Statins and serum cholesterol's associations with incident dementia and mild cognitive impairment

Abstract

Background: Statin use and serum cholesterol reduction have been proposed as preventions for dementia and mild cognitive impairment (MCI).

Methods: 1604 and 1345 eligible participants from the Baltimore Longitudinal Study of Aging (BLSA) were followed after age 50 for a median time of around 25 years, to examine the incidence of dementia (n=259) and MCI (n=138), respectively. Statin use (ever-use and time-dependent use), total cholesterol levels (TC; first visit and time-dependent), TC change trajectory from first visit and high-density lipoprotein (HDL-C):TC ratio (first visit and time-dependent) were the main exposures of interest. Cox proportional hazards models were used.

Results: Participants with incident dementia had a higher first-visit TC compared with participants who remained free of dementia and MCI, while first-visit TC was higher among statin ever-users compared with never-users (age-unadjusted associations). Statin users had a two- to threefold lower risk of developing dementia (HR=0.41; 95% CI 0.18 to 0.92), but not MCI, when considering time-dependent 'statin use' with propensity score model adjustment. This association remained significant independently of serum cholesterol exposures. An elevated first-visit TC was associated with reduced MCI risk (upper quartile (Q(4)) vs Q(1): HR=0.51; 95% CI 0.29 to 0.90). Compared with the lowest quartile (Q(1): 0.00-0.19), HDL-C:TC (time-dependent) in (Q(2): 0.19-0.24) was associated with reduced MCI risk (HR=0.58; 95% CI 0.34 to 0.98). Among men only, TC decline from first visit was significantly associated with increased dementia risk (HR=4.21; 95% CI 1.28 to 13.85).

Conclusions: Statins may have multifactorial effects on dementia but not MCI risk. Future interventions may be warranted, and research should focus on optimal serum TC, HDL-C:TC ratio and TC change trajectories.

Figure 1

Diagram for inclusion and exclusion of BLSA participants into main analyses Notes: BLSA=Baltimore Longitudinal Study on Aging; Sample 1 was used for prediction of TC trajectories with linear mixed models; Samples 3 was used for fitting Cox proportional hazard models and running Kaplan-Meier survival curves. “Subjects immune to statin use” are those with visits that preceded the introduction of statins into the market (i.e. prior to 1985). “Subjects with less accurate year of onset” are those whose diagnosis of dementia or MCI was done retrospectively since case conferencing was initiated in the mid-80s.

Figure 2

Figure 2a. Kaplan-Meier survival curve of time to incidence of dementia by use of statins (time-independent): Cox Proportional Hazards model and Log-rank test. Notes: A participant is defined as a statin user prior to onset of dementia or MCI or by end of follow-up if a non-case but beyond age 50 years. Cox PH model analysis controlled for sex, education, race/ethnicity, age at first-visit (continuous), smoking status at first-visit, chronic conditions at first-visit (type 2 diabetes, hypertension, dyslipidemia and CVD), body mass index and systolic blood pressure (continuous) at first-visit and was based on 1,561 participants at risk for dementia and for use of statins (visits at or after 1985) and 252 failures (person-years= 37,860). Log-rank test was based on 259 incident cases. Six statin-users were observed incident dementia cases, while 22.7 were expected to become incident cases by chance, which yielded a Log-rank χ² test of 13.93 (1 d.f.); p=0.0002. *p<0.05 for null hypothesis that Loge(HR)=0. Figure 2b. Kaplan-Meier survival curve of time to incidence of mild cognitive impairment (MCI) by use of statins (time-independent): Cox Proportional Hazards model and Log-rank test. Notes: Statin use was defined the same way as in Figure 1a. Cox PH model analysis controlled for the same covariates as in Figure 1a, but was based on 1,308 subjects at risk for MCI and at risk of using statins (visits at or after 1985), with 133 MCI failures (person-years= 29,600). Log-rank test was based on 138 incident MCI cases. Seven statin-users were observed incident MCI cases, while 16.2 were expected to become incident cases by chance, which yielded a Log-rank χ² test of 6.07 (1 d.f.); p=0.0138. *p<0.05 for null hypothesis that Loge(HR)=0.

Figure 2

Figure 2a. Kaplan-Meier survival curve of time to incidence of dementia by use of statins (time-independent): Cox Proportional Hazards model and Log-rank test. Notes: A participant is defined as a statin user prior to onset of dementia or MCI or by end of follow-up if a non-case but beyond age 50 years. Cox PH model analysis controlled for sex, education, race/ethnicity, age at first-visit (continuous), smoking status at first-visit, chronic conditions at first-visit (type 2 diabetes, hypertension, dyslipidemia and CVD), body mass index and systolic blood pressure (continuous) at first-visit and was based on 1,561 participants at risk for dementia and for use of statins (visits at or after 1985) and 252 failures (person-years= 37,860). Log-rank test was based on 259 incident cases. Six statin-users were observed incident dementia cases, while 22.7 were expected to become incident cases by chance, which yielded a Log-rank χ² test of 13.93 (1 d.f.); p=0.0002. *p<0.05 for null hypothesis that Loge(HR)=0. Figure 2b. Kaplan-Meier survival curve of time to incidence of mild cognitive impairment (MCI) by use of statins (time-independent): Cox Proportional Hazards model and Log-rank test. Notes: Statin use was defined the same way as in Figure 1a. Cox PH model analysis controlled for the same covariates as in Figure 1a, but was based on 1,308 subjects at risk for MCI and at risk of using statins (visits at or after 1985), with 133 MCI failures (person-years= 29,600). Log-rank test was based on 138 incident MCI cases. Seven statin-users were observed incident MCI cases, while 16.2 were expected to become incident cases by chance, which yielded a Log-rank χ² test of 6.07 (1 d.f.); p=0.0138. *p<0.05 for null hypothesis that Loge(HR)=0.

Figure 3

Figure 3a. Kaplan-Meier survival curve of time to incidence of dementia by use of statins (time-dependent): Cox Proportional Hazards model and Log-rank test. Notes: A participant is defined as a statin user at first prescription onwards, prior to onset of dementia or MCI or by end of follow-up if a non-case but beyond age 50 years. Cox PH model analysis controlled for the same covariates as in Figure 1a, but was based on 1,560 participants at risk for dementia and for use of statins (visits at or after 1985) and 252 dementia failures (person-years=37842). Log-rank test was based on 259 incident cases. Six statin-users were observed incident dementia cases, while 14.3 were expected to become incident cases by chance, which yielded a Log-rank χ² test of 5.26 (1 d.f.); p=0.0219. *p<0.05 for null hypothesis that Loge(HR)=0. Figure 3b. Kaplan-Meier survival curve of time to incidence of mild cognitive impairment (MCI) by use of statins (time-dependent): Cox Proportional Hazards model and Log-rank test. Notes: Statin use was defined the same way as in Figure 2a. Cox PH model analysis controlled for the same covariates as in Figure 1a, but was based on 1,308 subjects at risk for MCI and for use of statins (visits at or after 1985) and 133 failures (person-years= 29,600). Log-rank test was based on 138 incident cases. Seven statin-users were observed incident MCI cases, while 9.9 were expected to become incident cases by chance, which yielded a Log-rank χ² test (1 d.f.) of 0.92; p=0.3378.

Figure 3

Figure 3a. Kaplan-Meier survival curve of time to incidence of dementia by use of statins (time-dependent): Cox Proportional Hazards model and Log-rank test. Notes: A participant is defined as a statin user at first prescription onwards, prior to onset of dementia or MCI or by end of follow-up if a non-case but beyond age 50 years. Cox PH model analysis controlled for the same covariates as in Figure 1a, but was based on 1,560 participants at risk for dementia and for use of statins (visits at or after 1985) and 252 dementia failures (person-years=37842). Log-rank test was based on 259 incident cases. Six statin-users were observed incident dementia cases, while 14.3 were expected to become incident cases by chance, which yielded a Log-rank χ² test of 5.26 (1 d.f.); p=0.0219. *p<0.05 for null hypothesis that Loge(HR)=0. Figure 3b. Kaplan-Meier survival curve of time to incidence of mild cognitive impairment (MCI) by use of statins (time-dependent): Cox Proportional Hazards model and Log-rank test. Notes: Statin use was defined the same way as in Figure 2a. Cox PH model analysis controlled for the same covariates as in Figure 1a, but was based on 1,308 subjects at risk for MCI and for use of statins (visits at or after 1985) and 133 failures (person-years= 29,600). Log-rank test was based on 138 incident cases. Seven statin-users were observed incident MCI cases, while 9.9 were expected to become incident cases by chance, which yielded a Log-rank χ² test (1 d.f.) of 0.92; p=0.3378.