Alzheimer's and HDL

There are a number of December papers I've been wanting to blog about, but other things came up along the way.  But here I have a moment before the children come home, and the house is quiet except for the cats... I ought to be wrapping presents... but here is a new Alzheimer's paper to add more confusion to the cholesterol and Alzheimer's information.  Overall, the data have suggested that high cholesterol in midlife and low cholesterol in late life both increase risk for the development of Alzheimer's in late life. 

As usual the lipid hypothesis holds sway, and when one reads the analysis in the literature, one gets the idea that the high cholesterol in midlife is likely a causative factor, whereas low cholesterol in late life is "part of the disease process."  (For example, Grandfather must be eating less because he is getting demented, so his cholesterol drops.  For years prior to severe symptoms that might legitimately lead to eating less.)  Of course I'm of the opinion that cholesterol is good for the brain.  But not too many people listen to me.  Or else the  The Primal Blueprint Cookbook: Primal, Low Carb, Paleo, Grain-Free, Dairy-Free and Gluten-Free would be in the top 5 bestselling cookbooks rather than number 5 on the Physician's For Responsible Medicine's Worst Cookbooks of the Year. (Hah they even have the huevos to remark upon the silly "low carb animal" vs. "low carb vegetable" study that came out earlier this year as evidence for avoiding Mark's book!!)  I think I might pick up a few more books on that list of the worst five, frankly.  They look as if they contain many delicious recipes.   

Okay, back to the paper.  Did you know that more than 50% of the adult US population has high cholesterol?  And 1% of people ages 60-69 will develop Alzheimer's, increasing to more than 60% of those over 95.  "There is evidence that cholesterol alters the degredation of the amyloid precursor protein" (supposedly bad) but "cholesterol depletion induces [Alzheimer's Disease]-type injuries in cultured hippocampal slices" (now that sounds quite bad.)  Overall, the observational studies linking dyslipidemias to Alzheimer's have been inconsistent (with the typical take from the literature what I discussed in the 2nd paragraph above).  

Well, high LDL and low HDL have been linked in the past to vascular dementia.  Vascular dementia is kind of the brain version of heart disease.  Arteries get clogged up with plaque (different plaque, actually, than amyloid plaque, things get blocked, mini-strokes occur, and someone gets gradually demented as the amount of damage builds up. Anyhoo, Alzheimer's is a bit different - neuronal amyloid plaque builds up, then you get inflammation and tau tangles, and neuron damage and death.

The authors of this study wanted to examine a cohort of people after the start of widespread use of lipid-lowering agents (primarily statins) in the 1990s.  So these folks in "Northern Manhattan" were recruited from the Medicare roles in 1999-2001, baseline measures of general health and cognitive function were gathered, and they were followed up every 18 months or so.  Out of 1130 individuals who completed the study, 101 were diagnosed with AD, 89 diagnosed as having probable AD, and 12 as possible AD (while Alzheimer's Dementia can only be definitively diagnosed via autopsy, there is a characteristic style of progression of memory loss that makes the performance on certain cognitive tests a decent way of diagnosing the disease).

The mean age of onset of the disease was about 83.  Higher HDL (especially over 56 mg/dl) was protective after adjusting for all sorts of things, including age, ApoE4 status, sex, education, ethnic group, and even vascular risk factors and lipid-lowering treatment.  Interestingly, higher total cholesterol levels and higher LDL cholesterol levels were also protective through all the adjustments except the last two, though became nonsignificant when lipid-lowering treatment and vascular risk factors were adjusted for. (In this cohort, high insulin levels were a strong risk factor also).

The authors put forth the "HDL as garbage trucks" hypothesis of HDL cleaning the cholesterol out, and they postulate the following: "High-density lipoprotein cholesterol might also be linked with small-vessel disease by ...interaction with with APOE and heparan sulfate proteoglycans in the subendothelian space of cerebral microvessels.  Thus, a low HDL-C level could precipitate AD through a cerebralvascular pathway."  (Or how about this theory, which is my own little edit - high HDL-c is associated with low amounts of inflammation and that is the secret to a healthy brain). And more discussion in the paper is about how the study of lipids and Alzheimer's has been confusing all along, and certainly low HDL is associated with stroke, so maybe also some linked pathology is responsible in AD... and previous cohorts with higher total cholesterol in midlife blah blah...  this paper twists and turns about so many times I get confused.

Don't be confused.  Let go of the lipid hypothesis.  Think inflammation.  It's the immune system, not the liver, that is trying to kill us.  Then everything becomes clear, and things start making sense again.  Peace.

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