Summary: cholesterol plays critical roles in cell membranes and steroid hormone production. This study associates low LDL cholesterol with worse cognitive performance. As expected, the effect is amplified by inflammation. Care should be taken to apply a balanced approach to cholesterol lowering therapies.

A truly fascinating study was just published in the journal Neurobiology of Aging investigating lipoproteins and loss of cognitive function. The authors state:

“The aim of this study was to examine the associations between high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides, and cognition and focus on the modifying effect of inflammation.”

They collected biological and cognitive data on 1003 persons ≥ 65 years of age over 6 years of follow-up, measuring cognition with the Mini-Mental State Examination (general cognition), Auditory Verbal Learning Test (memory), and Coding Task (information processing speed). High HDL was associiated with better memory performance, but their data seem to suggest the importance of sufficient LDL cholesterol in brain neuronal membranes:

“We found an independent association between high HDL cholesterol and better memory performance. In addition, low LDL cholesterol was predictive of worse general cognitive performance and faster decline on information processing speed.”

Not at all surprisingly they found that inflammation compounds the adverse effects of low LDL:

“Furthermore, a significant modifying effect of inflammation (C-reactive protein, α-antichymotrypsin) was found. A negative additive effect of low LDL cholesterol and high inflammation was found on general cognition and memory performance.”

And since high triglycerides are commonly provoked by the high insulin levels due to insulin resistance which also have deleterious effects on the brain…

“Also, high triglycerides were associated with lower memory performance in those with high inflammation.”

The authors conclude by suggesting that HDL, LDL and inflammatory indicators can be used as predictors of poor cognitive function:

“Thus, a combination of these factors may be used as markers of prolonged lower cognitive functioning.”

This compels us to use caution and see the ‘big picture’ when designing strategies to manage lipids—care should be taken to not suppress LDL cholesterol to too low a level.

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That serving of french toast may be doing more to contribute to cardiovascular disease than promoting insulin resistance and dyslipidemia. A paper just published in the journal Diabetes details how excess blood sugar causes LDL cholesterol to stick more readily to arterial plaque. Inflamed vulnerable plaque on arterial walls is the main precipitating factor for heart attacks and strokes. The authors set out to…

“…study whether modification of LDL by methylglyoxal (MG), a potent arginine-directed glycating agent that is increased in diabetes, is associated with increased atherogenicity.”

Glycation is the damaging process by which sugar binds to substances in the body that it shouldn’t do normally. As the practitioners reading this know, hemoglobin A1c (HbgA1c, produced by glycation of hemoglobin) is an important laboratory metric for determining how high a person’s blood sugar has been on average over the previous few months. People with pre-diabetes (metabolic syndrome) and type 2 diabetes have higher levels. By modifying human LDL by methylglyoxal to reproduce what happens in vivo, the authors were able to measure the effect on LDL particle characteristics and its tendency to deposit in the arterial wall. What did they find?

“MGmin-LDL [glycated LDL] had decreased particle size, increased binding to proteoglycans, and increased aggregation in vitro. Cell culture studies showed that MGmin-LDL was bound by the LDL receptor but not by the scavenger receptor and had increased binding affinity for cell surface heparan sulfate–containing proteoglycan. Radiotracer studies in rats showed that MGmin-LDL had a similar fractional clearance rate in plasma to unmodified LDL but increased partitioning onto the aortal wall…A computed structural model predicted that MG modification of apoB100 induces distortion, increasing exposure of the N-terminal proteoglycan–binding domain on the surface of LDL. This likely mediates particle remodeling and increases proteoglycan binding.”

In other words, glycated LDL is a nasty compound that is less likely to be scavenged from the bloodstream; and it is smaller, denser and stickier than normal LDL so that it has a higher tendency to adhere to the blood vessel well. Glycated LDL has been called the “ultra-bad cholesterol“. It also shows part of the reason why blood sugar lowering therapies reduce cardiovascular disease. The authors conclude:

“MG modification of LDL forms small, dense LDL with increased atherogenicity that provides a new route to atherogenic LDL and may explain the escalation of cardiovascular risk in diabetes and the cardioprotective effect of metformin.”

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A study recently published in The Journal of Clinical Endocrinology & Metabolism proves that we must take the menstrual cycle into consideration when testing cholesterol in cycling women.

“The objective of the study was to evaluate the association between endogenous [internally produced] estrogen and serum lipoproteins across the menstrual cycle.”

The authors found that total and LDL cholesterol were lower during the luteal phase (second half, when progesterone is higher) than the follicular phase:

“More women were classified above the desirable range (LDL ≥130 mg/dl or total cholesterol ≥200 mg/dl) when measured during the follicular phase [first half].”

HDL was higher when estradiol had peaked, corresponding also to lower LDL and triglycerides.

“Because lipoprotein cholesterol levels vary across the menstrual cycle, cyclic variations in lipoprotein levels may need to be considered in the design and interpretation of studies in reproductive-age women and in the clinical management of women’s cholesterol.“

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We use the natural statin red rice yeast only with caution (and coenzyme Q10 restoration) as a palliative when cholesterol is high and may be contributing to vascular disease due to inflammation and oxidation. But why use it instead of pharmaceutical statins? This randomized trial published in the journal Annals of Internal Medicine documents that patients who had to discontinue conventional statin therapy due to muscle pain could tolerate red rice yeast. The authors set out to…

“…evaluate the effectiveness and tolerability of red yeast rice and therapeutic lifestyle change to treat dyslipidemia in patients who cannot tolerate statin therapy.”

They examined 62 patients with dyslipidemia who had to discontinue statin therapy due to muscle pains. Patients were randomly assigned to receive red rice yeast or placebo and were checked for LDL cholesterol, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, liver enzymes, and creatinine phosphokinase (CPK) levels after 24 weeks. What did the data show?

“Low-density lipoprotein cholesterol level was significantly lower in the red yeast rice group than in the placebo group at both weeks 12 and 24. Significant treatment effects were also observed for total cholesterol level at weeks 12 and 24. Levels of HDL cholesterol, triglyceride, liver enzyme, or CPK; weight loss; and pain severity scores did not significantly differ between groups at either week 12 or week 24.”

In other words, the red rice yeast was effective and well tolerated by this group of patients who had adverse reactions to other statins, compelling the authors to conclude:

“Red yeast rice and therapeutic lifestyle change decrease LDL cholesterol level without increasing CPK or pain levels and may be a treatment option for dyslipidemic patients who cannot tolerate statin therapy.”

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