The suggestion that raising blood levels of HDL or ‘good’ cholesterol may help to arrest cognitive decline has been bolstered by results from a large-scale observational study of British civil servants.

New data from the Whitehall II study, which is part-funded by the UK’s Medical Research Council, the Department of Health and the British Heart Foundation among others, were published in the American Heart Association journal Arteriosclerosis, Thrombosis and Vascular Biology.

Tracking 3,673 of the more than 10,000 participants in Whitehall II, which has been running since 1985, the researchers found that falling levels of HDL cholesterol were predictors of declining memory by the time subjects reached the age of 60.

The team led by Dr Archana Singh-Manoux, senior research fellow with the French National Institute for Health and Medical Research (INSERM) and University College London in the UK, compared blood-lipid and short-term memory data collected in phases five (1995-1997) and seven (2002-2004) of the Whitehall II study, when the average ages of the participants were 55 and 61 years respectively.

Low HDL cholesterol was defined as under 40mg/dL and high HDL as 60mg/dL and above. The analysis showed that at age 55, study participants with low HDL cholesterol had a 27% increased risk of memory loss versus those with high HDL. At age 60, participants with low HDL had a 53% increased risk of memory loss compared with the high-HDL group.

Short-term verbal memory was assessed using 20 one- or two-syllable words read aloud at two-second intervals. During the five years between phases five and seven of the Whitehall II study, the researchers found, participants with decreasing HDL cholesterol had a 61% increased risk of decline in their ability to remember words versus those with high HDL.

“Memory problems are key in the diagnosis of dementia,” commented Singh-Manoux. “We found that a low level of HDL may be a risk factor for memory loss in late midlife. This suggests that low HDL cholesterol might also be a risk factor for dementia.”

Dementia most often occurs in people aged 65 years and over, the fastest-growing age group in the industrialised world. But the precise mechanism linking HDL cholesterol and dementia remains unclear, the researchers noted. One possibility is that HDL helps to control the formation of beta-amyloid, the major component of the protein plaques found in the brains of Alzheimer’s patients.

HDL could also affect memory through its influence on atherosclerotic disease and stroke, or vascular injury, Singh-Manoux added. Alternatively, the key may be HDL cholesterol’s anti-inflammatory and anti-oxidant effects.

Be cautious

An accompanying editorial by Drs Anatol Kontush and John Chapman of INSERM and Pierre and Marie Curie University in Paris recommended against jumping to any conclusions.

“It is tempting to speculate that increasing levels of HDL-C, or ‘good cholesterol’, might protect our memories,” they wrote. “However, unfortunate results in large interventional trials with dietary antioxidants suggest that we should remain cautious when proposing therapeutic intervention on the basis of observational studies which do not allow causation to be inferred.”

Nonetheless, Kontush and Chapman suggested, “these studies demand that we focus more effort on research at the interface between HDL and brain function”.

Lowering levels of LDL (‘bad’) or total cholesterol has also been associated in previous research with reducing the risk of dementia or Alzheimer’s disease, although other studies have ruled out any such association. Recently the largest ever clinical trial of cholesterol-lowering statins as a treatment for Alzheimer’s disease drew a disappointing blank.

Presented at the annual American Academy of Neurology meeting in April, results from the 18-month study with Pfizer’s blockbuster Lipitor (atorvastatin) showed that adding the drug to Aricept (donepezil), the Alzheimer’s therapy co-promoted by Pfizer with Eisai, produced no significant differences in cognition or global function – key measures of Alzheimer’s progression – compared with placebo plus Aricept.

Nor did the trial observe any statistically significant differences in various cognitive, behavioural and functional secondary endpoints.

In the results reported from the Whitehall II study, no link was found between total cholesterol/triglycerides and declining memory. Moreover, the research did not establish any association between memory loss and using statins to raise HDL and/or lower LDL cholesterol.