An Aspirin a Day Does Not Keep Dementia at Bay

Damian McNamara

March 27, 2020

A daily regimen of low-dose aspirin has no impact on the prevention of mild cognitive impairment (MCI), cognitive decline, or dementia, results of a large randomized trial show.

Investigators found that over 5 years, incident dementia rates in adults taking daily low-dose aspirin were nearly identical to those taking placebo.

"Our results suggest aspirin should not be prescribed solely on the basis of potential cognitive benefits, as there is no evidence to suggest this, nor that low-dose aspirin could reduce the risk of Alzheimer's disease," study investigator Joanne Ryan, PhD, dementia leadership fellow, National Health and Medical Research Council (NHMRC), School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia, told Medscape Medical News.

The study was published online March 25 in Neurology.

Major Hemorrhage Risk

The researchers tested the hypothesis that aspirin's anti-inflammatory properties could help delay or prevent onset of MCI, dementia, or Alzheimer's disease.

"Findings from some prior observational studies indicated that aspirin use was associated with lower dementia risk. However, findings from such studies must be considered with caution, as many other factors could help explain the association," Ryan said.

For a more definitive answer, the researchers conducted a large, randomized placebo-controlled trial as a follow-up to the 2018 Aspirin in Reducing Events in the Elderly (ASPREE) study, of which Ryan was a coinvestigator.

As previously reported by Medscape Medical News, ASPREE demonstrated that daily low-dose aspirin did not prolong disability-free survival in older adults, but increased the risk of major hemorrhage compared with placebo. Disability-free survival included all-cause death, dementia, or physical disability.

The study included 19,114 healthy adults ages 65 to 98 years who were randomized to daily 100-mg enteric-coated aspirin (n = 9525) or placebo (n= 9589). Participants were dementia-free at study enrollment and were followed for a mean of 4.7 years.

At study conclusion, 488 participants in the aspirin group and 476 in the placebo group met criteria for suspected dementia (hazard ratio [HR], 1.03; 95% CI, 0.91 - 1.17).

Further cognitive assessment using Modified Mini-Mental State Examination self-reports of memory concerns, clinical diagnoses of dementia, or prescriptions for cholinesterase inhibitors showed there was no difference between the two groups.

Global cognition or specific cognitive domains such as memory, psychomotor speed, language, and executive function did not significantly differ between groups. In addition, factors including age, sex, ethno-racial group, health factors, or prior NSAID use did not make a significant difference.

Follow-Up Too Brief?

A total 389 participants developed incident MCI. Rates of MCI were similar between the two study groups.

In addition, 1654 participants developed cognitive decline. The rate was 26.5 per 1000 person-years in the aspirin group versus 25.6 per 1000 person-years in the placebo group (HR, 1.04; 95% CI, 0.94 - 1.14).

"There were small changes in cognitive function over time but there was no evidence that the average trajectory differed between aspirin and placebo groups," the researchers note.

The null findings did not meet the researchers' expectations.

"Given that inflammation plays an important role in Alzheimer's disease, we were hopeful that low-dose aspirin might be beneficial in reducing risk," Ryan said.

However, the relatively brief follow-up was a potential study limitation, said Ryan.

"Because dementia can take years to develop, it is possible that ASPREE was not a long enough trial to show possible benefits from aspirin," Ryan said. "So we will continue to follow these participants and investigate any long-lasting effects of aspirin in the coming years."

She also plans to investigate new options for early intervention to reduce dementia risk or delay its onset. Other avenues are currently under investigation such as the impact of including stress-reduction interventions and statins from the ongoing Statin Therapy for Reducing Events in the Elderly (STAREE) trial.    

Unanswered Questions

In an accompanying editorial, David S. Knopman, MD, and Ronald C. Petersen, MD, PhD, Mayo Clinic Department of Neurology in Rochester, Minnesota, note the study's findings are "in keeping with the conclusions from the main report of ASPREE in which no benefits occurred in the composite of death, dementia, or persistent physical disability. The current report explores the cognitive outcomes in greater detail and offers insights that may be valuable for future prevention studies."

With more than 19,000 participants analyzed over nearly 5 years, "the failure to detect benefits in ASPREE means that a clinical effect of aspirin on cognition must be very small if such benefits exist at all," the editorialists write.

Like the researchers, they questioned whether a longer follow-up period was necessary. Another unanswered question is whether aspirin-sensitive risks start earlier, perhaps in midlife.

Further, "because the favorable consequences of aspirin have been seen mainly in individuals with symptomatic cardiovascular disease or cerebrovascular disease, perhaps it was the low burden of pathology in asymptomatic ASPREE participants that led to the null result with aspirin."

Knopman and Petersen note they "would have greatly preferred to have seen benefits from aspirin."

"But the ASPREE trial results have public health significance nonetheless in that we can conclude that aspirin therapy offers no protective effects for later-life cognition, cardiovascular disease, disability, or death," they add.

The study was funded by the National Institute on Aging, National Cancer Institute at the National Institutes of Health (NIH), NHMRC of Australia, Monash University, and Victorian Cancer Agency. The editorial was funded by an NIH grant. Knopman has reported being an investigator for clinical trials sponsored by Biogen, Lilly, and the University of Southern California and serving as a consultant for Samus Therapeutics, Third Rock, and Alzeca Biosciences, but receives no personal compensation. Petersen has reported being a consultant for Biogen, Roche, Merck, Genentech, and Eisai; giving educational lectures for GE Healthcare; and receiving publishing royalties from Mild Cognitive Impairment (Oxford University Press, 2003) and UpToDate. Ryan has reported no relevant financial relationships.

Neurology. Published online March 25, 2020. Abstract, Editorial

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