Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama Study.

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Hepoberman
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Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama Study.

Postby Hepoberman » Mon Dec 15, 2014 4:41 pm

Michael Greger M.D says, "Since studies show “even moderately elevated cholesterol increased dementia risk,” the cognitive impairment more often seen in those eating meat may be due to atherosclerotic plaque building in the brain’s blood vessels, which can cause micro-infarctions or “ministrokes” that can kill off little parts of the brain the way clogged coronary arteries can kill off parts of the heart during a heart attack. A new autopsy study found that those with cholesterol levels over 224 had up to 25 times the odds of having Alzheimer’s pathology (neuritic plaques) in their brains compared to those with cholesterol under 224."

He uses this study to back his claim: http://www.ncbi.nlm.nih.gov/pubmed/21911734

Is it fair to say even moderately elevated cholesterol increased risk from this study? If not, what is wrong with this study? Seems like we should avoid dyslipidemia, especially us ~4's. Two paths towards dyslipidemia are 1) carbohydrate overload (if your liver creates VLDL when you eat carbs, you've absorbed too much carbohydrate) and 2) fat overload. If you're tg's are not under 100 mg/dl at 6 hours postprandial, you've over ate fat. (sat fat clears more slowly, btw)

Still looking for answers, Hep

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Re: Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama Study.

Postby Julie G » Mon Dec 15, 2014 5:02 pm

I'd like to see full-text of the study...Stavia, dear? :D

FWIW, dyslipidemia is defined as more than elevated LDL. It's a bigger atherogenic clinical picture including depressed HDL and elevated TGs...kind of puts a different spin on interpreting the study. Why just pick on LDL?

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Re: Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama Study.

Postby Stavia » Mon Dec 15, 2014 9:01 pm

looking for the study I found this comment on the study: I'm posting it first:

Association of alzheimer disease pathology with abnormal lipid metabolism: the hisayama study

Mascitelli, Luca; Seneff, Stephanie; Goldstein, Mark R.

Author Information

Udine, Italy

Cambridge, MA

Naples, FL


Responding to the study by Matsuzaki et al., which found an association between high cholesterol levels and Alzheimer disease (AD) pathology, Dr. Mascitelli et al. suggest the alternative interpretation that statin therapy may be responsible for the increased risk of dementia in these patients. The authors counter that, while they did not address this question directly, most other studies on the subject have not found a significant association between statin use and AD risk. Drs. Park and Koltzenburg point out that small sample size and broader inclusion criteria may explain why Burakgazi et al. found that oxaliplatin causes only mild axonal loss, compared to previous studies that showed more significant amplitude reductions. They also comment that the reductions in intraepidermal nerve fiber density are surprising and that these findings should be replicated in a larger population. Authors Klassen and Ahlskog respond to Dr. Rosenbaum's inquiry, clarifying that the normal pressure hydrocephalus patients in their study were assessed with videotaped gait examinations before and about 30 minutes after high-volume lumbar puncture as part of their diagnostic evaluation. Megan Alcauskas, MD, and Robert C. Griggs, MD


Matsuzaki et al.1 found that dyslipidemia may increase the risk of plaque-type pathology, and suggested that adequate control of cholesterol, in addition to the control of diabetes, might contribute to a strategy for the prevention of Alzheimer disease (AD). However, the most significant result reported in this study is that the highest quartiles of low-density lipoprotein (LDL), total cholesterol/ high-density lipoprotein (HDL), LDL/HDL, and non-HDL cholesterol showed increased risk for neuritic plaque compared to the lowest quartiles, where cholesterol status was measured at least 10 years prior to plaque measurement. After correcting for major confounding variables, there was no significant difference for the middle quartiles compared to the lowest. A plausible explanation for this finding might also be that statin therapy, more likely to be used in those with high cholesterol, could be the main cause of the increased risk of dementia. Otherwise, this study is inconsistent with other studies that have shown an inverse relationship between cholesterol levels and mental decline in the elderly.2,3 Furthermore, such an interpretation would confirm the results reported in the Cardiovascular Health Study,4 where “ever used statins” were associated with a 1.21 hazard ratio for dementia, and “previously used statins” were associated with a 2.5-fold increased risk compared to “never used statins.”


Author Response: Kensuke Sasaki, Toru Iwaki, Fukuoka, Japan: Mascitelli et al. question whether statin use could be an important confounding factor for the risk of Alzheimer pathology. They stated that “previously used statins” were associated with a 2.5-fold increased risk compared to “never used statins” in the Cardiovascular Health Study.4 However, most related studies including the Cardiovascular Health Study itself claimed no significant association of statins with a risk of AD.4–6 Moreover, the Rotterdam Study reported that statins are associated with a reduced risk of AD.7 We did not directly evaluate the risk of statin use because it was difficult to determine separately the impact of high cholesterol and statin use in our observational study.1 Currently, we do not know if statin therapy may cause increased risk of AD. It is plausible that adequate control of metabolism and lifestyle modifications may lessen the need for statin therapy and may contribute to a strategy for the prevention of AD. Ongoing analyses in the Hisayama Study for the association between dyslipidemia and AD, in relationship to many confounding factors, may contribute to further clarification.


1. Matsuzaki T, Sasaki K, Hata J, et al.. Association of Alzheimer disease pathology with abnormal lipid metabolism: The Hisayama Study. Neurology 2011; 77: 1068–1075 . [Context Link]


2. Tilvis RS, Valvanne JN, Strandberg TE, Miettinen TA. Prognostic significance of serum cholesterol, lathosterol, and sitosterol in old age: a 17-year population study. Ann Med 2011; 43: 292–301 . [Context Link]


3. Presecki P, Muck-Seler D, Mimica N, et al.. Serum lipid levels in patients with Alzheimer's disease. Coll Antropol 2011; 35 (suppl 1): 115–120 . [Context Link]


4. Rea TD, Breitner JC, Psaty BM, et al.. Statin use and the risk of incident dementia: the Cardiovascular Health Study. Arch Neurol 2005; 62: 1047–1051 . [Context Link]


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Re: Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama Study.

Postby Julie G » Mon Dec 15, 2014 9:25 pm

Thanks, Stavia. Yeah, I saw that too, statins MAY have been confounders.

I also found this; VERY interesting. It's another spin-off paper from the Hisayama Study looking specifically at ApoE4 implications. No surprise; looks like insulin resistance is the big player for us.

Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study.
http://www.ncbi.nlm.nih.gov/pubmed/20739649
Abstract
OBJECTIVE:
We examined the association between diabetes-related factors and pathology of Alzheimer disease (AD) to evaluate how diabetes affects the pathogenic process of AD.
METHODS:
This study included specimens from a series of 135 autopsies of residents of the town of Hisayama in Fukuoka prefecture (74 men and 61 women) performed between 1998 and 2003, who underwent a 75-g oral glucose tolerance test in clinical examinations in 1988. We measured diabetes-related factors including fasting glucose, 2-hour post-load plasma glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) in 1988. Neuritic plaques (NPs) were assessed according to the Consortium to Establish a Registry for Alzheimer's Disease guidelines and neurofibrillary tangles (NFTs) were assessed according to Braak stage. The associations between each factor and AD pathology were examined by analysis of covariance and logistic regression analyses.
RESULTS:
Higher levels of 2-hour post-load plasma glucose, fasting insulin, and HOMA-IR were associated with increased risk for NPs after adjustment for age, sex, systolic blood pressure, total cholesterol, body mass index, habitual smoking, regular exercise, and cerebrovascular disease. However, there were no relationships between diabetes-related factors and NFTs. Regarding the effects of APOE genotype on the risk of AD pathology, the coexistence of hyperglycemia and APOE epsilon4 increased the risk for NP formation. A similar enhancement was observed for hyperinsulinemia and high HOMA-IR.
CONCLUSION:
The results of this study suggest that hyperinsulinemia and hyperglycemia caused by insulin resistance accelerate NP formation in combination with the effects of APOE epsilon4.

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Re: Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama Study.

Postby Stavia » Mon Dec 15, 2014 9:31 pm

I couldn't download the pdf but here is a word document of the Hiyama study copied and pasted

Association of Alzheimer disease pathology with abnormal lipid metabolism.docx


Moderator note - I deleted the attached paper (doi: 10.1212/WNL.0b013e31822e145d) because our copyright infringement policy prohibits it. Members in jurisdictions for which access to Sci-Hub is legal may want to search for the paper there.

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Re: Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama Study.

Postby Hepoberman » Tue Dec 16, 2014 5:10 am

It seems to me the correlation is clear and solid. If we accept the data then the next question to ask is which way is the causation arrow pointing, if any?

One of the following possibilities must be true;

1) Higher cholesterol leads us towards Alzhiemers in time.

or

2) Neuritic plaques up regulate cholesterol. (keep in mind though, the data is stratified on Cholesterol levels, not NP)

or

3) Neuritic plaques and high cholesterol by coincidence correlate in autopsy. (No relation)

"the most significant result reported in this study is that the highest quartiles of low-density lipoprotein (LDL), total cholesterol/ high-density lipoprotein (HDL), LDL/HDL, and non-HDL cholesterol showed increased risk for neuritic plaque compared to the lowest quartiles, where cholesterol status was measured at least 10 years prior to plaque measurement."

Its hard to imagine all those high cholesterol brains have Neuritic plaques because they were ALL on statins. Highly unlikely. It is quite likely that high cholesterol leads to more plaque, though. Don't ya think? Its a hard pill to swallow because we ~4's are hard wired for higher cholesterol levels but lets find the truth, not a convenient excuse. I doubt they all had MetS but they definitely had high cholesterol (over 224).
Hep

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Re: Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama Study.

Postby Julie G » Tue Dec 16, 2014 7:08 am

The correlation between cholesterol and Alzheimer's MAY not be as clearcut as the Hisayama Study indicates. Here's a few other threads that we've put together on the topic.

Correlation between Cholesterol and Alzheimer's
viewtopic.php?f=4&t=202

HDL Plays a Pivotal Role in Preserving Cognition
viewtopic.php?f=4&t=757

Hypercholesterolaemia effect on BBB
viewtopic.php?f=4&t=653

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Re: Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama Study.

Postby Hepoberman » Tue Dec 16, 2014 7:13 am

Juliegee wrote:The correlation between cholesterol and Alzheimer's MAY not be as clearcut as the Hisayama Study indicates. I'Here's a few other threads that we've put together on the topic.

Correlation between Cholesterol and Alzheimer's
viewtopic.php?f=4&t=202

HDL Plays a Pivotal Role in Preserving Cognition
viewtopic.php?f=4&t=757

Hypercholesterolaemia effect on BBB
viewtopic.php?f=4&t=653


Its very clear in the study cited though, wouldn't you agree?

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Re: Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama Study.

Postby Julie G » Tue Dec 16, 2014 7:41 am

First, Thanks to Stavia for providing the link- very kind of you. Unfortunately, I was unable to pull up the tables (needed username/password?) to best see data. But, YES, (per the text) it looks like high cholesterol is correlated with neuritic plaques in this study. HDL-C, however, does seem to temper the impact. I found this a little confusing:
The relationship between HDLC levels and the risk of NPs was diminished after adjustment for APOE genotype, which suggested that APOE genotype was a confounding factor that had distorted the relationship between HDLC and NPs

And, the authors themselves, acknowledge that insulin resistance per data from the Hisayama Study, was strongly correlated with plaque burden especially in E4 carriers. It would be interesting to play with data and see if high LDL was correlated with higher neuritic plaques in the absence of insulin resistance.

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Re: Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama Study.

Postby Hepoberman » Tue Dec 16, 2014 10:58 am

Speaking of MetS, my A1c is back down to 5.4, woot! There are many studies correlating higher LDL with more plaque. I really liked that study because you can't fool an autopsy (many studies use questionnaires or written tests). They literally sliced up the brains and found more plaque in people who had higher cholesterol levels. Pretty straight forward and not what I wish.

Here's another study


Associations between serum cholesterol levels and cerebral amyloidosis.

https://www.ncbi.nlm.nih.gov/pubmed/24378418
"Elevated cerebral Aβ level was associated with cholesterol fractions in a pattern analogous to that found in coronary artery disease."

In my mind, the question becomes... How do we drive our cholesterol levels down safely while retaining an optimal lifestyle?


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