In this study performance in all cognitive domains declined significantly over time in elderly individuals without dementia or cognitive impairment, while there was no association between levels of any plasma lipid or lipid lowering treatment and memory, cognitive/visuospatial or language performance at any interval. Higher age at baseline was related to lower scores in all three domains at each interval, while higher education and Caucasian ethnicity were associated with higher scores in all domains.
The role of dyslipidemia in the development of cognitive impairment remains unclear. Brain cholesterol alters the degradation of APP(2), which contributes to the pathogenesis of AD (13
). Several lines of evidence indicate that lowering plasma cholesterol levels prevents AD development by reducing Aβ production and secretion (40
). These findings seem to contradict previous studies demonstrating that cholesterol protects PC12 cells from fibrillar Aβ peptide, that cholesterol depletion induces AD-type injuries in cultured hippocampal slices (40
), and that brain cholesterol is almost entirely synthesized in situ and not transferred from the plasma into the brain (41
). Few studies have examined the association of plasma lipid levels to cognitive function, and they reported inconsistent results (5
). Results in animal studies (45
), and studies relating plasma lipid lowering treatment to cognitive functioning (7
) have also been conflicting. Most observational studies were cross-sectional (9
), and some of the few longitudinal studies included individuals with QD or AD and did not provide methods to limit inclusion of such individuals (52
). Our results are consistent with the idea that lipid levels do not affect cognition directly.
There are several potential explanations for our findings of no association of plasma lipids and lipid lowering treatment to cognitive change. One explanation is measurement error. We had only one measure of plasma lipids which may not take into account intrapersonal variation. If the measurement error was random, this would have underestimated the association between lipids and cognitive changes, thus resulting in finding of no association. Another possibility is that our sample was relatively homogeneous in plasma lipid levels, thus not permitting enough variability to detect an association. Another potential explanation is bias related to selection into this study. It is possible that plasma lipid levels are related to cognitive decline in younger individuals but not the older sample in our study. Our sample was older than 65 years with a mean age of 75.7 years. It is possible that individuals with adverse outcomes related to plasma lipid levels did not survive to inclusion in our study, or that the plasma lipid levels at the age of entry in the study did not reflect lipid levels earlier in life. Finally, it is possible that plasma lipid levels are not related to cognitive decline as indicated by our results.
The main limitation of this study is that we used only one measurement of lipid levels, which could have led to measurement error due to intraperson variability and underestimation of the association between lipid levels and cognitive impairment.
This study has important strengths. This is a prospective cohort study designed for the diagnosis of cognitive decline, and with complete clinical and neuropsychological evaluation at each interval. Our study has sensitive measures of cognitive change in several specific domains including memory. In addition, we had the ability to diagnose dementia and cognitive impairment without dementia at baseline, thus allowing us to follow an unbiased sample. Other longitudinal studies used global cognitive assessments or may not have had the ability to detect early stages of cognitive impairment at baseline (43
An important consideration in the interpretation of the results of this study is its generalizability. This study was conducted in an urban multiethnic elderly community with a high prevalence of risk factors for mortality and dementia. Thus, our results may not be generalizable to cohorts with younger individuals or to cohorts with participants with a lower morbidity burden.