New paper suggests that statins may be beneficial for E4 homozygotes

[Julie G]

Now this is interesting! A new paper re-analyzes datasets from older papers and concedes that statins may be particularly beneficial for E4 homozygotes. Your thoughts?

Evidence for benefit of statins to modify cognitive decline and risk in Alzheimer's disease.
https://www.ncbi.nlm.nih.gov/pubmed/28212683

Abstract
BACKGROUND:
Despite substantial research and development investment in Alzheimer's disease (AD), effective therapeutics remain elusive. Significant emerging evidence has linked cholesterol, β-amyloid and AD, and several studies have shown a reduced risk for AD and dementia in populations treated with statins. However, while some clinical trials evaluating statins in general AD populations have been conducted, these resulted in no significant therapeutic benefit. By focusing on subgroups of the AD population, it may be possible to detect endotypes responsive to statin therapy.
METHODS:
Here we investigate the possible protective and therapeutic effect of statins in AD through the analysis of datasets of integrated clinical trials, and prospective observational studies.
RESULTS:
Re-analysis of AD patient-level data from failed clinical trials suggested by trend that use of simvastatin may slow the progression of cognitive decline, and to a greater extent in ApoE4 homozygotes. Evaluation of continual long-term use of various statins, in participants from multiple studies at baseline, revealed better cognitive performance in statin users. These findings were supported in an additional, observational cohort where the incidence of AD was significantly lower in statin users, and ApoE4/ApoE4-genotyped AD patients treated with statins showed better cognitive function over the course of 10-year follow-up.
CONCLUSIONS:
These results indicate that the use of statins may benefit all AD patients with potentially greater therapeutic efficacy in those homozygous for ApoE

[LG1]

Ugh, I don't want this to be true.

Going to check out the study. I am curious to know if they mentioned anything about their cardiovascular health etc....

Looking forward to hearing members' theories on WHY the statins caused a decreased cognitive decline.

[Stavia]

I'm still intruiged about the ability of the word "statin" to create an emotional reaction!
I'll bet any positive effect is related to inflammation not the lipid lowering effect. But it's just a guess.

[Julie G]

I hear you, LG1 and agree, Stavia. We know statins exert an anti-inflammatory effect. I suspect the dataset didn't include many, like us, taking extraordinary measures to reduce inflammation in other ways. This could be a plausible MOA. If the mechanism was purely cholesterol lowering, wouldn't we see seniors with low cholesterol enjoying neuroprotection? Instead, we see the opposite. Those with higher cholesterol levels have greater cognition and longevity. At this point, I remain humbled at how much we don't know.

[KatieS]

Wish we could see the entire article. I suspect the 4/4s were a smaller subset, so what about the 3/4s? Was SV the only significantly protective statin? As you might recall SV was what famous Longevity/Gene projects, Craig Venter who upon learning his 3/4 results stated on SV. The mouse research seems to hint toward SV being the most neuroprotective. SV is what my 3/4 (but has other AD genetic risks too) 99 y/o mom has been on the lowest dose of 10 mg for decades. Unfortunately I couldn't tolerate the 20 mg dose, so I'm on pravastatin, but if this finding is supported again in humans , it would be time to reconsider the low-dose.

[MarcR]

It's an open access paper - full text is here.

Looking forward to hearing members' theories on WHY the statins caused a decreased cognitive decline.

In the paper is an extensive discussion of the flaws and weaknesses in this after-the-fact analysis. After reviewing those equivocations, I'm not persuaded that adding statins to a lifestyle already marked by cardiovascular and muscular fitness and supported by regular fasting, avoidance of overnutrition, and sufficient sleep would be helpful. Based on this paper, I would use "are weakly associated with" rather than "caused".

[Julie G]

I've only quickly scanned, but found some of the information intriguing. See Figure 2 below. It addresses your question re. the difference between how 3/4s and 4/4s responded. Shockingly, the cognition of 3/4s worsened on SV, over time, especially evident at the 18 month time frame. Your Mom continues to defy all odds and statistics- yay .

13195_2017_237_Fig2_HTML.gif

The cognition of 4/4s also worsened over time for both the controls and those on SV. This isn't particularly surprising given the mean age around 74 y/o and high risk genotype. Those on SV did slightly better than the control group, but also worsened over time if you cut to the 18 month data point.

The authors make a point of noting that the SV benefit for homozygotes isn't statistically significant, but a trend was detected. They also point out that no correlation was found between ADAS-cog scores and total cholesterol or triglyceride levels perhaps corroborating our theory that the benefit was from a reduction in inflammation (?) I need to read the paper more carefully and look forward to other's insights.

[circular]

Katie I'm just curious if you've ever looked at your mother's TOMM40 SNP. It's usually in linkage disequilibrium with ApoE4, but occasionally normal. It would be interesting to see if our outliers, including Starfish too, happen to have a normal TOMM40. Here's a paper about it and the mitochondrial cascade hypothesis.

[Starfish77]

I don't know how or where to look up my TOMM40 snp. I tried entering it on the 23andme raw data and it didn't take it.
Tell me what to do and I will look it up.
Starfish

[Harrison]

I don't know how or where to look up my TOMM40 snp. I tried entering it on the 23andme raw data and it didn't take it.
Tell me what to do and I will look it up.
Starfish

Here are two TOMM40 snps. G "may" be the at risk allele: rs2075650 and rs157580

As circular noted, researchers have found that TOMM40 is in linkage disequalibrium with APOE4, meaning they are likely travel to together. ApoE4 carriers are likely to be G/G. I am ApoE3/4 and A/G on both TOMM40 snps.

Allen Roses has gone further and said the length of the TOMM40 snp is the important information, and that cannot be gleaned from 23andme (or probably any non-specialty genetic testing): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946560/. However, others have been unable to replicate his work: See this story: http://www.alzforum.org/news/research-n ... -age-onset.