strongly associated with early onset AD

APP – strongly associated with early onset AD

TREM2 – Increases risk for late onset AD

EPHA1 – Slightly reduces risk for AD

PICALM – Slightly reduces risk for AD

SORL1 – Slightly reduces risk for AD

MS4A6A – Slightly reduces risk for AD

Lifestyle options/labs/medications/supplements to risk mitigate for dementia

Lifestyle/Basic Items to Track

Use your brain to do complex things as much as possible. Passively watching things is fine for relaxation, but make your brain do repetitive hard work! It is likely that doing a substantial variety of tasks is beneficial as part of this.

Stay mentally active and socially engaged

Have a diet with more veggies, pholyphenols, flavonoids, limited extra virgin olive oil likely good, and fiber to >30-40 g/day

Limit or better yet eliminate artificial sweeteners

Minimize exposure to plastics – especially anything heated in plastic that you would then consume

No processed foods

Limit anticholingeric medications (for example Benadryl or Amitryptyline, Oxybutynin, many antipsychotics/bipolar disease medications). Limit antiepileptics like carbamazepine or oxcarbazepine. Opioids might also

Limit or eliminate medications like benzodiazepines (Ativan, Xanax, Valium) or other similar (like Ambien) and narcotics.

Don’t smoke cigarettes or THC (or anything else)

Normalize hormones for life (some question on late introduction of estradiol in ApoE4 individuals)

Optimized blood pressure (SBP 110-120/70-77 mmHg), insulin sensitivity (HOMA-IR<2) and blood lipids (target to ApoB/Lp(a))

Optimize omega 3 index if ApoE4 positive then 10% (8% otherwise). If ApoE4 positive, then supplement with phospholipid forms of DHA. Read this article: Healthspan Research Review | Dr. Rhonda Patrick on DHA in Phospholipid Form for Alzheimer's Prevention in APOE4 Carriers

Maintain a Vitamin D ~50 ng/mL is likely optimal.

Sleep monitoring to get at least 7 hours of sleep nightly, but not more than 9 hours. Be aware glymphatic activation occurs in deep sleep phase N3. Consider an Oura Ring or similar.

Regular aerobic exercise 150 minutes/week of zone 2, and 2 sessions of weight lifting (at least) weekly

Minimize alcohol and THC consumption

Optimize B12 (also measure MMA to confirm)

Look at Ferritin/HsCRP for any iron overload

Optimize peripheral lipids, but consider avoiding agents that decrease cholesterol in the brain

Optmize insulin sensitivity

Optimize Blood Pressure, goal 110-120/70-77 mmHg (https://www.youtube.com/watch?v=5yCsB1iRR1o&authuser=0)

Assess for chronic infections, particularly HSV-1, and if present treat this

Periodontal health optimization. If missing teeth, place implants. Check oral microbiome and if Porphyromonas gingivalis is present eliminate it and confirm on repeat retesting. Testing available here: https://fidalabus.com/at-home-test-for-individuals/ Select the Oral Periodontal Pathogen Test, also note they have a specific Dental Probiotic available. Their Disease Risk Genetic Test is also excellent and includes and ApoE. Use discount code FRASER to get a discount on any of their products.

The Lancet article https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)01296-0/abstract discussed the following as risk factors, and if none were present 50% rate reduction of dementia:

Get more education

Avoid/Treat hearing loss

Avoid/Treat hypertension

Don’t smoke

Don’t be overweight or obese

Avoid depression, physical inactivity, Type 2 Diabetes, Excessive alcohol intake (>12 standard U.S. drinks/week), traumatic brain injury, air pollution and social isolation.

Stay up to date with essential immunizations, primarily Tetanus (may be sensible to do every 3 years), Influenza, Shingles Vaccine, and Pneumovax The surprising relationship between vaccinations and Alzheimer’s disease New study reveals a major link between vaccines and Alzheimer's - The Brighter Side of News

Tests to consider (In addition to genes listed above)

Definitions

Aβ42:Aβ40 (beta-amyloid) ratio is a critical biomarker in the diagnosis and monitoring of Alzheimer’s disease (AD). This ratio compares the levels of amyloid-beta 42 (Aβ42) to amyloid-beta 40 (Aβ40) in biological fluids such as cerebrospinal fluid (CSF) and plasma. A lower Aβ42/40 ratio is indicative of AD, as it reflects the deposition of Aβ42 in the brain, a hallmark of the disease.

P-tau 217 and P-tau 181 are phosphorylated tau proteins that serve as important biomarkers in the context of Alzheimer’s disease (AD). These biomarkers are used to detect and monitor the progression of AD, as they are associated with the accumulation of tau pathology in the brain, a hallmark of the disease.

P-tau 181 has been extensively studied and is considered a reliable biomarker for detecting AD pathology. It is associated with cerebral AD pathology and cognitive decline, making it a useful tool for diagnosing and monitoring the disease

Plasma P-tau 181 levels have been shown to correlate with AD neuropathology and can differentiate between individuals with and without AD, even in preclinical stages.

P-tau 217 is emerging as a potentially superior biomarker compared to P-tau 181. It has demonstrated higher consistency with amyloid PET results and is a better predictor of amyloid positivity, which is crucial for diagnosing AD.

P-tau 217 has shown reliability in diagnosing AD and may enhance diagnostic accuracy, prognosis, and patient monitoring by effectively staging the disease

Aβ42:Aβ40 ratio and p-Tau217 are the only tests seen that are predictive of later dementia https://jamanetwork.com/journals/jama/fullarticle/2821669 https://scholarworks.indianapolis.iu.edu/server/api/core/bitstreams/b6003149-da86-47ae-9824-551d8cf641b2/content

Note, can get both through LabCorp for $225 each (FidaLabUS.com is going to be offering a panel with all 3 of these for a lot less than the $675 it would cost through LabCorp)

LabCorp pTau-181 483745: Phosphorylated Tau 181 (pTau-181), Plasma | Labcorp Test 483745. Plasma Phospho-Tau-181 as a Diagnostic Aid in Alzheimer’s Disease - PMC

LabCorp pTau-217 test 484390 484390: Phosphorylated Tau 217 (pTau-217), Plasma | Labcorp The Taiwan‐ADNI workflow toward integrating plasma p‐tau217 into prediction models for the risk of Alzheimer's disease and tau burden - PMC

LabCorp A42/40 505725: Beta Amyloid 42/40 Ratio, Plasma | Labcorp. Labcorp test 505725 https://scholarworks.indianapolis.iu.edu/server/api/core/bitstreams/b6003149-da86-47ae-9824-551d8cf641b2/content

Vitamin D goal for ~50 ng/mL

Check for heavy metals, mold exposure, chronic infections (especially H pylori, HSV 1)

Consider Cunningham test or Vibrant NeuroZoomer (more cost effective) Well ProZ

Consider checking for environmental and other exposures, such as Vibrant total tox and PFAS

Total Tox: https://22446299.fs1.hubspotusercontent-na1.net/hubfs/22446299/Sample%20Reports/MK-0125-00%20Total%20Tox%20Burden%20Sample%20Report.pdf 1

Total tox includes mold, organic toxins/PFAS, heavy metals, environmental toxins

Consider chronic infections, Vibrant Infection panel and also Tick 1.0 or 2.0 https://hello.vibrant-wellness.com/hubfs/Tests/Viral-Infections/Viral-Infections-Sample-Report.pdf 1

Consider micronutrient panel (Vibrant) https://hello.vibrant-wellness.com/hubfs/Tests/Micronutrient-Panel/Micronutrient-Sample-Report.pdf

Consider Salivary Cortisol testing with ZRT or similar as abnormal cortisol levels and pattern will promote dementia

Medications/Supplements/Devices to consider:

Rapamycin/Sirolimus, if ApoE4, consider q14 day dosing with goal 100 hr level of ~3 ng/mL

GLP-1 agonist

SGLT2-i

Telmisartan

Low dose lithium

Fish/Algae oil with goal as above with Omega 3 index

Vitamin D optimize to 50 ng/mL

Vitamin B2/Riboflavin

Turmeric/Curcumin/Black Pepper Extract Nanoparticle, NanoCur, 2 capsules daily Amazon.com: Turmeric Curcumin - 100x More Active Than Turmeric, 170% More Active Than Curcumin + Black Pepper Extract. Joint Support, Relief, and Energy You’ll Feel. Organic Curcumin/Plant-Based Carrier. : Health & Household

Ezetimibe could be useful

Hormone normalization for life

Methylene blue

Nattokinase/Serrapeptase

Dihydroquercetin – URL for buying here: Amazon.com: Supersmart - Taxifolin Dihydroquercetin 60mg per Day (90% DHQ Supplement) - Russian Siberian Dahurian Larch Tree Extract - Antioxidant Bioflavonoid | Non-GMO & Gluten Free - 100 Tablets : Health & Household 3

Ubiquinol or CoQ10 should be optimized given relationship of low levels with dementia

Low dose aspirin (if no contraindication) Long-term low-dose acetylsalicylic use shows protective potential for the development of both vascular dementia and Alzheimer’s disease in patients with coronary heart disease but not in other individuals from the general population: results from two large cohort studies | Alzheimer's Research & Therapy | Full Text

Alpha GPC Cognitex® Alpha GPC, 30 softgels - Life Extension

Alpha Klotho – great at the point in time we can easily measure levels (Jfinity will test for ~$300). Work on driving it up with exercise/rapamycin

17 Alpha Estradiol

Astaxanthin https://us.fullscript.com/o/care-center/products/U3ByZWU6OlByb2R1Y3QtOTgwMjE=/U3ByZWU6OlZhcmlhbnQtMTE1MDg5 4

Black Seed (Cumin) Oil via Thymoquinone https://us.fullscript.com/o/care-center/products/U3ByZWU6OlByb2R1Y3QtOTM0OTc=/U3ByZWU6OlZhcmlhbnQtMTEwNDcx 1

Spermidine (Doublewood) 10 mg/day Amazon.com: Spermidine Supplement (10mg of 99% Spermidine 3HCL - Third Party Tested) 120 Capsules - Over 100x More Potent Than Wheat Germ Extract for Cell Membrane, Telomere Health and Aging by Double Wood : Health & Household

NT Factor Lipids NTFactor® Lipids Powder – NTFactor 4

Carnosine 500 mg daily Amazon.com: NOW Foods Supplements, L-Carnosine (Beta-Alanyl-L-Histidine) 500 mg, Healthy Aging, 100 Veg Capsules : Health & Household

NAC Ethyl Ester with Glycine, 1 capsule daily Amazon.com: N-Acetyl Cysteine Ethyl Ester 100mg - More Absorption Than 1000mg NAC - with Glycine 600mg - Benefit Glutathione - Good for Immune System & Antioxidant for Adults, NACET ( 60 Capsules - 2 Pack) : Health & Household

Creatine monohydrate, 5 grams dissolved in 8-12 oz of water daily Amazon.com: BulkSupplements.com Creatine Monohydrate Powder - Creatine Supplement, Micronized Creatine 1kg, Creatine Powder - Unflavored & Gluten Free, 5g (5000mg) per Servings, 1kg (2.2 lbs) (Pack of 1) : Health & Household

Berberine 500 mg daily (1 capsule) Amazon.com: Berberine Supplement 500mg, 60 Capsules (Third Party Tested, Non-GMO, Gluten Free, Vegan Safe) AMPK Activator - Berberine HCL for Cardiovascular Health by Double Wood : Health & Household

Creatine 5 grams daily Amazon.com: BulkSupplements.com Creatine Monohydrate Powder - Creatine Supplement, Micronized Creatine, Creatine Powder - Unflavored & Gluten Free, 5g (5000mg) per Servings, 500g (1.1 lbs) (Pack of 1) : Health & Household

40 Hz light and sound

Article on 40 Hz vibrations reduce Alzheimer’s pathology, symptoms in mouse models | MIT News | Massachusetts Institute of Technology

Helmet with light

https://symbyxbiome.com/blogs/symbyx-blog/light-therapy-helmets-for-parkinsons-disease-the-san-trial-results-explained

https://symbyxbiome.com/blogs/symbyx-blog/5-years-of-continue-light-therapy-use-for-parkinsons-trial-results-now-published

Glasses with sound and light https://amzn.to/3CIw5c4

Head band with Gamma Light at 40Hz https://koushicare.com/

Vagus Nerve Stimulator https://pulsetto.tech/products/pulsetto-bundle here is one article on this topic https://www.sciencedirect.com/science/article/pii/S1878747923000892

**P. gingivalis treatment/testing/**Periodontal Health and Cognitive Decline

https://youtu.be/UqX3sbJKk0c Dr. Greger discussing

https://youtu.be/sa2S90cYzzA Dr. Stanfield discussing how to maximize periodontal health

Do this routine twice daily items 1-5

  1. First Floss, use Reach Mint Floss (has no PFAS and is cheap)

  2. Then use water flosser to the gums (waterpik) https://amzn.to/3DfNxEX

  3. Brush with electric toothbrush, vibration superior to others, use Phillips Sonicare 2100

  4. Fluoride Toothpaste - best choice is Colgate Cavity Protection with Fluoride https://amzn.to/4hTxBr7

  5. Use Xylitol a few times daily via mints or gum https://amzn.to/3QvywlF

  6. See a Dentist/Dental Hygienist for formal dental cleaning and review every 6 months.

  7. If missing teeth, have implants placed

  8. Check oral microbiome and if Porphyromonas gingivalis is present eliminate it and confirm on repeat retesting. Testing available here: https://fidalabus.com/at-home-test-for-individuals/ Select the Oral Periodontal Pathogen Test, also note they have a specific Dental Probiotic available. Their Disease Risk Genetic Test is also excellent and includes and ApoE. Use discount code FRASER to get a discount on any of their products.

On having a microbiome test showing p gingivalis, as it tends to be protected under a biofilm, it is best to get a professional dental cleaning and then immediately and meticulously follow steps 1-5 above.

Consider a probiotic meant to improve oral microbiome such as one of these:
Probiomax Oral or Biogaia.

If oral hygiene is excellent and we enact these items above and still testing positive, then:
-Consider short course of chlorhexidine mouthwash
-Consider short course of metronidazole (doxycycline, amoxicillin, and azithromycin also work, but have more effect on the other oral bacteria, whereas metronidazole is a little more limited in its reach)
-Add Turmeric based toothpaste

Retest post therapy.

5 Likes
#205

Agree. Alzheimer’s is Now Optional - WTF ? - FU ! Tell that to millions of Americans that get diagnosed with AD every year. What an arrogant, click bait title.

4 Likes
#206

Any experience with NMN for prevention or for MCI/early dementia ?

I stayed away from NMN given the scarcity of evidence for longevity or any benefits in the studies. However at least it appeared safe in the short term studies.

Recently, I was battling a post viral syndrome for few weeks and run it to some evidence that it may be useful in that setting (Long Covid etc -depleted NAD).

So I figured, WTH I will give it a try. I ordered the sublingual version of NMN from Renue. I tried the 500 mg dose under tongue (supposedly 30% absorption) and really NOT expecting much.

Holy crap, this thing hit me like cocaine within few minutes. I haven’t been this alert and clear minded in a while. The effect lasted for few hours. I only use half the dose now.

I am still not sure what NMN can do long term but just as Noortropic this thing is awesome. Hopefully this effect is not subject to tolerance.

My mother is suffering from early stage of Alzheimer’s/MCI, I already have her on creatine, choline, NAC, B complex, etc. I hate to experiment on her but she couldn’t tolerate donepezil and I wonder if NMN would be appropriate. I think the liposomal version, slow release version may be more appropriate.

Thoughts?

4 Likes
#207

@Dr.Bart Got no thoughts on NMN as I’ve never used it though your comment made me NMN curious. Just here to say don’t feel bad experimenting, even though it’s your mom, or especially since it’s your mom. You do know what happens if you don’t do anything and it’s not pretty. All these supplements are GRAS so worst case you’re just financing expensive urine. Best case they do something real.

Have you tried / considered exogenous ketones?

2 Likes
#208

Yes, but they are pretty pricey. I figure I will try the NMN first, then maybe tried delta G ketones next.

#209

I can’t speak to anything scientific here, but years ago, my doc told me to take NMN and I did feel it, so I do believe it does ‘something’.

However, I stopped taking it a couple years ago when hearing all the Sinclair hate and how he recommends a lot of garbage, this being one of them. Based on that, I assumed it must not do anything for my actual health.

I’ll look forward to this discussion!

1 Like
#210

I don’t know about NMN but NR was successful in a phase 2 trial in Parkinson’s disease and phase 3 results will be published soon. Could it work for AD as well? :man_shrugging:

3 Likes
#211

I had not heard this!!!

Does this mean we are replacing our DHA with NR (or NMN)???

Am I going back on the juice?

#212

Have you tried / considered the gamma wave stimulation devices? Less than $100 on Amazon, 20 min a day protocol.

2 Likes
#213

FWIW, I experienced no effect from up to 2g of sublingual NR and/or NMN. I did measure NAD through Jinfiniti and my levels were very high normal, so perhaps that’s why I didn’t notice anything.

2 Likes
#214

While NR-recipients exhibited a slight initial rise in serum homocysteine levels, the integrity of the methyl donor pool remained intact

I am surprised they didn’t supplement with TMG especially with these super high doses.

1 Like
#215

I think that’s the KEY, I doubt that people with normal NAD levels can truly benefit from… more NAD.

4 Likes
#216

I’m considering a 6 month blast of endogenous ketones but not sure what to “measure” before and after.

Also, a random thought… do exogenous ketones help eyes/optic nerve? That would be easy to test impact

#217

I’m not sure what to measure either. When it’s about cognitive performance I put a lot of stock on subjective measurement. In 2019 when I was full on keto and working out my mind was sharp as a diamond. I well remember that!

#218

Better than ketones in a bottle for sure. I went from full keto to low carbs but I’m staying in mild ketosis which I find to be enough to keep a sharp mind.
I also credit the SGLT2i (empagliflozin), and running, form helping with that.

3 Likes
#219

I’m convinced that there is something here:

This is supposedly the sound used by the MIT researchers: https://www.youtube.com/watch?v=UVne_84qZkA&ab_channel=DJNizzo

Some members of the research team started a company to make a device that applies visual and audio stimulation based on their research: https://www.cognitotx.com/

3 Likes
#220

I have the cheapy device that just synchronizes the sound from headphones and the flashes of a light strobe to 40 hz. It’s pretty simple. Less than $100 on Amazon and not unpleasant other than the whiteness of the light which I get around by wearing red light glasses in the evening anyway.

2 Likes