den Heijer T, Geerlings MI, Hofman A, de Jong FH, Launer LJ, Pols HA, Breteler MM.
Higher estrogen levels are not associated with larger hippocampi and better memory performance.
Arch Neurol. 2003 Feb;60(2):213-20.
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I’d like to comment on the Luchsinger and the follow-up Rotterdam studies on fats, and the apparent discrepancies thus far. This is a very new area of research, and it is difficult to assess at this point what is truth and what are chance findings. I believe that it is possible that none of these dietary components may be associated with Alzheimer's disease.
On more specific points, I do not see a discrepancy between the Luchsinger/New York findings and the Chicago or Rotterdam studies. We did not observe a protective effect from vitamin E intake around 7 IU/d, nor did the Rotterdam study. This was the mean of the highest quartile of intake from food in the Luchsinger study. So, actually all three studies are consistent in that none of them find protection against Alzheimer's disease from supplements, or from low intake of vitamin E in food.
On the differences between the Rotterdam six-year follow-up and the Chicago study on dietary fats, I am not sure these findings were discrepant, either. We also did not observe much association when the data were analyzed without adjustment for other types of fat. Intakes of the different types of fat are correlated and sometimes are in opposite directions, so this can confuse the observed associations. Also, most of the effects we observed for saturated and trans-unsaturated fats were at the extremes of the distribution, and the associations with the individual fats of poly and mono fats were marginally significant. We hope that we can study the population further and with more subjects to test these associations more conclusively. I think it will be critical in the longer follow-up of the population to have updated dietary intake. Those most likely to change their diets are people with disease, and disease is frequent in old age, so updated measurement of diet is crucial in these older populations especially.
I hope this area of research continues so we can learn more about the complex associations between diet and neurodegenerative decline.
I basically agree with the conclusions. Intake of vitamin E and C really made little to no difference. The same was true with fat, though we have not yet separated the types of fats. The highest fat intake was among individuals who developed AD.
Most agree that dietary interviews in the form of food-frequency questionnaires are semiquantitative methods to allow investigators to rank intake of macro and micro nutrients. We have validated our interviews in New York using the 24-hour food intake recall method (actually 72 hours, because it is done three times). The validity was modest, but acceptable for these types of questionnaires.
However, this does not address the major issues of these studies, which are timing and direction. If we accept that AD has a long prodromal period (studies from Framingham and other places suggest that the disease may start 10 to 20 years before it is clinically recognized), then whatever is observed may be an effect, not a cause. To be more specific, dietary patterns may change during the prodromal phase of AD. If this is the case, then what is being observed is a manifestation of the disease.
I am not sure that this is correct, but it certainly could be. I think longer follow-up over a longer period will be the only way to figure out whether or not vitamin E or C, or a lean, low-fat diet can help.
It is difficult to understand why the results of the Rotterdam study and ours are different. The analyses were different, the measures of estrogen were different (in our study we did not measure levels, but only looked at estrogen replacement or not), and it is not clear how different the subjects might have been. So I think we will need more data.
Estrogen may be helpful after menopause, but less so once there is neuronal stress. Two randomized controlled trials of estrogen treatment for AD showed worse results in the estrogen-treated groups, and the recently published results from Cache County suggested no benefit—indeed, possibly an increased risk of AD incidence—in women who had used HRT recently but not years earlier.
Saturated and partially hydrogenated fats are risk factors for cardiovascular and cerebrovascular disease, and these are increasingly recognized as risk factors for AD. Until we can control for this sort of confounding, we must be cautious in interpreting the new findings in terms of direct implications for AD risk. Even if one could do a randomized trial with dietary fat, there would be no easy way to differentiate between effects mediated by fat intake directly versus those mediated by resulting vascular risks.
Studies such as these test the limits of inference possible in the customary kinds of epidemiological analyses.
The paper by Den Heijer et al. referred to in the above article reported that, in a normal ageing cohort, women with higher estradiol levels had smaller hippocampal volumes and poorer memory performance than did women with lower estradiol levels. This finding is consistent with work by the Oxford Project to Investigate Memory and Ageing (OPTIMA) that has shown, contrary to expectation, that women with AD have higher blood levels of estradiol than age-matched controls (Hogervorst and Smith, 2002). We have suggested that one reason why others have not obtained this result is related to the sensitivity of the assay method used for estradiol (Hogervorst et al., 2003). It is, of course, well-known that patients with AD have smaller hippocampi than do controls. There is a clear need for reappraisal of the role of female sex hormones in dementia (see Cochrane review by Hogervorst et al., 2002).
Hogervorst E, Smith AD.
The interaction of serum folate and estradiol levels in Alzheimer's disease.
Neuro Endocrinol Lett. 2002 Apr;23(2):155-60.
Hogervorst E, Yaffe K, Richards M, Huppert F.
Hormone replacement therapy to maintain cognitive function in women with dementia.
Cochrane Database Syst Rev. 2002;(3):CD003799.
Hogervorst E, Williams J, Combrinck M, David Smith A.
Measuring serum oestradiol in women with Alzheimer's disease: the importance of the sensitivity of the assay method.
Eur J Endocrinol. 2003 Jan;148(1):67-72.
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