In this population-based cohort of older adults, we found that older individuals with elevated non-HDL-C levels had an increased odds of cognitive impairment compared to those with lower levels. These findings suggest that non-HDL-C levels, a surrogate for apolipoprotein B-containing atherogenic lipoproteins, may be a better indicator of cognitive risk than total cholesterol or HDL-C levels alone. In our analysis, the impact of high non-HDL-C levels on impaired cognition became even greater after adjusting for factors related to survivor bias (age and sex) and subclinical atherosclerosis (CIMT). Since persons having CIMT measured tended to be healthier, however, selection bias limited our ability to comment on the impact of subclinical atherosclerosis on the relationship of non-HDL cholesterol with cognition. Given the widespread use of non-HDL cholesterol levels in risk assessment for cardiovascular disease prevention, use of this marker in assessing cognitive risk can be readily implemented by clinicians.28
Since non-HDL-C levels can be measured fairly accurately in a non-fasting state, these findings also may have important implications for the design and analysis of future epidemiological studies.28
In unadjusted analyses, we found suggestive evidence that use of statins was associated with better cognition. However, statin use also was associated with numerous conditions that both positively and negatively affect cognition, and after adjusting for these factors, statins were not related to better cognitive function. Confounding by indication may arise when use of a drug (such as a statin) serves as a marker for a clinical characteristic (younger age, higher education, regular exercise) or medical condition (diabetes mellitus, higher BMI, vascular disease, higher mean CIMT level) that triggers the use of the treatment and also increases the risk of the outcome under study (cognitive impairment).30
The association of statin use with numerous potential confounding conditions in our study suggests that indication bias could have affected prior study results by leading to incomplete adjustment of vascular risk factor burden on cognitive function in statin users vs. non-users. For example, if in one study the most common indication for statin use is established cardiovascular disease and in another study it is treatment of hypercholesterolemia for primary prevention, then participants in these two study cohorts may have significantly different levels of diffuse underlying cerebrovascular dysfunction leading to chronic cerebral hypoperfusion and cognitive decline. Due to confounding by indication and inadequate adjustment for underlying subclinical atherosclerosis, the potential protective effects of statins in these two study cohorts could look vastly different. In support of the idea that prior studies may have inadequately adjusted for underlying vascular risk burden, we found that 62% of persons in the highest quartile of CIMT measures had no self reported vascular disease, suggesting that prior studies relying on self report may not capture the full atherosclerotic burden of participants, and, thus, may have inadequately adjusted for this critical confounding factor. Although we were able to control for degree of underlying atherosclerosis and serum cholesterol levels in our analysis, we did not have data on more dynamic assessments of vascular function, such as endothelial function, which could potentially significantly affect cerebral perfusion and risk of cognitive decline.
While our sample size may have limited our ability to comment on the differential effects of lipophilic vs. hydrophilic statins on cognition, neurobiological evidence supports the idea that the ability of these medications to cross the BBB may impact their cognitive effects.31, 32
However, use of newer hydrophilic vs. older lipophilic statins may be confounded with other dementia risk factors, most notably age. 33
Thus, future longitudinal analyses evaluating statins and cognition will need to include not only objective measures of vascular dysfunction, but also further investigate the effects of lipophilic vs. hydrophilic statins on cognitive outcomes.
Despite conflicting data from epidemiological studies, animal and clinical data support that statins may have a role in the prevention and/or treatment of dementia.31
In addition to their role in the prevention of stroke34
and subsequent vascular dementia, statins reduce β-amyloid levels, the pathologic hallmark of Alzheimer’s disease, in the CSF and brains of animals.31
Statins also reduce inflammation and improve endothelial function – two additional processes that may be closely related to the development of dementia.35–37
In addition, some clinical trials have shown some mild cognitive benefits from statins in persons with AD38
and at risk for the disease.39
While statins may potentially have a role in delaying the progression of dementia once it develops, the high level of underlying neurodegeneration that is present by the time clinical symptoms develop may limit the utility of statins in treating established disease. Many suspect that, if statins are effective, they may be most useful for the primary prevention of dementia. Further prospective clinical trials are needed to clarify the role of statins in the prevention and treatment of cognitive impairment.
Some of the strengths of this analysis include the availability of data on HDL cholesterol, measures of subclinical atherosclerosis, and other vascular and lifestyle factors related to cognition. In addition, we anticipate that the findings presented in this analysis are generalizable to other older adults, since this large subset of older participants from this population-based cohort has mean values of vascular risk factors that are similar to older persons throughout the United States.22, 40
There are some limitations to this study. Our study is limited by its cross-sectional design which precludes making a temporal association between elevated serum cholesterol levels and the development of cognitive impairment.41
Given the relatively few older adults who were prescribed statins at the BDES2/ EHLS visit in 1993–1995, we were not able to comment on the longitudinal effects of statins on incidence of cognitive impairment at the 1998–2000 follow up visit. We also did not have data on dose and duration of statin therapy which could influence cognitive effects. Although the MMSE is a widely-used cognitive screen, its sensitivity to detect cognitive impairment in a general community-based population is limited.42, 43
To account for this, we analyzed MMSE score as a continuous variable and found similar results to using cognitive impairment as a categorical variable. Full medical, neurological, and neuropsychological evaluations were not available on participants, limiting our ability to diagnose clinical dementia. We also did not have information on apolipoprotein E ε4 (APOE4
) genotype, a genetic risk factor for late-onset Alzheimer’s disease and cardiovascular disease.44
These issues are all being addressed in an ongoing, prospective longitudinal study of middle-aged adults at increased risk for Alzheimer’s disease.45