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From the GRECC, St Louis VA Medical Center, St Louis, and the Division of Geriatric Medicine, St Louis University, St Louis.
See corresponding article on page 687.
Son of man, eat that thou findest; eat this roll, and go speak unto the house of Israel. . . . Son of man, cause thy belly to eat, and fill thy bowels with this roll that I give thee. (Ezekiel 3:1–3:3)
The concept that ingestive processes may be linked to memory stretches back to biblical times. However, only in the last decade has a concerted effort been made to understand the mechanisms by which food may modulate memory. In this issue of the Journal, Kaplan et al (1) showed that protein, fat, and carbohydrates can acutely enhance memory processing in older people.
Such memory enhancement may occur through the release of gastrointestinal peptides, such as cholecystokinin. In animals, cholecystokinin enhances memory retention by stimulating ascending vagal fibers (2). These vagal fibers then transmit messages to the nucleus tractus solitarius and from there to the amygdala and hippocampus. The amygdala and hippocampus are parts of the brain circulatory system responsible for laying down and recalling memories. Like humans, mice had enhanced recall of memories related to food ingestion. In mice, this enhanced recall was attenuated by the use of a cholecystokinin antagonist (3). Several other gastrointestinal peptides such as gastrin-releasing peptide (4) and amylin (5) also improve memory in rodents.
Perhaps of more interest is the ability of glucose to modulate memory. Increasing glucose concentrations in patients with dementia of the Alzheimer's type improves their cognition (6). This improvement in cognition appears to be dependent on the increase in insulin concentrations produced by elevated glucose concentrations. In contrast with the acute enhancement of memory function by glucose, studies in animals and humans showed that poor glucose control in diabetics is associated with impaired cognition (7). When the glucose concentration returns to normal, cognition improves. This shows that hyperglycemia per se can have a deleterious effect on cognition. In addition, patients with long-term, poorly controlled diabetes can develop small infarcts in the central nervous system, resulting in vascular dementia that produces permanent memory dysfunction.
The Rotterdam Study examined the effect of food intake on the development of dementia in a large population of people older than 55 y (8). The eventual development of dementia was positively associated with intakes of total fat, saturated fat, and cholesterol. Of particular interest was the fact that fish consumption, associated with a high intake of docosahexaenoic and eicosapentaenoic fatty acids, was associated with a reduced risk of dementia.
The SAMP8 mouse is a spontaneous animal model of Alzheimer disease (9) that overproduces ß-amyloid. This overproduction is associated with early onset of deficits in learning and retention. Blockade of ß-amyloid reverses these deficits and increases the production of acetylcholine in the hippocampus. Late in life, the SAMP8 mouse develops amyloid plaques in the central nervous system. Kumar et al (10) found that the activity of stearoyl-CoA desaturase (9-desaturase) in the brains of these mice is reduced by 50% because of a specific decrease in the messenger RNA for stearoyl-CoA desaturase. This decline in stearoyl-CoA desaturase is associated with the expected decrease in unsaturated fatty acids and an increase in saturated fatty acids in the brain. Improved learning ability in this animal model of Alzheimer disease was produced by dietary supplementation with perilla oil, which is rich in -linolenate (11). The relevance of these studies to humans is supported by the findings of Yehuda et al (12), who provided short-term supplementation of a compound containing a 1 to 4 ratio of n-3 to n-7 fatty acids to 100 patients with Alzheimer disease. The patients receiving this compound had an enhanced ability to find their way home and an improvement in short-term memory. In addition, they reportedly had a better mood, were more cooperative, had an enhanced appetite, and slept better. As might be expected, the responses varied among patients.
These results from animal and human subjects support the concept that the fat content in the diet can modulate cognition both acutely and chronically. The most likely explanation for the chronic modulation of memory is that fat ingestion alters neuronal mobility by altering the ratio of fatty acids in neuronal cell membranes. This alteration in neuronal mobility leads to an altered effectiveness of neurotransmitters when they bind to the neuronal membranes, leading to modulation of cognitive function.
Obviously, there are several other mechanisms by which nutrition can modulate memory processing. In the New Mexico Aging Process Study, Goodwin et al (13) showed that even mild protein-energy malnutrition and borderline vitamin deficiencies were associated with cognitive decline in older people. Anorexia and protein-energy malnutrition are extremely common problems in older people, particularly when they develop diseases or take medications (14).
The ability of severe vitamin deficiencies to cause cognitive deficiencies is well recognized among nutritionists. Thus, thiamine deficiency can lead to the acute delirium of Wernicke encephalopathy associated with ocular nerve palsies. Niacin deficiency is associated with dementia and dermatoses in sun-exposed areas of the body that are typical of pellagra. Vitamin B-12 deficiency may be associated acutely with cognitive impairment and perhaps chronically with elevated homocysteine concentrations, which can lead to vascular dementia.
The study by Kaplan et al certainly provides food for thought and reminds us that we are, to some extent, what we eat. Older people often have poor dietary intake, which makes them particularly vulnerable to the effects of nutrition on cognition. Although in most cases the effects of nutrition are small, when older people begin to develop mild cognitive impairment, nutrition may play a dramatic role in slowing down the process. Epidemiologic studies have provided some tantalizing suggestions that a lifetime of food intake may affect whether or not we develop dementia in our old age. At the very least, the study by Kaplan et al suggests that when Cicero commented in De Senectute that old age had increased his desire for good conversation and decreased his desire for food, his decreased food intake most likely had caused him to forget just how good the conversation may or may not have been. Let us hope that the present editorial will stimulate sufficient food for thought and that it will lead to an increased awareness of the need for research on the effects of nutrition on cognition in older people.
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