Growing old is associated with a greater risk of falls, reduced bone volume, vascular events, cognitive decline, and depression. Although it is relatively straightforward to study the effects of interventions on the physical risks associated with ageing, studying effects on cognitive function is more difficult. Age related cognitive impairment affects about 5% of people over 65 in the developed world, and about half of those affected have memory loss.1
In this week's BMJ
, Kang and colleagues assess the impact of aspirin on cognitive function in a subgroup of elderly women enrolled in the women's health study2—
a randomised controlled trial of the effect of aspirin on cardiovascular morbidity and cancer.
What is the evidence on interventions for delaying or preventing age related cognitive decline? Drugs for dementia produce transient symptomatic improvements by enhancing cholinergic neurotransmission but they do not delay progress to severe dementia. Molecular neurobiological and epidemiological studies suggest several interventions (such the possible neuroprotective effects of non-steroidal anti-inflammatory drugs 3
) that may slow cognitive decline and postpone the onset of dementia. Many of these population based studies identify risk factors for vascular disease as targets for preventing dementia. These studies also highlight the fact that complex research designs are necessary to take account of confounding by the differential effects of survival and the contribution of lifelong habits associated with retention of good health. Persisting uncertainty about the timing and nature of the prodromal phase of dementia remains an important obstacle to assessing the efficacy of interventions. Including participants in trials who are not at increased risk of cognitive decline will reduce the likelihood of detecting efficacy.
So far, results have been encouraging. Treatment of hypertension is beneficial in older people, with well established cognitive benefits, possibly including reduced risk of transition to dementia.4
Evidence is strengthening in support of folic acid supplementation to reduce hyperhomocysteinaemia (a putative vascular risk factor), which in turn improves cognition,5
although it is unclear whether supplementation will prevent dementia. The case for antioxidant vitamin supplements remains weak, because although some reduction in the incidence of dementia seems plausible, good quality trials are lacking. Likewise, marine oil supplementation has not been adequately tested.6
A case therefore exists for reducing vascular risk factors to maintain cognitive function. The preventive role of different drug groups with contrasting actions on the cascades of molecular events that lead to vascular disease also needs to be investigated. Aspirin has a 30 year track record as a candidate for overall reduction of cardiovascular risk. The women's health study offered a golden opportunity to examine its potential to delay cognitive decline.
The study by Kang and colleagues1
found no significant difference in cognitive function at any of the three assessments (the first one on average 5.6 years after randomisation) administered every two years. The mean difference in decline in the global score from the first to the final cognitive assessment was 0.01 (95% confidence interval −0.02 to 0.04). The study recruited healthy women over 45 and achieved high follow-up rates. Efforts were made to control for confounders (smoking, alcohol, exercise, body mass index, blood pressure, diabetes, and incident depressive and vascular disease). High completion rates of repeated cognitive assessment using telephone administered tests with prespecified “real world” outcome measures in a large well powered study allow conclusions to be drawn about the lack of effect of aspirin on cognition in this population.
Limitations—including sampling bias towards inclusion of white American women with low morbidity—preclude generalising the results to other populations at higher risk, and of course to men. Doctors who prescribe aspirin will be aware of the gastrointestinal complications identified in this study.
In addition, cognitive function was assessed by telephone interview, and was therefore entirely verbal and dependent on memory. This may seem reasonable when memory impairment is a core concept in research into dementia. However, there is a contrary view that the prodrome of Alzheimer's disease (the most common form of dementia) extends beyond memory loss to include deficits in executive functions, mental speed,7
and that visuospatial learning may also be important. These reports, with others, lead to the proposition that the early signs of dementia arise not from selective damage to key anatomical (“bottleneck”) structures crucial for verbal memory, but from pathology that breaks connections between brain structures serving several cognitive domains.9
In these terms, impairment of verbal memory alone is not the best early indicator of the dementia prodrome—deficits in attention and executive function are better predictors. Some support for this “disconnection hypothesis” is derived from the study's finding of impairments on “category fluency,” a seemingly explicit task of memory requiring the naming of as many animals as possible in one minute. While interpretation of this test is complex—involving effortful retrieval, loss of knowledge, and both directed and sustained attention10
—its potential importance as a marker of frontal or executive integrity should not be overlooked if premature conclusions on aspirin are to be avoided.
Better quality research into cognitive decline in later life is needed, but many pitfalls blight the road to success. Ultimately, once multiple risk factors are identified, common pathways to the onset and prevention of Alzheimer's disease will be charted.11
As this is achieved, measurements and study designs will need to move away from categorical approaches to assess the confounding effects of ill health in old age and to place people in their correct social context in terms of dependency and lifelong cognitive abilities. The US health and retirement study design is informative about many of these issues.12
Ongoing developments into the sources of individual differences in cognitive ageing acting across the life course13
will provide some solutions to these taxing methodological problems.