To our knowledge, this is the first report of a randomized placebo controlled CPAP trial in AD patients with OSA. While changes in neuropsychological functioning across treatment groups (i.e., comparing 3-weeks of therapeutic CPAP to 3-weeks of placebo CPAP) were not statistically different, the composite neuropsychological scores from combined therapeutic periods suggested modest but statistically significant improvements in cognitive functioning associated with 3-weeks of therapeutic CPAP.
Results of two separate meta-analyses concluded that vigilance, executive functioning, or coordination are most affected by OSA (2
). Published literature reviews suggest much variability in which cognitive deficits are seen in OSA and in whether these deficits are reversible after treatment. As reviewed by Engleman et al. (14
), most studies have shown at least trends towards better performance after CPAP compared to placebo. The authors concluded that the small changes may have been due to the relatively mild study population, poor CPAP compliance or to an irreversible component in cognitive impairment. Nevertheless, at least three studies comparing neuropsychological test scores of OSA patients before and after six months of CPAP treatment with healthy controls found some cognitive improvement (6
). The present results are consistent with these studies of cognitive effects of CPAP in non-demented OSA patients.
A recent study, exploring the effect of CPAP on memory impairment in non-demented OSA patients, suggested that impaired verbal memory improved in those using CPAP for an average of six hours a night (30
). In the current study, AD patients used their CPAP for an average of five hours a night (5
). Future studies will need to examine if longer use per night in patients with AD results in greater cognitive improvements.
Standard treatment of AD is aimed at improving memory by ameliorating the cholinergic deficit. To date, acetylcholinesterase inhibitors have shown the most promising results, with reported treatment effects of approximately one point on the MMSE over six months compared to placebo (13
). Our treatment lasted only three-six weeks and although there was no effect on MMSE, we did find significant improvement in cognition. It is possible that our study was underpowered or of too short duration to see improvement in the MMSE.
This in fact is the one limitation of the study, i.e., due to the difficulty in participant recruitment, the study was underpowered to detect meaningful changes across treatment arms. With the available sample-size there was 80% power to detect an effect-size of 0.8 when comparing changes across treatment arms. The only analysis that compared treatment vs. placebo for which the randomization ensured a valid interpretation was from baseline to three weeks. The paired analysis did not allow for comparison between treatment groups but did test the hypothesis that there was a change in scores with treatment within groups. However, in the therapeutic CPAP group mean, change in composite score from baseline to 3 weeks was greater than the minimal change seen during placebo CPAP (mean change score of 0.028 vs. 0.008 respectively), yielding an effect-size of 0.11.
The study was also underpowered to make definitive statements about improvements within specific cognitive constructs. Our composite score has not been validated on a population basis. However, exploratory post-hoc examination of change scores for individual tests suggested improvements in episodic verbal learning and memory and some aspects of “executive functioning” such as cognitive flexibility, and mental processing speed.
In summary, there were significant improvements in cognition while patients were on therapeutic CPAP but not on placebo CPAP. It must be noted, however, that the direct 3-week comparison of those randomized to therapeutic versus placebo CPAP did not result in significant differences. Thus our findings tentatively suggest that AD patients with OSA may show some general cognitive benefits from OSA treatment, but more confidence in such conclusions await independent replication with sufficiently powered studies.
This study was not an epidemiological study and the prevalence of OSA among those with mild-moderate AD is uncertain; however, our data clearly show there is a non-trivial proportion of AD patients for whom 0SA is a clear problem. Bliwise suggested that OSA might be a reversible cause of cognitive loss and dementia and that treatment of OSA, especially in the early stages of dementia when patients are still largely independent, may slow dementia progression (9
). The results of this study in which CPAP treatment of OSA improved cognitive function in patients with mild-moderate AD, lend support to Bliwise's hypothesis. Further studies will need to determine whether CPAP treatment of OSA in AD patients might actually slow dementia progression. In the meantime, clinicians who care for AD patients with OSA need to consider implementing CPAP treatment.