High-density lipoprotein cholesterol - a link to memory?

A low level of high-density lipoprotein (HDL) cholesterol in middle-aged people is associated with poor memory, according to a recent study. The study was reviewed in an accompanying editorial by Professor John Chapman, HDL Forum Editor and Dr Anatol Kontush, INSERM, Hopital de la Pitie, Paris, France.

 Singh-Manoux A, Gimeno D, Kivimaki M et al. Low HDL cholesterol is a risk factor for deficit and decline in memory in midlife. The Whitehall II study. Arterioscler Thromb Vasc Biol 2008;28:1556-62.

Over the last decade, abnormalities in brain lipid metabolism have been linked to the pathogenesis of degenerative neurological disorders such as Alzheimer’s disease and vascular dementia.1 Furthermore, there is some evidence to indicate that dementia itself modifies lipid levels, leading to low total cholesterol or low-density lipoprotein (LDL) cholesterol,2 which suggests that examination of the effects of lipids on cognition in the elderly may produce misleading results. While associations between mid-life lipid levels and late-life dementia appear to be more robust, which lipid(s) are important in this process remains unclear. 

The current study investigated the prospective association between lipids and short-term verbal memory over 5 years in middle-aged individuals. The study included 3,673 participants (27% women) of the Whitehall II study which is a major long-term study of more than 10,000 British civil servants working in London, UK. The researchers measured lipids (total cholesterol, HDL cholesterol and triglycerides) and short-term verbal memory at two time points: 1) between 1995 and 1997 when subjects had a mean age of 55 years and 2) between 2002 and 2004 when subjects had a mean age of 61 years. Short-term memory was assessed using a 20-word recall test. Subjects were given a list of 20 1- or 2-syllable words at 2-second intervals, and were then given 2 minutes to write down as many of these words as possible. Memory deficit was defined as recall of 4 or fewer words (cross-sectional study). Memory decline between the two time points was defined as a decrease in recall of 2 or more words (longitudinal study).

Analyses were adjusted for age, sex, education, employment grade, coronary heart disease, stroke, hypertension, use of medication, diabetes, smoking and alcohol consumption.    

At each time point, low HDL cholesterol (<40 mg/dL) in both males and females was associated with short-term memory deficit (Table 1).  However, there was no association with elevated total cholesterol or triglycerides or any of the other risk factors that were evaluated.

Table 1. Association between lipids and memory deficit, odds ratio (95% CI)

When the lipid levels at the two time points at which memory was measured were analysed, only changes in HDL cholesterol levels were associated with a decline in memory. Compared with subjects with high levels of HDL cholesterol (³60 mg/dL), subjects with progressively decreasing levels of HDL cholesterol over the study period had a greater risk of memory decline (odds ratio 1.61, 95%CI 1.19 to 2.16, p=0.03). Total cholesterol and triglycerides did not show any association with memory loss.

In their conclusions, the researchers commented: ‘We found that a low level of HDL cholesterol may be a risk factor for memory loss in later midlife. This suggests that low HDL cholesterol might also be a risk factor for dementia.’ The researchers did, however, note that the precise mechanism linking HDL cholesterol to dementia remains unclear, although it was possible that HDL cholesterol may a) prevent the formation of beta-amyloid, a major component of protein plaques found in the brains of Alzheimer’s patients, or b) affect memory via its influence on atherosclerotic disease or vascular injury, or via anti-inflammatory or anti-oxidant effects.

However, the accompanying editorial highlights the need for caution in extrapolating these results.

Kontush A, Chapman MJ. HDL: close to our memories? Arterioscler Thromb Vasc Biol 2008;28:

The Editors note that while low HDL cholesterol has been reported in association with dementia,3 most of these reports have been from cross-sectional studies. They note that elevated HDL cholesterol levels, potentially mediated by low activity of cholesteryl ester transfer protein (CETP) are also associated with longevity, improved cognition and dementia-free survival.4 However, none of these previous studies have inferred causality because plasma lipids change considerably during the development of dementia. Therefore, the time point at which HDL cholesterol is measured during this disease process is critical. This is an important caveat of the current study.

The results of the current study do not offer any insight into potential mechanisms that may underlie the observed effects. A number were suggested by the Editors, mediated via Ab metabolism, the main pathway involved in the pathogenesis of Alzheimer’s disease (Table 2). These mechanisms emphasise the complexity of any possible relationship between HDL and brain function.

Table 2. Possible mechanisms that may link HDL cholesterol to Alzheimer’s disease

 None of these postulated mechanisms provide any rationale, however, for linking plasma levels of HDL cholesterol to defective functionality of HDL in the brain, notably in the CSF.

 There are clearly a number of limitations to this study, as highlighted by both the researchers and the Editors (Table 3):

 Table 3. Limitations of the study

Kontush and Chapman concluded: ‘It is tempting to speculate that increasing levels of HDL cholesterol might protect our good memories…..However, we should remain extremely cautious when proposing therapeutic intervention on the basis of observational studies that do not imply causation. This is particularly true for a study with a number of limitations, such as that of Singh-Manoux et al.  While HDL cholesterol remains a potentially promising but still remote target in the prevention of dementia and memory loss, these studies demand that we focus more effort on research at the interface between HDL cholesterol and brain function.’

Finally, as low HDL cholesterol is a hallmark of type 2 diabetes, it is possible that this may underlie the association of low HDL cholesterol and memory decline observed in this study. The Editors emphasised the link between type 2 diabetes, low HDL cholesterol and memory decline and advocated the need for further study.

 References

1. Reitz C, Tang MX, Luchsinger J et al. Relation of plasma lipids to Alzheimer disease and vascular dementia. Arch Neurol 2004;61:705-14.

2. Kivipelto M, Solomon A. Cholesterol as a risk factor for Alzheimer’s disease. – epidemiological evidence. Acta Neurol Scand Suppl 2006;185:50-7.

3. Michikawa M. Cholesterol paradox: is high total or low HDL cholesterol level a risk for Alzheimer’s disease? J Neurosci Res 2003;72: 141-6.

4. Barzilai N, Atzmon G, Derby CA et al. A genotype of exceptional longevity is associated with preservation of cognitive decline. Neurology 2006;67:2170-5.


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