Statins and Cognitive Decline in Older Adults
Table 1 shows the demographic and clinical features of participants stratified according to cognitive status at baseline (normal, MCI) and statin use (nonuser, user). As expected, statin users were significantly more likely to report a history of heart disease, diabetes mellitus, hypertension, and stroke. Of those who were cognitively normal at baseline, statin users had a significantly higher (worse) CDR-SOB.
Participants used six different statins: simvastatin (41%), atorvastatin (37%), lovastatin (10%), pravastatin (6%), rosuvastatin (5%), and fluvastatin (1%).
Table 2 shows the coefficients for the main effects for statin use and time (from the main effects model) and their corresponding P-values and the coefficient for the interaction between statin use and time (after adding an interaction term to the main effects model) and its corresponding P-value. The main effects term for those with normal cognition at baseline show that, across all visits, statin users had significantly better scores on Trails A and better scores on Digit Symbol (P = .07). Of those with MCI at baseline, statin users had significantly better scores across all visits for Trails A, Trails B, Digit Symbol, category fluency, and Digits Backward. The main effects term for time indicate the change over time for each test (statin users and nonusers combined). Most tests, as expected, showed significant deterioration over time. Exceptions were the Boston Naming Test in participants with normal cognition and the Logical Memory test for immediate and delayed recall in participants with normal cognition, which showed significant improvement over time. This probably reflects learning how to take the test. This same phenomenon was not seen for subjects with MCI.
Of particular interest is the interaction term between time (or visit number) and statin use, which indicates whether change over time differs in statin users and nonusers. Of those with normal cognition at baseline, there was significantly less deterioration over visits (over time) for statin users on the CDR-SOB and less decline on the MMSE, although the latter fell short of statistical significance after adjusting for multiple comparisons (Figures 1 and 2). There were no significant differences in change over time for those diagnosed with MCI at baseline.
(Enlarge Image)
Figure 1.
Decline in Mini-Mental State Examination (MMSE) score over annual visits for participants with normal cognition at baseline for statin users and nonusers, from linear regression model.
(Enlarge Image)
Figure 2.
Increase in mean predicted Clinical Dementia Rating Sum of Boxes (CDR-SOB) over annual visits for participants with normal cognition at baseline, statin users vs nonusers, using predicted CDR category from the logistic regression model.
Using an ordinal logistic regression model instead of a linear regression model for the CDR-SOB resulted again in a highly significant interaction term between time and statin use (P < .001 vs P = .006 for the linear regression model) for those with normal cognition at baseline. This model fit the data better (root mean squared error 0.67) than the linear regression model (root mean squared error 0.82). For participants with MCI at baseline, the ordinal logistic model resulted in a nonsignificant interaction term between time and statin use (P = .92).
Supplemental stratified analyses considered the approximately 60% of the population with data on apolipoprotein E (APOE). The data were stratified according to APOE4 status (variant present or absent), and then the interaction term between statins and time was evaluated as before. A stronger protective effect of statins against MMSE decline was found in participants with normal cognition at baseline in those without the APOE4 variant, although this protective effect was not significant (P = .08 for interaction term between statin use and visit); no suggestion of a protective effect was found for those with the variant (P = .95). In participants with MCI, a significant protective effect for MMSE was seen for those who were APOE4 negative (P = .03 for the interaction term); for APOE4-positive participants with MCI, the interaction term was in the wrong direction and not significant (P = .10). For the CDR-SOB, in individuals with normal cognition, a protective effect of statins against decline was seen for APOE4-positive (P = .01) subjects for the interaction term between statin use and visit and APOE4-negative (P = .01 for the interaction term) subjects using the ordinal logistic regression model. In individuals with MCI, statins did not affect decline over time regardless of APOE genotype. No multiple comparison adjustments were used in these targeted analyses.
Results
Table 1 shows the demographic and clinical features of participants stratified according to cognitive status at baseline (normal, MCI) and statin use (nonuser, user). As expected, statin users were significantly more likely to report a history of heart disease, diabetes mellitus, hypertension, and stroke. Of those who were cognitively normal at baseline, statin users had a significantly higher (worse) CDR-SOB.
Participants used six different statins: simvastatin (41%), atorvastatin (37%), lovastatin (10%), pravastatin (6%), rosuvastatin (5%), and fluvastatin (1%).
Table 2 shows the coefficients for the main effects for statin use and time (from the main effects model) and their corresponding P-values and the coefficient for the interaction between statin use and time (after adding an interaction term to the main effects model) and its corresponding P-value. The main effects term for those with normal cognition at baseline show that, across all visits, statin users had significantly better scores on Trails A and better scores on Digit Symbol (P = .07). Of those with MCI at baseline, statin users had significantly better scores across all visits for Trails A, Trails B, Digit Symbol, category fluency, and Digits Backward. The main effects term for time indicate the change over time for each test (statin users and nonusers combined). Most tests, as expected, showed significant deterioration over time. Exceptions were the Boston Naming Test in participants with normal cognition and the Logical Memory test for immediate and delayed recall in participants with normal cognition, which showed significant improvement over time. This probably reflects learning how to take the test. This same phenomenon was not seen for subjects with MCI.
Of particular interest is the interaction term between time (or visit number) and statin use, which indicates whether change over time differs in statin users and nonusers. Of those with normal cognition at baseline, there was significantly less deterioration over visits (over time) for statin users on the CDR-SOB and less decline on the MMSE, although the latter fell short of statistical significance after adjusting for multiple comparisons (Figures 1 and 2). There were no significant differences in change over time for those diagnosed with MCI at baseline.
(Enlarge Image)
Figure 1.
Decline in Mini-Mental State Examination (MMSE) score over annual visits for participants with normal cognition at baseline for statin users and nonusers, from linear regression model.
(Enlarge Image)
Figure 2.
Increase in mean predicted Clinical Dementia Rating Sum of Boxes (CDR-SOB) over annual visits for participants with normal cognition at baseline, statin users vs nonusers, using predicted CDR category from the logistic regression model.
Using an ordinal logistic regression model instead of a linear regression model for the CDR-SOB resulted again in a highly significant interaction term between time and statin use (P < .001 vs P = .006 for the linear regression model) for those with normal cognition at baseline. This model fit the data better (root mean squared error 0.67) than the linear regression model (root mean squared error 0.82). For participants with MCI at baseline, the ordinal logistic model resulted in a nonsignificant interaction term between time and statin use (P = .92).
Supplemental stratified analyses considered the approximately 60% of the population with data on apolipoprotein E (APOE). The data were stratified according to APOE4 status (variant present or absent), and then the interaction term between statins and time was evaluated as before. A stronger protective effect of statins against MMSE decline was found in participants with normal cognition at baseline in those without the APOE4 variant, although this protective effect was not significant (P = .08 for interaction term between statin use and visit); no suggestion of a protective effect was found for those with the variant (P = .95). In participants with MCI, a significant protective effect for MMSE was seen for those who were APOE4 negative (P = .03 for the interaction term); for APOE4-positive participants with MCI, the interaction term was in the wrong direction and not significant (P = .10). For the CDR-SOB, in individuals with normal cognition, a protective effect of statins against decline was seen for APOE4-positive (P = .01) subjects for the interaction term between statin use and visit and APOE4-negative (P = .01 for the interaction term) subjects using the ordinal logistic regression model. In individuals with MCI, statins did not affect decline over time regardless of APOE genotype. No multiple comparison adjustments were used in these targeted analyses.