Thought the shades were drawn on statins and Alzheimer’s disease? Not so. A December 12 JAMA Neurology report reopens the curtains just a crack with a large observational study on a diverse cohort of almost 400,000 Medicare beneficiaries who were prescribed statins to lower their cholesterol. Scientists led by Julie Zissimopoulos, Robert Diaz Brinton, and Geoffrey Joyce, University of Southern California, Los Angeles, found that cognitively normal people who took these drugs regularly over a three-year period were 10 percent less likely to develop Alzheimer’s than those who took them only part of that time. While the risk differed slightly depending on a person’s race, gender, and type of statin, a drop occurred almost across the board. The results revive the debate about whether statin use is associated with a lower incidence of AD.
“This goes a long way toward answering a nagging question,” said Ben Wolozin, Boston University, who was not involved in the research. “Statins have been shown in mixed and male populations to be associated with protection, but are they effective in women and the major nonwhite populations? The answer there is yes.” It’s yet another example of statins working to prevent AD when used for a prolonged period before cognitive impairment, Wolozin said. However, he believes the results don’t necessarily justify another clinical trial.
Previous epidemiological studies by Wolozin and others have hinted that statins reduce the risk of Alzheimer’s disease (Jick et al., 2000; Jul 2007 news). Other studies reported a neutral or even negative relationship (e.g., Zandi et al., 2005), and the question remained unsettled (see AlzRisk assessment of statin literature).
The prospect that an approved, inexpensive, widely available class of drugs might head off AD created intense excitement in the field for some years. Alas, as was the case with other potential treatment approaches that emerged from epidemiological observations, subsequent clinical trials failed to find a protective effect (e.g. Feldman et al., 2010; Sano et al., 2011).
These trials tended to enroll white men, have limited follow-up, and exclude people with hyperlipidemia—those who stand to benefit the most from taking these drugs, said Zissimopoulos. Many trials also compared users to nonusers. A more apt comparison would come from matching high to low users, as being prescribed these medications in the first place would indicate a more similar cardiovascular risk profile, she said. Zissimopoulos and colleagues realized they could use Medicare data to make these comparisons and follow people for years after exposure.
They chose the time period from 2006 to 2013 to examine nearly 400,000 Medicare beneficiaries aged 65 and older. Included among them were 310,240 white, 32,658 Hispanic, and 32,278 black people. Another 24,803 were of Asian, Native American, or unknown ancestry. Everyone was cognitively normal during the first three years of the study. During that time, the researchers noted which medicines were prescribed and how often people filled those prescriptions. They then checked who was diagnosed with AD over the next five years. The group was divided according to how often they took a statin: High users frequently filled their prescriptions for two years straight. Low users took their meds only part of the time.
Between 2009 and 2013, 1.72 percent of women and 1.32 percent of men were diagnosed with Alzheimer’s annually. Overall, high statin users had a 10 percent reduced chance of developing AD than low users. Both groups together had an average 20 percent lower chance of being diagnosed when compared to an additional 405,000 people who used no statins at all.
Analyzing the data by gender, race, and statin type suggested that risk depended somewhat on each of these factors. For example, simvastatin, the most commonly prescribed drug, lowered risk for all whites, Hispanics, and for black women. Atorvastatin lowered risk for white and black women as well as Hispanics. Pravastatin and rosuvastatin only worked to reduce risk in white women. Though there was a trend toward lowered risk, no statin reached statistical significance in black men. Zissimopoulos noted that black men comprised the smallest subsample of the study. With more samples, they might have seen an effect, she said.
“We are finding that statins are associated with reducing the risk of AD, and this is fairly robust,” said Zissimopoulos. She cautioned that only a clinical trial can prove causation. If a future trial included people with hyperlipidemia, followed them for several years, and analyzed people of diverse races and ethnicities, the trial could turn out differently than the negative trials so far, she believes. She is currently examining how statins combined with other drugs affect the risk of Alzheimer’s.
Other scientists took a more reserved stance. “This paper may help clarify at least some of the conflicting literature about the statin-AD relationship and, in particular, the failure of several trials to show a significant benefit of these drugs,” wrote John Breitner, McGill University, Montreal, to Alzforum. “But with an effect size so small, [a clinical trial] would require huge numbers of enrollees and cost tens of millions of dollars,” he wrote. Breitner doubts any company would sponsor it.
Wolozin agrees the expense would be prohibitive. “We have to pick and choose how we spend research dollars,” he told Alzforum. A prospective clinical trial for statins would have to run for a long time and is likely to have only a small effect. “I don’t consider that a good use of funds, particularly given that we already know we should take statins for cardiovascular disease.” People should be cautious taking these drugs solely to prevent Alzheimer’s, because lowering cholesterol too much may be bad for cognition, he pointed out.
Wolozin speculated that epidemiological studies on statins consistently find a positive effect on AD risk because participants take the drugs over a long period, sometimes from middle age, during which time they maintain cerebral blood flow and perhaps reduce levels of amyloid. In contrast, treatment trials enroll people with or close to dementia, in whom blood flow is already compromised and amyloid has built up. “Statins do not miraculously open up the blood vessels, nor do they get rid of amyloid. They are good at keeping the system healthy, not at switching the system once it is unhealthy.”—Gwyneth Dickey Zakaib
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