Statin Effects on Alzheimer's Vary by Race, Sex

Nancy A. Melville

December 14, 2016

The high use of statins, compared with low use, is associated with a reduction in the risk for Alzheimer's disease in different magnitudes across racial, ethnic, and sex groups, with variance also according to the type of statin, suggests new research delving into the long-debated relationship between statins and Alzheimer's disease.

"[C]ertain patients, facing multiple, otherwise equal statin alternatives for hyperlipidemia treatment, may reduce Alzheimer's disease risk by using a particular statin," the researchers, with first author Julie Zissimopoulos, PhD, from the Price School of Public Policy at the University of Southern California, in Los Angeles, write.

"The right statin type for the right person at the right time may provide a relatively inexpensive means to lessen the burden of Alzheimer's disease."

With serum cholesterol levels shown to be associated with deposits of amyloid plaque in the brain, a hallmark of Alzheimer's disease, cholesterol-lowering statins have long been speculated to influence Alzheimer's onset and progression, the authors point out. However, clinical trials have been inconsistent and fallen short in establishing an association.

To take a closer look at the potential relationship in a large, longitudinal database, the authors turned to a sample of Medicare beneficiaries from 2006 to 2013, identifying 399,979 persons aged 65 or older with high or low exposure to statins.

The study, published online December 12 in JAMA Neurology, focused on the four most commonly prescribed statins: simvastatin, atorvastatin, pravastatin, and rosuvastatin.

Patients with high exposure were defined as anyone with at least two prescription fills of any statin between 2006 and 2012 who fell into at least the 50th percentile of days of filled prescriptions in a given year from 2006 through 2008, with follow-up extended through 2013.

Among the participants, 1.95% were black men, 6.12% were black women, 2.80% were Hispanic men, 5.36% were Hispanic women, 28.77% were white men, and 48.80% were white women.

Overall, 1.72% of women and 1.32% of men were diagnosed with Alzheimer's disease annually, with the lowest rate among white men (1.23%). The rate among those who had not used statins (not included in the analysis) was 1.99% over the same time period.

Compared with those with lower levels of exposure to statins, high exposure to the drugs was associated with a significant reduction in Alzheimer's disease diagnoses among women (hazard ratio [HR], 0.85) as well as men (HR, 0.88; both P < .001).

"Beneficiaries exposed to higher levels of statins from 2006 to 2008 were 10% less likely to have an [Alzheimer's disease] diagnosis in the subsequent 5 years than similar beneficiaries with lower statin exposure," the authors write.

Simvastatin, the most commonly used statin, was associated with lower Alzheimer's disease risk among all groups with the exception of black men, with reductions seen in white women (HR, 0.86; P < .001), white men (HR, 0.90; P = .02), Hispanic women (HR, 0.82; P = .04), Hispanic men (HR, 0.67; P = .01), and black women (HR, 0.78; P = .005).

The risk for Alzheimer's disease was also significantly reduced with high use of atorvastatin compared with low use among white women (HR, 0.84), black women (HR, 0.81), and Hispanic men (HR, 0.61) and women (HR, 0.76). Approximately half of men and women in the sample had used atorvastatin.

High use of pravastatin and rosuvastatin was associated with reduced risk among white women (HR, 0.82 and 0.81, respectively).

In general, black and Hispanic participants had lower use of statins and higher rates of Alzheimer's disease and associated diseases than whites, the authors noted.

The reduced risk for Alzheimer's disease risk was stronger with lipophilic statins, such as simvastatin, than with less commonly used hydrophilic statins, among Hispanics and black women; however, no difference between the two groups was seen among white women.

The stronger effect with lipophilic statins in most groups is speculated to be attributable to greater penetrability through the blood-brain barrier.

"Lipophilic statins cross the blood-brain barrier more readily, leading to hypotheses that they could have a stronger association with Alzheimer's disease risk than hydrophilic statins," the authors said.

"Our findings generally support this theory for Hispanic men and women, and for black women, [but] white women had a reduced Alzheimer's disease risk from all statins tested, regardless of lipophilicity."

Dr Zissimopoulos noted that the lack of significant risk reduction associated with any statins in black men may have simply been related to the numbers of black men in the study.

"It may be that there is a reduction [with black men] — we just did not find a statistically significant one," she told Medscape Medical News.

"The sample size for black men is the smallest of any demographic group in our study, so it may be that there is a reduction, and our estimates are not precise enough to find it."

The study nevertheless benefited overall from data on a broad spectrum of patients and drug types.

"We had data on Medicare beneficiaries; thus we had large sample sizes and data on individuals who had been followed over many years combined with a rigorous methodological approach," Dr Zissimopoulos said. 

"This allowed us to analyze not only the association, but how the association between statins and Alzheimer's disease onset varied for men and women, by race/ethnicity and across statin types. This was a gap we were trying to fill."

Previous studies showing no association between statins and Alzheimer's disease risk include a placebo-controlled trial on simvastatin and Alzheimer's disease, published in 2011 in the journal Neurology, showing no benefit on the progression of symptoms in patients with mild to moderate Alzheimer's disease over 18 months of statin treatment, despite a significant lowering of cholesterol.

While that study notably did not include patients with dyslipidemia, others did include those patients, said Mary C. Sano, PhD, who was first author on that study and is the director of the Alzheimer's Disease Research at Mount Sinai School of Medicine in New York City.

"Others did studies of those with dyslipidemia and found great cardiovascular protection and no effect on cognition," she told Medscape Medical News.

Examples include the MRC/BHF Heart Protection Study and another randomized controlled trial looking at pravastatin in elderly patients.

"These studies included thousands of people and were published years ago; [they] measured cognition and found no benefit of statin treatment," Dr Sano said.

In a more recent study, published in 2015 in Ethnicity and Disease, researchers did find that consistent use of statins in 8 years of follow-up was associated with a significantly decreased risk for incident dementia (odds ratio [OR], 0.44; P = .029) and incident Alzheimer's disease (OR, 0.40; P = .029) in elderly African Americans.

Hugh C. Hendrie, DSc, from the Indiana University Center for Aging Research, in Indianapolis, first author of that study, said the new research adds important insights to the debate.

"The value of the study is the use of a large ethnically diverse cohort and the ability to determine dose, which we were not able to do," he told Medscape Medical News.

"The main limitation, as the authors note, is that it is an observational study, albeit large, which makes determination of causality difficult."

This research was supported by the National Institute on Aging of the National Institutes of Health and the University of Southern California Zumberge Research Fund. Coauthor Dr Barthold is supported through the Schaeffer-Amgen Fellowship Program funded by Amgen.The authors, Dr Sano, and Dr Hendrie have disclosed no relevant financial relationships.

JAMA Neurol. Published online December 12, 2016. Abstract

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