We found that middle-aged and older people with age-related cognitive complaints improved in executive functioning and language or semantic memory after 18 months of daily celecoxib treatment compared with placebo. Moreover, celecoxib treatment resulted in significant increases in cerebral glucose metabolic rates in the prefrontal cortex. These results support our hypothesis that a selective COX-2 inhibitor drug may benefit cognitive performance in people with mild memory complaints, when taken on a daily basis.
Celecoxib significantly improved performances relative to placebo in two of six cognitive domains, suggesting that the effects of celecoxib are modest. Moreover, such effects may have most clinical relevance for cognitive functions involving complex attention, information processing speed, and retrieval of semantic information. By contrast, benefits were not observed in episodic memory performance scores.
The brain region showing the greatest increases in glucose metabolism, the prefrontal cortex, controls executive planning, complex reasoning, and semantic memory, among other mental functions.52,53
The neuropsychological tests we used to measure executive functioning also have been used to measure the integrity of the prefrontal cortex.54
Evidence from cognitive behavior paradigms, functional brain imaging, and neuropsychological studies of patients with focal insults also points to the prefrontal cortex as a site for semantic memory retrieval.55
Thus, our results from cognitive testing and PET imaging of glucose metabolism yielded parallel findings; the cognitive functions showing significant improvement on neuropsychological testing are known to measure functions controlled by brain regions that showed the greatest increases in PET activity.
Several mechanisms have been posited to explain the connection between anti-inflammatory treatments and improved cognitive function. Previous research suggests that inflammatory mechanisms resulting from amyloid β
) deposition play an important role in neurodegeneration.56
Brain pathology in amyloid plaques shows evidence of inflammatory activity, including activated microglia and cytokines, suggesting inflammatory mechanisms as contributing to neuronal damage in AD.57
The presumed mechanism involves activation of microglia and increased expression of proinflammatory cytokines. The anti-inflammatory effects of NSAIDs are presumed to disrupt this cascade; however, this mechanism may not be relevant to the present study, because celecoxib is not among those NSAIDs that lower production of the 42-residue form of amyloid β
) in mouse models.58
Another proposed mechanism involves disruption of Aβ
peptide aggregation into insoluble plaques. Our group has found that some NSAIDs (e.g., ibuprofen, naproxen) exhibit antiaggregation effects on Aβ
peptides, suggesting that the binding site on Aβ
fibrils and plaques may be a site of antiaggregation drug action.6
A recent pooled dataset from six prospective studies found that NSAID use reduced the risk for AD; however, there was no advantage for NSAIDs shown to selectively lower Aβ42
COX modulation reduces formation of inflammatory prostaglandins and is an alternate pathway for the putative neuroprotective effects of COX-2 inhibitors. COX-2, an enzyme critical to the synthesis of prostaglandins and the inflammatory process, is expressed in neurons and up-regulated in AD.60
Expression of cyclooxygnase-2 has been observed in the frontal cortex of patients with AD,61
and overexpression of COX-2 is associated with elevated production of Aβ
Another potential mechanism that has received less attention posits that neuroprotection from NSAID use is indirectly modulated through cardiovascular effects on brain function. In other words, people taking NSAIDs might experience less joint discomfort and, thus, spend more time in physical activity. People who are physically active in midlife have been found to have a lower risk for dementia three decades later.63
This mechanism also could explain the observational results of previous epidemiological studies—people reporting a history of prior NSAID use—those with a lower risk for AD might be more likely to have a history of higher physical activity and joint injury leading to greater NSAID use.
In support of this explanation is evidence that aerobic exercise in older adults results in cognitive and cerebral effects consistent with those found in the present study. For example, a 6-month randomized trial comparing aerobic exercise to toning and stretching demonstrated significant increases in pre-frontal temporal gray matter and anterior white matter in the exercise group but not in the control group.64
Aerobic conditioning also has been found to alter frontal lobe functional MRI patterns related to significant improvement in selective attention tasks.65
Other studies show that physical activity leads to improved executive functioning.66
Although subjects with arthritis were excluded from the present study, it is possible that subjects taking celecoxib engaged in more physical activity because the medication relieved minor joint pain and, thus, improved mobility. Future trials that monitor physical activity levels could determine whether this explanation for the findings of the present study holds true.
Another prospective study found that long-term NSAID use may reduce the incidence of AD when treatment is started years before the age at dementia onset67
supporting the notion that a critical intervention period may exist before dementia onset. A recent study68
found that the COX-2 inhibitor rofecoxib was no better than placebo in delaying conversion to dementia in patients with mild cognitive impairment, suggesting that if such a critical treatment period exists, it probably occurs before people develop mild cognitive impairment. To further address such issues, the National Institute on Aging initiated the Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT) to determine the effects of naproxen or celecoxib in preventing dementia and age-related decline. Recently published results from that study69
found that use of naproxen or celecoxib did not improve cognitive function. Moreover, there was weak evidence for a detrimental naproxen effect. Although the ADAPT findings add to the negative evidence for treatment and secondary prevention trials, inflammatory processes are clearly complex and may have both reparative and detrimental effects on neurons.70
The ADAPT results may reflect detrimental effects after starting treatment in people with subclinical neuropathology, whereas protective effects may occur when treatment is initiated earlier. To this point, subjects in the ADAPT study were on average more than a decade older than those in the present study. Other studies have shown apparent protective cognitive effects resulting from more distant rather than recent NSAID use.2,67
Because of cardiovascular safety concerns, the ADAPT trial was terminated prematurely (December, 2004).71
The present study also was terminated at that time, which led to a relatively small sample size warranting caution in interpreting our results. With the sample sizes realized in the present study, we would be able to detect a relatively large effect size of 0.89 for the change across testings with 80% power at a significance level of 0.05. The fact that we did find a significant improvement in the celecoxib group suggests that, at least in this small sample, the impact of the treatment was clinically meaningful. Such a small sample, of course, limits the generalizability of any findings. In addition, our study design limited assessments to only two time points and, thus, providing only a “snapshot” of celexocib effects and further restricting the scope of our conclusions. We also included volunteers who were free of common age-related illnesses that could increase risks of adverse effects from taking a COX-2 inhibitor.
The initial enthusiasm for the COX-2 inhibitors because of their perceived lower side effect profile compared with other NSAIDs has been dampened by greater awareness of treatment-emergent side effects since the initial approval of these drugs. Patients enrolled in the present study who received celecoxib had a significantly higher rate of gastrointestinal side effects, particularly transient abdominal pain, gastritis, and nausea, compared with those taking placebo (). Although use of COX-2 inhibitors is associated with morbidity and mortality related to cardiovascular effects,15,16
our sample size was too small for such adverse effects to emerge. However, it is important to avoid overinterpretation of our results and inappropriate prescription of celecoxib for dementia prevention, to avoid the emergence of untoward and dangerous cardiovascular and gastrointestinal incidents from widespread use.
Despite such concerns, our positive findings that daily use of celecoxib improves cognitive functioning and increases prefrontal regional glucose metabolism are encouraging that NSAID treatment may exert beneficial cognitive effects in people with relatively mild age-related cognitive complaints, perhaps before subclinical neuropathological changes emerge. These results warrant further study in similar populations to confirm the possible cognitive benefits of these drugs and to elucidate the underlying mechanisms that may exert such effects.