From: Ian Goddard (Ian@Goddard.net)
Date: Thu Dec 09 1999 - 00:33:39 MST
The following contains much information about the "tofu study"
reported: http://starbulletin.com/1999/11/19/news/story4.html
http://the.honoluluadvertiser.com/1999/Nov/20/localnews3.html
I contacted Lon White, lead researcher in the tofu study
to ask some questions. I asked him about the statistical
significance of the findings in the study. He informed
me that there were four major endpoints in the study:
1. cognitive impairment of men (number of men=3734)
2. cognitive impairment of sample of wives (n=502)
3. brain atrophy by weight of men who died (n=290)
4. brain atrophy by volume measured via MRI (n=574)
The probability (p) value was less than .05 (significant)
for a correlation between each endpoint and tofu intake
(there was no significant correlation for other foods).
In some cases the p value is less than .001 (if the p
value is more than .05, it's not significant, if it's
.05 or less, it's significant). Here's what this means:
IF p = .05 there's 95% chance the correlation is true
IF p = .01 there's 99% chance the correlation is true
IF p = .001 there's 99.9% chance the correlation is true
So the correlation between the four endpoints listed above
and tofu consumption had an over 95% probably of being true,
with a probability of truth as high as 99.9%. Of course this
cannot be read as proof that tofu causes those problems, but
at the least it signals the need for further investigation.
What is perhaps most significant is that Dr White informed
me that there is a dose-dependent relationship between
tofu consumption and the endpoints, ie, the more tofu was
eaten, the more impairment and/or atrophy is found. The
odds that such findings would be chance are extremely low!
=============================================================
Here are two papers Dr. White, et al., have had published:
White, L., Petrovitch, H., Ross, G.W., & Masaki K.H. (1996)
Association of mid-life consumption of tofu with late life
cognitive impairment and dementia: The Honolulu-Asia Aging
Study. The Neurobiology of Aging, 17 (suppl 4), S121.
White, L., Petrovich, H., Ross, G. W., Masaki, K. H.,
Abbot RD, et al. (1996) Prevalence of dementia in older
Japanese-American men in Hawaii. JAMA, 276, 955-960.
=============================================================
More: http://www.soyonlineservice.co.nz/References/Brain.htm
=============================================================
Here's a brief review of those two papers found in a letter
to the FDA from Daniel Sheehan, PhD, Director of the Estrogen
Base Program Division of Genetic and Reproductive Toxicology,
and Daniel Doerge, PhD, Division of Biochemical Toxicology:
==============================================================
On 02/18/99, Dr. Sheehan & Dr. Doerge comment on White's work
==============================================================
Finally, initial data from a robust (7,000 men) long-term
(30+ years) prospective epidemiological study in Hawaii showed
that Alzheimer's disease prevalence in Hawaiian men was similar
to European-ancestry Americans and to Japanese (White, et al,
1996a). In contrast, vascular dementia prevalence is similar
in Hawaii and Japan and both are higher than in European-
ancestry Americans. This suggests that common ancestry or
environmental factors in Japan and Hawaii are responsible for
the higher prevalence of vascular dementia in these locations.
Subsequently, this same group showed a significant dose-dependent
risk (up to 2.4 fold) for development of vascular dementia and
brain atrophy from consumption of tofu, a soy product rich in
isoflavones (White, et al, 1996b). This finding is consistent
with the environmental causation suggested from the earlier
analysis, and provides evidence that soy (tofu) phytoestrogens
causes vascular dementia. Given that estrogens are important
for maintenance of brain function in women; that the male brain
contains aromatase, the enzyme that converts testosterone to
estradiol; and that isoflavones inhibit this enzymatic activity
(Irvine, 1998), there is a mechanistic basis for the human findings.
==================================================================
Full Letter: http://www.soyonlineservice.co.nz/files/nctrpti.doc
==================================================================
The following is the abstract to the recent study, which
should be published by April. Below that is a memorandum
sent out by Doctor White after the newspaper publications:
===============================================================
ABSTRACT TO UPCOMING PUBLICATION OF TOFU STUDY
===============================================================
Association of high midlife tofu consumption with accelerated
brain aging . Lon White, MD, MPH (From the Pacific Health
Research Institute, Honolulu, HI.)
This investigation utilized the resources of the Honolulu
Heart Program, a longitudinal study of Japanese-American men
established in 1965 for research on heart disease and stroke.
Questions regarding frequency of consumption of tofu and 26
other foods were asked at interviews in 1965-67 and again
in 1971-74. Cognitive testing was done (n=3734) and cases
of dementia identified (n=225) at the 1991-93 examination,
when participants were aged 71-93 years. Atrophy was assessed
by neuroimaging (n=574) or autopsy (n=290). Cognitive test
data were also analyzed for wives of a sample of study
participants (n=502) who had been living with the participants
when their dietary interviews were done. Poor cognitive test
performance in late life was associated with higher midlife
tofu consumption. An independent association of similar
magnitude and direction was apparent among wives of cohort
members, using the husband's answers as proxy for the wife's
consumption. Midlife tofu consumption was independently
associated with low brain weight and with ventricular
enlargement. Independent associations of more frequent
midlife tofu consumption with clinically diagnosed Alzheimer's
disease and with poor cognitive functioning among non-demented
subjects were demonstrated. Associations generally followed
a dose-response pattern, were statistically significant after
controlling for all relevant and potentially confounding
factors, and remained apparent after stratifying for age or
obesity. These data suggest that regular consumption of tofu
over many years in middle life may have an adverse influence
on brain aging manifest as accelerated atrophy, cognitive
decline, and a lowering of the threshold for the clinical
manifestations of Alzheimer's disease. We speculate that
these may reflect chronic sub-optimal neuronal plasticity
caused by isoflavone inhibition of tyrosine kinase activity
and/or by interference with estrogen-related mechanisms.
=============================================================
MEMORANDUM
TO: HHP/HAAS and PHRI Staff
FROM: Lon White, M.D., M.P.H., Senior Neuroepidemiologist, HAAS and PHRI
DATE: November 30, 1999
RE: Responding to questions about tofu
The articles that recently appeared in the Star Bulletin
and the Advertiser have caused a great deal of distress
locally, and have elicited a number or requests for
information. While we cannot give advice and no definitive
statements are possible at this time, the following can be said:
1. We observed a consistent pattern of association between
answers given by men interviewed in 1965 and in 1971
regarding the number of servings of tofu consumed per week -
and their scores on a test of cognitive function when examined
1991-93. Higher frequencies of tofu consumption were
associated with poorer test scores. This observation remained
strong after controlling for all relevant factors (such as age,
education, occupation, etc.) and no other foods or drink showed
such an association.
2. Separately, we observed an association of high midlife
tofu intake with low brain weight determined at autopsy,
again after controlling for all other relevant factors.
3. Separately, we observed an association of high midlife
tofu intake with enlarged ventricles identified by MRI.
4. Although we did not find an association of high midlife
tofu intake with the brain lesions that characterize Alzheimer's
disease in our autopsy study, we did find high midlife tofu
intake to be a risk factor for the clinical diagnosis of
Alzheimer's disease.
Taken together, we interpret these as suggesting that consumption
of tofu over many years during middle life is linked to a mild
to moderate acceleration in brain aging, perhaps similar to
that which might occur in a woman who did not receive hormone
replacement therapy after menopause. We cannot be sure that
the causal factor was really the tofu, but no other alternative
is apparent at this time.
We believe that the most reasonable mechanism would be an
interference with the normal mechanisms in the brain that
maintain the connections between neurons during aging (i.e.,
brain plasticity mechanisms), caused by the isoflavone
phytoestrogens that are known to be present in pharmacologically
significant concentrations in most soy foods.
Although the findings are very consistent, it is never proper
to draw definitive conclusions from a single study. It would
be premature to advise anyone that they should change their
diets based on a single research study. In addition, there
is evidence that consumption of soy foods may have beneficial
effects related to improving blood lipid levels, and reducing
risks for breast cancer.
Unfortunately it is likely that independent confirmation or
refutation of our findings will require 1-3 years. In the
meantime no definitive statements can be made. Individuals
will have to weigh the evidence and make their own decisions
concerning their consumption of soy foods and their isoflavone
derivatives.
LR White
================== End Of Forward Material ====================
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