Statins Assume a Starring Role in Prevention of Alzheimer’s Disease

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Rhonna Shatz, DO, at the 2016 Sunflower Rev It Up Symposium & Expo. Photo by Cindy Starr.

Rhonna Shatz, DO, at the 2016 Sunflower Rev It Up Symposium & Expo. Photo by Cindy Starr.

Rhonna Shatz, DO, director of the UC Memory Disorders Center, hears the question at least once a week from patients or family practitioners: “Can statins really help prevent Alzheimer’s?”

The question is a hopeful and exciting one, heightened by recently published findings that high exposure to statins is associated with a lower risk of Alzheimer’s disease in certain populations.

“There is overwhelming evidence that statin use is protective, particularly early, before any cognitive symptoms are present,” Shatz says. “This means that statins – in addition to high-quality sleep — may be the most available treatment for dementia that we have in 2017.”

What does this mean for you and your loved ones? Dr. Shatz answers questions about statins, cholesterol, Alzheimer’s and findings from the study published in the December 27, 2016 issue of JAMA Neurology. The study of nearly 400,000 statin users over age 65 and older was led by researchers at the University of Southern California.

Q: Statins lower low-density lipoprotein (LDL) cholesterol, the “bad” cholesterol. What is the link between cholesterol and Alzheimer’s disease and other non-Alzheimer’s dementias?

A: Cholesterol is linked to the formation of beta-amyloid, the protein associated with Alzheimer’s disease. By decreasing cholesterol levels with statins, we may be able to reduce beta-amyloid production and influence the onset or progression of Alzheimer’s. The economic potential of this is profound. Because there are no cures for Alzheimer’s or Parkinson’s/Lewy body disease, any drug that can delay disease onset by a year could reduce costs of care of dementia patients by $223 billion in 2050.

Of course, millions of people are already taking statins. Of the 40 million Americans who take cholesterol-lowering drugs, 93 percent take statins. This may be the reason for the overall declining incidence of Alzheimer’s disease.

Q: Did the JAMA Neurology study find that statins reduced the risk of Alzheimer’s equally among various ethnic groups?

A: Unfortunately, no. The benefits were seen in black, Hispanic and white women, and in Hispanic and white men. We did not see any benefits for African American men. Although African Americans and Hispanics are at higher risk for Alzheimer’s and dementia and are more likely to have high cholesterol, they are also more likely to be resistant to treatment designed to lower cholesterol. African Americans are the most resistant to the benefits of statins. They most likely have genetic variants that cause them to metabolize the statins too quickly.

In addition, while all statins lower LDL cholesterol levels, they differ in molecular structure, how well they lower cholesterol, how they are metabolized in the body, and how easily they can be absorbed into fatty tissue. That last property is important because the brain is mostly fat. In short, different statins perform differently in different people.

The Statins_boxThis leads us to the need for personalized medicine. We need to prescribe the right type of statin to the right type of person.

  • Simvastatin (Zocor) or atorvastatin (Lipitor) will benefit Hispanic men or women
  • Only simvastatin will benefit white men
  • Any statin – simvastatin, atorvastatin, pravastatin (Pravachol) or rosuvastatin (Crestor) — will benefit white women
  • Statins do not appear to provide any benefit for black men

Q: Can statins provide other benefits in addition to lowering cholesterol?

A: Yes, and these may be even more important. Statins increase blood flow to the brain and offer neuroprotection because of their antioxidant and anti-inflammatory qualities. They may also stimulate the NMDA receptor, which is important in the formation of long-term memories.

Personally, I am most intrigued by evidence that the anti-inflammatory effect of statins is more likely to be at work in dementia prevention. Inflammation occurs early in Alzheimer’s, up to two decades before the disease becomes apparent. There is also evidence of high inflammation in Parkinson’s and Lewy body dementia.  This time period corresponds to the epidemiological evidence that early statin use in mid-life prevents dementia, but later use is ineffective.

Interestingly, there is emerging evidence that depression and anxiety are associated with inflammation in the brain.  Mood changes are recognized now as the earliest symptom of both Alzheimer’s and Parkinson’s/Lewy body dementia.  There is also a high correlation between untreated depression and anxiety symptoms and risk for Alzheimer’s disease.  Statins improve mood, and the mechanism may be through the reduction of inflammation.

Taken together, these factors tell us that we need to prescribe statins at the right time. Prevention is better than treatment. From epidemiological data we know that statin use beginning in mid-life reduces the risk of Alzheimer’s disease independent of their cholesterol lowering effect.

Q: What evidence is there that cholesterol plays a role in memory and thinking?

A: We know that having high LDL cholesterol in mid-life increases the risk of Alzheimer’s disease and that people with Alzheimer’s disease decline faster if they also have high LDL and elevated blood sugar. Further, research has found that people with cholesterol-induced fatty liver disease (non-alcoholic fatty liver disease) have smaller brain volumes, which is a measure of brain aging. Large, long-term randomized controlled trials have shown that exercise and diet can help elderly, at-risk patients improve or maintain cognitive function. We also know that exercise and diet can alter cholesterol and glucose metabolism, which affect the production and clearance of beta-amyloid (which forms senile plaques) and tau (which forms neurofibrillary tangles), and leads to neurodegeneration (cell death).

 Q: Why did the FDA issue a warning about statins and dementia?

A:  In 2012 the U.S. Food and Drug Administration (FDA) issued a warning that statins could cause cognitive impairment. This ruling was based on 60 patient-initiated reports of confusion while taking statins. Since then, however, several meta-analyses of controlled trials of statin use and cognitive function have found no statistically significant effects of statin treatment on cognition in cognitively healthy and cognitively impaired individuals. These results suggest that the FDA warning about potential adverse effects of statins on cognition should be re-evaluated.

In 2013 the American College of Cardiology and American Heart Association advised that it is reasonable to evaluate people who suffer confusion or memory impairment while on statin therapy “for non-statin causes.” These causes could include interactions of statins with other medications or foods (e.g., grapefruit juice) or other co-occurring medical conditions.

Q: When should people in middle age consider taking statins?

A:  Research has not definitively identified the age at which statins should be initiated.  At any age, and as early as possible, statin therapy should be prescribed for high LDL cholesterol. Because of increasing childhood obesity, which is associated with high cholesterol, screening should begin in childhood.

However, the data suggests several “out of the box” ideas regarding statin therapy. Individuals with a family history of Alzheimer’s and Parkinson’s/Lewy body might consider initiating statins independently of LDL cholesterol levels. Chronic depression and anxiety therapy might include statins in addition to anti-depressants and anti-anxiety medications. New-onset anxiety or depression in mid-life should be recognized as a symptom of brain stress, and statins may be the most targeted treatment, not only for mood but also for the underlying brain inflammation related to neurodegenerative changes.

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