A study of the factors that may render people vulnerable to memory loss in old age suggests that low levels of vitamin B-12 are associated with significantly worse performance on memory tests among healthy people 75 and older who have the genotype associated with a higher risk for Alzheimer's disease. The vitamin, part of the eight-member, water-soluble "B-complex" group, works like other vitamins: It acts as a chemical catalyst to help break down fats and proteins, turn carbohydrates into glucose and aid the nervous system, skin, hair, eyes, mouth and liver. It's one of the reasons we're told to eat our vegetables, try fortified cereals and pop multivitamins.

The findings, reported in the April issue of Neuropsychology, support a sort of domino theory of cognitive problems. In this case, to have significantly worse memory for a list of words, three dominoes had to fall: Participants had to carry the genotype associated with Alzheimer's, have low blood levels of vitamin B-12 and be tested without any sort of cues or hints to aid recall.

Changes to any one of these factors--a slightly different genotype, normal B-12 or greater cognitive support--was associated with more normal memory.

"This is an impressive study with many commendable features," says Fergus Craik, PhD, senior scientist at the Rotman Research Institute in Toronto. "And it was carried out on a large sample of older adults whose medical and cognitive functions have been measured extensively and documented over many years, so the authors were able to take into account medical histories as well as later incidence of dementia." Craik, who is also on the faculty of the psychology department at the University of Toronto, is an expert in aging and memory.

The study, part of a long-term multidisciplinary project that follows older people living in Stockholm's Kungsholmen parish, was conducted by David Bunce, PhD, a psychologist at Goldsmith's College, University of London, Miia Kivipelto, PhD, MD, of the Aging Research Center at the Karolinska Institute in Stockholm and the Stockholm Gerontology Research Center, and Åke Wahlin, PhD, a psychologist at the University of Stockholm.

Previous research had identified a genetic predisposition for Alzheimer's disease. Low levels of two B vitamins--B-12 and folate (B-9, also called folic acid)--have also been linked to problems. However, few studies had examined nutrition and genotype together relative to cognition in order to reflect what real people carry into old age--a mix of inborn traits and environmental factors such as nutrition, including undiagnosed vitamin B deficiencies. The results of this work are significant because they suggest cognitive vulnerability might not be a matter of "on" or "off," but exist along a sliding scale--depending on the presence or absence of certain central factors, the degree to which they interact and the difficulty of cognitive demands.

The real allele

To better understand B vitamin effects, it helps to know the independent roles that they and genes play. First, genetics: The gene that helps move cholesterol in the body is known as apolipoprotein E, APOE for short. APOE comes in three somewhat different flavors, or alleles: Œ2, Œ3 and Œ4. The Œ4 allele, carried by perhaps 15 percent of the population, is a risk factor for dementia. Current data suggest that nearly one out of four carriers with one copy of this allele and nearly half carrying two copies will develop Alzheimer's disease. Noncarriers also can get Alzheimer's.

The evidence is mixed on whether the Œ4 genotype makes nondemented older people more vulnerable to milder cognitive problems. However, people with the Œ4 allele who have medical problems such as peripheral vascular disease and atherosclerosis also experience cognitive problems. Researchers speculate that because Œ4 carriers have smaller hippocampi, brain areas associated with memory, they may have a smaller biological buffer against disease. An additional physiological shortfall, such as low vitamin B, could further deplete those reserves.

Says Bunce, "Perhaps Œ4 carriers have fewer neuroanatomical reserves or poorer protection/repair mechanisms, and so any factor that further compromises these reserves or mechanisms may hurt cognitive function."

What kinds of factors? The B vitamins raised a red flag, given mounting evidence that reduced levels of B-12 and folate are linked with diminished cognitive powers (including episodic, spatial and working memory) and increased risk for Alzheimer's. On the flip side, cognition has improved in demented or impaired people given nutritional support. Some studies suggest that even subtle, undiagnosed differences in B-12 and folate may influence cognitive performance. Bunce and his co-authors estimate that perhaps 10 percent of adults aged 75 years and older have low B-12 or folate.

Testing the hypothesis

Given the body's complexity, could genes and B vitamins possibly interact in some way? To test this, Bunce, Kivipelto and Wahlin studied 167 healthy older people, averaging about 83 years old; they ruled out those who took B-12 or folate supplements at the time of the study or had abnormally high folate. On the morning of the memory tests, the researchers checked blood samples for vitamin levels and genotype. Some 82 participants had low B-12 (28 with the Œ4 allele; 54 without).

Bunce and his co-authors assessed episodic memory using a variety of conditions to make their tests more sensitive to any underlying disorder. Some conditions offered structure and hints, but the most demanding conditions offered no help whatsoever. By testing sheer memory power alone, those conditions had the greatest potential to expose problems.

Participants listened to two lists of 12 unrelated nouns, presented either rapidly at two seconds per word or slowly at five seconds per word. They were given two minutes to say what they remembered right after they heard the list.

Other participants heard a list of 12 nouns sorted by unstated categories, such as clothes, furniture, professions or musical instruments--a procedure that makes it easier to remember words. Cognitive support was then phased in: In free recall, participants had two minutes to remember as many of the words as possible; in the following cued recall condition, the categories served as cues ("Do you remember any clothes?").

Among carriers of the Œ4 APOE allele, people with normal B-12 levels recalled a greater number of words. More time to encode (five as opposed to two seconds) also was associated with greater recall--strengthening memory more for the Œ4-low vitamin group than it did for other participants.

A significant difference showed up in the experiment's most demanding condition, when participants had just two seconds to encode words. In that situation, the high-risk genotype plus low B-12 levels was significantly associated with poorer memory.

As for the influence of folate, the authors didn't find anything of significance, but believe they might have with a larger sample size.

Among the notable findings, Craik points out, is that "Carriers of the allele with normal levels of vitamin B-12 actually performed better than any other group; it seems that vitamin B-12 deficiency is a more potent determinant of memory performance than the presence or absence of the allele."

To B or not to B?

How might vitamin B-12 support memory? One hypothesis suggests that B-12 deficiency inhibits the metabolism of the neurotransmitters dopamine, norepinephrine and serotonin to the detriment of cognitive function. An alternate hypothesis proposes that low vitamin B-12 means higher homocysteine levels, which causes damaging vascular changes in the brain.

According to Bunce, "Œ4 APOE carriers may derive relatively greater cognitive benefits from B-12 and folate supplements. Supplement treatment is relatively inexpensive and may be required as part of preventive health regimes for older persons."

Ultimately, says Pamela Greenwood, PhD, a psychologist who studies the genetics of Alzheimer's at Catholic University of America in Washington, D.C., "This study adds to increasing evidence of links among diet, cardiovascular health and risk of Alzheimer's disease, as well as the growing evidence that APOE genotype modulates the brain response to insult generally."

Rachel Adelson is a writer in Raleigh, N.C.