This study of middle aged adults suggests a robust association between low HDL-C and poor memory. Furthermore, decreasing HDL-C was associated with decline in memory over a 5-year follow-up. These associations remained after adjustment for the effects of education, occupational position, prevalent disease or medication use and they were independent of APOE e4 status. Serum concentrations of total cholesterol and triglycerides show no association with memory deficit or decline. Thus, our results identify HDL-C as being important for memory.
Many previous investigations into the association between lipids and memory in the elderly have focused on total or LDL-C,5,33
perhaps because of their status as proven risk factors for cardiovascular disease. Our findings emphasize the need to expand the focus to HDL-C. In our study on middle aged adults, the associations of low levels of HDL-C with memory deficit and decline were independent of other lipids and robust to adjustments for a number of potential confounding factors. There are a number of plausible mechanisms connecting low levels of HDL-C and memory, as HDL-C is the prominent lipoprotein in the human brain27
and is involved in the regulation of amyloid β protein metabolism and deposition in the brain.34
Deficit in HDL-C could also affect memory through its influence on atherosclerotic disease and stroke,35
or subclinical vascular injury not reflected in the covariates examined. Other possible mechanisms linking low levels of HDL-C to neurodegenerative processes might involve its anti-inflammatory36
Although memory deficits are critical to the diagnosis of mild cognitive impairment38
and Alzheimer’s disease, the association between lipids and memory remains little explored in midlife. Dementia occurs late in life but it is increasingly recognized that there is a long preclinical phase characterized by progressive neuropathological changes that become clinically detectable later. The “life-long” view of dementia stresses the importance of risk factors in midlife.39
Our findings on individuals aged 55 and 61 at the two phases of data collection suggest that low levels of HDL-C may be an important risk factor. Among the elderly, there is also some evidence of a link between HDL-C and poor memory,10
and Alzheimer’s disease. However, some previous studies on the elderly have found low HDL-C to be associated with vascular dementia but not with Alzheimer’s disease.8,14
The inconsistency in findings needs to be viewed in light of the fact that dementia itself modifies lipid levels;6,7
necessitating further research where lipids are measured before the diagnosis of dementia.
The association between low levels of HDL-C and poor memory is unlikely to be simply an accidental finding in our data as the cross-sectional findings were consistently replicated across two study phases. There is some evidence of increase in association over time as the Phase 7 data show stronger associations between HDL-C and memory deficit. Furthermore, decreasing HDL-C level was also predictive of decline in memory. We undertook further analysis in sub samples in order first to assess whether this association held in APOE e4 negative subjects. APOE e4 is widely regarded as being implicated with adverse outcomes for dementia.1,5,23,24,40
Our results on APOE e4 negative individuals show decreasing levels of HDL-C to be associated with greater odds of memory decline. In the second analysis on a sub sample we reran the longitudinal analysis by replacing total cholesterol with LDL-C. Here again, results were not much different.
There are a number of potential limitations to this study. First, causality cannot be inferred from observational data and a randomized controlled trial with treatment specifically targeted at elevating HDL-C levels and measurements of change in memory performance would be necessary to establish causality. A further possibility would be to examine this issue using brain imaging data. Second, despite extensive adjustments for a variety of potential confounding factors, it is possible that some unmeasured variable causes decline in both HDL-C and memory. Third, data here are drawn from the 5th and 7th phase of a study, implying both survival and selection effects. Therefore, it is possible that the association between lipids and cognition is underestimated in our sample.
In conclusion, our results show low levels of HDL-C (<40 mg/dL) to be associated with poor memory. Furthermore, decline in HDL-C was associated with declines in memory over a five-year period. The National Cholesterol Education Program29
has stressed the importance of lowering LDL-C in order to reduce the burden of cardiovascular disease. Our results suggest that increasing HDL-C might also be important, for cognitive outcomes in particular.