Does elevated LDL have a role in early-onset Alzheimer’s disease?

Senior woman losing parts of head feeling confused as symbol of decreased mind function.

That is one possible interpretation of a new study, just published in JAMA Neurology.

As we have covered previously, the incidence of Alzheimer’s disease is expected to skyrocket in the coming years, and to date all drug treatment investigations have ended in failure. Although Alzheimer’s is commonly a disease of the elderly, around 10% of cases affect individuals younger than 65 years old, with even greater consequences for the patient, the caregiver and society as a whole than when it affects much older patients. Given these devastating consequences, there is an urgency to find a potential reversible cause.

Now the focus appears to be turning to LDL cholesterol. This is a murky field to say the least, with studies showing both high and low LDL levels having a potential correlation with dementia risk.

The latest study was a case series of 267 individuals with early-onset Alzheimer’s disease compared to controls without dementia. The investigators found those with early-onset Alzheimer’s had higher average LDL (131 mg/dL) compared to controls (104 mg/dL), and also had a higher frequency of an ApoB gene mutation (a gene implicated in familial hypercholesterolemia, a genetic disorder characterized by high cholesterol levels). As expected, there was also a higher frequency of ApoE4 mutation (54% vs 25%), a known risk factor for late-onset Alzheimer’s. However, the authors note that these genetic differences only account for a fraction of total cases, and that left many cases “unexplained.”

Does this prove that higher LDL causes early-onset Alzheimer’s disease?

No, it does not. It is merely an association. The same can be said for the higher triglyceride levels seen in those with early-onset dementia. In fact, the authors themselves acknowledge:

Thus, we were unable to conclude that the observed association is causal and not due to genetic pleiotropy {a fancy word for other effects from the genetic mutation}

and

(A) potential limitation of this study is that the LDL-C analysis may be confounded by unavailable data (such as the severity of Alzheimer’s, smoking, or use of drugs to lower cholesterol levels).

That is important missing data! Not controlling for smoking, hypertension, medication use, and I would add metabolic health to that list as well, leaves a number of unanswered questions. Once again, we see a focus on LDL cholesterol while essentially ignoring the role metabolic health plays on LDL as well as on dementia risk itself.

In addition, we need to incorporate the findings of this study with other observational trials that showed the opposite result. For instance, a review of the Prospective Population Study of Women showed no significant correlation between elevated cholesterol levels and risk of dementia or Alzheimer’s disease. In fact, decreasing cholesterol levels signified a higher risk of developing dementia.

In addition, a recent study from China, in subjects with a mean age of 68, suggested that those with higher levels of LDL cholesterol had a lower incidence of dementia. They found that those with LDL greater than 142 mg/dL (3.7 mmol/L) had a 50% lower incidence of dementia than those with LDL < 110 mg/dL (2.9 mmol/L). These findings are consistent with a prior study (also observational) examining the Framingham Heart Study data that found lower risk of dementia in those over 85 years old with higher cholesterol levels, and a 2004 observational study showing reduced dementia risk with higher LDL levels.

In fairness, these are all observational studies, so they do not prove higher LDL cholesterol directly protected against dementia, just as the recent study does not prove higher LDL causes dementia.

We can, however, hypothesize why higher levels of LDL-C could be associated with lower incidence of dementia. It could be a marker of overall health or nutritional status, it could be that LDL-C directly improves the health of neurons and prevents brain atrophy, or it could be more related to lack of diabetes or ApoE4 status for which a study may not always completely control.

Can we say the same for why higher LDL levels might cause Alzheimer’s disease? The authors did not even offer a hypothesis in their study, leaving us to guess if there is a potential mechanism.

In the end, we are left with another study that shows a potential association but says nothing about causation. When incorporated into the science as a whole, the findings may not stand up that elevated LDL is causative for early-onset Alzheimer’s disease, especially since they did not control for metabolic health. I am sure we will see more about this in the near future, but I am afraid the new study adds little to our current understanding of how to prevent early-onset dementia.

Instead, we recommend focusing on metabolic health to prevent Alzheimer’s disease, now often being referred to as “type III diabetes.” You can learn more about our approach to Alzheimer’s through our many articles and news stories, starting here.

Thanks for reading,
Bret Scher, MD, FACC

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