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1 From the Oxford Project to Investigate Memory and Ageing (OPTIMA), Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
2 Address reprint requests to AD Smith, OPTIMA, Department of Pharmacology, Mansfield Road, Oxford OX1 3QT, United Kingdom. E-mail: david.smith{at}pharm.ox.ac.uk.
See corresponding article on page 908.
Time wastes all things, the mind too: often I remember how in boyhood I outwore long sunlit days in singing; now I have forgotten so many a song. (Virgil, Eclogue IX, translated by JW Mackail)
The numbers are alarming: from incidence studies in the United Kingdom (1), it can be estimated that each year >1 million of the elderly in Europe and 750000 in the United States and Canada become cognitively impaired. Within a few years, 50% and possibly as many as 80% of those with cognitive impairment will develop dementia, principally Alzheimer disease (2, 3). Until recently, it was widely assumed that cognitive impairment was an inevitable part of aging and that nothing could be done about it. But the realization has been growing that most cases of cognitive impairment are the consequence of age-related disease processes. If we can identify the factors that cause these diseases, we might be able to prevent the consequential cognitive impairment and thus prevent or delay the progression into dementia.
What role might nutrition play in the causation of cognitive decline in the elderly? Although we should not forget the central role of macronutrients in the proper functioning of the brain (4), indirect evidence suggests that micronutrients might play a role in protecting the brain from age-related insults. Vitamin E has been the subject of clinical trials (5), low concentrations and intakes of vitamin C are associated with cognitive impairment in the elderly (6), and there is a long history of the possible role of B vitamins (7). In this issue of the Journal, Duthie et al (8) report their data from a cross-sectional study of B vitamins and homocysteine in community-dwelling elderly. They used several cognitive tests in 2 cohorts, one aged 63 y and the other aged 78 y, each of which comprised 150 subjects. With one exception, the only significant correlations between cognitive test scores and homocysteine, folate, or vitamin B-12 were found in the subjects aged 78 y. In these subjects, elevated plasma total homocysteine concentrations were correlated with lower scores on the Mini Mental State Examination (MMSE; 9), a nonverbal intelligence test, a constructional test, and a test of the speed of information processing. Plasma folate (itself correlated with homocysteine) was correlated with scores on several of these tests and, in addition, with scores on a verbal learning test. Vitamin B-12 concentrations (also correlated with homocysteine) were correlated only with scores on the MMSE and an intelligence test.
A unique aspect of Duthie et al'sstudy is that the older cohort had been cognitively assessed at the ages of 11 and 77 y with use of the same test. About 50% of the variance in cognitive test score at the age of 77 y could be accounted for by the score at the age of 11 y. Homocysteine concentrations measured at the age of 78 y independently contributed an additional 8% of the variance. It is noteworthy that a study of a community-dwelling elderly cohort (
Are we beginning to identify a significant, albeit modest, part of the environmental determinants of cognitive performance in the elderly as one that is potentially modifiable by nutrition? Is it biologically plausible that moderately elevated concentrations of homocysteine could cause atrophy of the brain and cognitive deficit or dementia? Homocysteine may simply be a marker for low concentrations of the vitamins that are its main biological determinants (folate and vitamin B-12) (7). Indeed, low concentrations of folate were associated with brain atrophy at autopsy in subjects with Alzheimer disease (21). Another possibility is that homocysteine itself is the damaging agent; homocysteine has been shown to be neurotoxic, leading to DNA damage and apoptosis (22). Furthermore, hyperhomocysteinemia in patients with Alzheimer disease is associated with activation of the cell cycle in hippocampal neurons, a plausible precursor of apoptosis and of Alzheimer-type pathology (23). The finding that vascular dementia (19, 24), as well as Alzheimer disease (12, 19), is associated with hyperhomocysteinemia raises the possibility that the brain suffers a double whammy from elevated concentrations of homocysteine: cerebrovascular damage that triggers or potentiates the effect of Alzheimer-type pathology together with a direct neurotoxic effect of homocysteine.
These ideas are currently speculations. We need more prospective studies of the association between elevated homocysteine concentrations, low B vitamin concentrations, and their combination and cognitive decline or dementia. So far, only 4 such studies have been published. In the first, patients with homocysteine concentrations >11.1 µmol/L showed a more rapid progression of Alzheimer disease over the next 3 y than did those with homocysteine concentrations below this cutoff (19). In the second study, hyperhomocysteinemia at baseline was independently associated with lower cognitive test scores 5 y later in a small cohort of normal elderly (16). In the third study, low concentrations of both folate and vitamin B-12 at baseline (homocysteine was not measured) were associated with twice the risk of developing Alzheimer disease 3 y later in a cohort of 370 elderly (25). In the fourth, an important community-based prospective study, total plasma homocysteine concentrations were measured up to 11 y before the onset of dementia (26). Subjects with baseline homocysteine concentrations in the top quartile had twice the risk of subsequently developing Alzheimer disease compared with those in the bottom quartile.
The ultimate proof of homocysteine'srole in cognitive decline will require clinical trials to establish whether lowering the concentration of homocysteine by giving B vitamins will prevent a proportion of the elderly from developing dementia. Some of the cardiovascular trials have added cognitive tests as an endpoint, but many of these trials were not conducted in the group at greatest risk, those over the age of 70 y. The Alzheimer'sDisease Co-operative Study is planning a multicenter trial in the United States to see whether B vitamins will slow the progression of disease in patients with Alzheimer disease. Also needed is a trial of homocysteine-lowering vitamins in those elderly who have developed mild cognitive impairment, a syndrome that can now be readily diagnosed (2). If lowering homocysteine could stop only 10% of those with mild cognitive impairment from developing Alzheimer disease, several hundred thousand persons worldwide would benefit every year.
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