Being diagnosed with a neurodegenerative disorder such as Parkinson’s disease, Alzheimer’s disease, or multiple sclerosis is devastating because the precise causes of these conditions remain a mystery and effective treatments are lacking. Alzheimer’s disease has been called “type 3 diabetes” owing to the prominence of reduced brain glucose metabolism that characterizes the disease. Multiple sclerosis is also associated with reduced glucose uptake in the brain, and amyotrophic lateral sclerosis (ALS) is associated with alterations in glucose metabolism as well—it’s increased in some brain regions and decreased in others. Turning to Parkinson’s disease (PD), there’s reason to believe that this condition may have roots in altered cellular energy production resulting from insulin resistance. All of these conditions appear to have a metabolic aspect—that is, they’re associated with impaired cellular energy generation that may be specific to glucose. However, alterations in another critically important factor may be playing a role in these neurodegenerative disorders: cholesterol.
Cholesterol—particularly that carried in LDL particles—has long been fingered as a primary causal factor in many health problems. However, recent research raises serious questions as to whether LDL plays any role in cardiovascular disease, and whether it’s wise to use statins for the purpose of lowering it. (At the very least, it may be prudent to stop referring to LDL-C prejudicially as the “bad cholesterol.”) Cholesterol is undeniably essential for healthy brain structure and function. Researchers state this in no uncertain terms: “Cholesterol is essential for neuronal physiology, both during development and in the adult life.” Although the brain accounts for only about 2 percent of an adult’s body mass, it contains as much as 20 percent or more of the body’s cholesterol, making it the most cholesterol-rich part of the body.
Zeroing in on Parkinson’s disease, a prospective cohort study showed that among men not taking statins, those with higher total cholesterol and LDL-C had significantly reduced risk for developing the condition. (This reduction was not significant for women.) This research amplifies earlier findings showing similar associations between higher cholesterol levels and reduced risk for PD. A study from the University of North Carolina School of Medicine determined that men with lower LDL-C (85 mg/dl) had about double the risk compared to men with higher LDL-C (135 mg/dl). Looking specifically at men aged 71-75, risk of PD declined from 38.5/10,000 person-years in those with LDL-C lower than 80 mg/dl to less than 9/10,000 person-years for in those with LDL-C greater than 140 mg/dl. As one of the study authors noted, this research is important because the subjects were not taking statins, so it removes the potential confounding these drugs might have introduced. They also noted that this was an association and doesn’t prove cause and effect. That’s correct: associations like this don’t prove cause and effect, but they certainly raise questions about “high” cholesterol automatically being harmful.
Research involving subjects who are taking statins shows similar findings. In one such study, statin use was associated with an increased risk for PD: an odds ratio of 2.39 (CI 1.11–5.13). After adjusting for statin use and confounders, this study also showed a significant association between higher total cholesterol and decreased risk for PD: compared to the lowest tertile of total cholesterol, the second and third tertiles (higher cholesterol) had odds ratios of 0.56 (CI 0.30–1.04) and 0.43 (CI 0.22–0.87), respectively. This still doesn’t prove cause and effect, but it casts yet more doubt on the purported dangers of higher cholesterol. Researchers from Penn State College of Medicine found that statin use was associated with higher risk for PD, and that this association was greater for lipophilic statins (which cross the blood-brain barrier) than for lipophobic types.
To be fair, however, other research suggests that statin use does not affect risk for PD, regardless of statin type or potency, and some research even suggests statins may help reduce risk for PD. It’s difficult to reconcile findings that indicate statins may reduce risk with findings that suggest higher cholesterol may be protective against PD. A systematic review and meta-analysis that looked at studies evaluating statin use and incident PD concluded that studies appearing to show a protective effect of statins were flawed by bias and confounding. Abnormal mitochondrial morphology and biochemical dysfunction have been demonstrated in several neurodegenerative disorders, including PD. To the extent that statins are believed to be neurotoxic and damaging to mitochondria, a potential connection between statin use and increased risk for PD is not surprising.
When looking at associations between serum cholesterol and adverse health outcomes, it’s essential to bear in mind that cholesterol from the periphery does not cross the blood-brain barrier. Cholesterol in the brain is synthesized on-site, and apart from its usual structural role in all plasma and mitochondrial membranes, the majority of brain cholesterol (as much as 70–80 percent) is used to form myelin. Alzheimer’s disease, PD, and Huntington’s disease are all associated with abnormal cholesterol metabolism in the brain.
Research regarding cholesterol, Parkinson’s disease, and neurodegeneration, in general, raises more questions than it currently answers. It remains unknown whether lower serum cholesterol is a causal factor in PD, but it may be time to lift the stigma against cholesterol—LDL-C, in particular—and look at it in a more unbiased manner.