Comorbidity burden in Alzheimer’s disease clinical trials

Background Individuals with AD may be healthier than the general older adult population. Clinical trials for AD have been known to enroll individuals who are not representative of the general population, but it is unclear to what extent comorbidity affects cognitive outcomes in clinical trials. Methods We included 10 studies with 4,002 subjects with AD from our meta‐database of 18 ADCS studies and ADNI. Comorbidity was measured using the RxRisk‐V, which provides a count of the total number of comorbid conditions based on medication data. Cognition was measured using the Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog). We used linear mixed effects models to examine the rate of cognitive decline by total comorbidity count, by individual disorders, and by presence of hypertension plus diabetes as known AD risk factors. Results Across all participants, the mean RxRisk comorbidity score was 1.90 (SD 2.04). Approximately 27% had 0 comorbidities, 27% had 1 comorbidity, and 46% had 2+ comorbidities. Across all studies, for each additional comorbidity, the rate of progression on the ADAS‐cog increased by 0.11 point/year (95% CI ‐0.05, 0.26), reflecting a non‐significant worsening of cognition (Figure). After adjusting for other comorbidities, the rate of progression was not significant for congestive heart failure (‐0.5 point/year, 95% CI ‐1.3, 0.3), COPD (‐0.1 point/year, 95% CI ‐1.6, 1.3), diabetes (‐1.2 point/year, 95% CI ‐2.5, 0.1), hypertension (0.7 point/year, 95% CI ‐0.1, 1.6), or ischemic heart disease (‐0.3 point/year, 95% ‐0.9, 0.4). The rate of progression was also not significant for the combination of hypertension plus diabetes (0.1 point/year, 95% ‐0.7, 0.9). Conclusions Comorbidity did not have a significant effect on rate of cognitive decline across AD clinical trials. As several comorbidities are known to affect the rate of AD progression, these findings suggest that AD clinical trials enroll participants with less severe comorbidities that do not affect cognitive decline. Further study of the effects of comorbidities on AD clinical trial outcomes are warranted, particularly study of severity of comorbidities.