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Hippocampus as a mediator of the role of vitamin B-12 in memory.

Since the original observations of Addison in the 19th century and more recently those of Lindenbaum et al. (1), it has been known that pernicious anemia may be associated with neurological and cognitive impairments (2). It has become common practice to reassure those with serum vitamin B-12 above the traditional cutoff for pernicious anemia (148 pmol/L) that their vitamin B-12 status is “normal” and so cannot be a cause of any observed cognitive impairment. This view can no longer be supported: there is abundant evidence that those with serum vitamin B-12 concentrations in the “low-normal” range (150–300 pmol/L) may, but not necessarily will, suffer cognitive impairment that can usually be corrected by vitamin B-12 supplementation (2–4). However, it is important to use appropriate tests when assessing cognition (2), and it also appears that the association of vitamin B-12 with cognition may be context-dependent: only certain individuals will show cognitive impairment as the serum vitamin B-12 concentration declines within the normal range. The subgroups particularly susceptible to cognitive impairment with low-normal vitamin B-12 include those who carry the e4 allele of APOE, are depressed, or have a very high folate status (5, 6). Other susceptible subgroups are likely; for example, it is possible that omega-3 fatty acid status influences the cognitive response to vitamin B-12 (7). How does low-normal vitamin B-12 status cause cognitive impairment (3)? One plausible mechanism extrapolates the white matter damage in the spinal cord characteristic of vitamin B-12 deficiency to the white matter in the brain, damage to which is known to be associated with cognitive deficit. It is notable that white matter changes in the brain can be detected byMRI across the entire normal range of serum vitamin B-12, with no obvious threshold (8). Another hypothesis is that atrophy of the brain, or of specific brain regions, might mediate the cognitive effects of low-normal vitamin B-12 status. Two longitudinal community studies in elderly individuals found that the rate of whole-brain atrophy increases as serum vitamin B-12 (or holotranscobalamin) concentrations decline through the entire normal range (9, 10). There was no obvious threshold, and subjects with vitamin B-12 in the bottom tertile showed twice the rate of atrophy (1.05%/y) as those in the other tertiles (0.51%/y) (9). In this issue of the Journal, Köbe et al. (11) describe a novel mechanism linking low-normal vitamin B-12 status with cognition: microstructural damage in subfields of the hippocampus. The authors divided subjects with mild cognitive impairment (a prodromal stage of dementia, in particular Alzheimer disease) into those with low-normal serum vitamin B-12 (153–303 pmol/L) and those with high-normal values (304–934 pmol/L). Those with low-normal vitamin B-12 performed more poorly in memory tests and showed evidence from diffusion tensor imaging by MRI of damage to the microstructure in specific regions of the hippocampus. The hippocampal subfield that was most clearly associated with low-normal vitamin B-12 status was the CA4–dentate gyrus (CA4-DG) region (Figure 1). Damage to microstructure of the hippocampus in MRI has previously been shown to be related to memory impairment, but this fine-structural analysis is the first to associate such subtle structural changes with vitamin B-12 status. By mediation analysis, the authors showed that this association was more than a correlation: up to 48% of the effect of low vitamin B-12 status on memory was actually mediated by the microstructural damage in the subfield CA4-DG. As can be seen from Figure 1, this subfield is only a small part of the hippocampus, which itself accounts for only;0.5% of the volume of the whole brain. This important report will be recognized as a landmark study on nutrition and the brain. The new study raises some important questions for science and for medicine. First, why is the microstructural damage due to lownormal vitamin B-12 status restricted mainly to the CA4-DG subfield? This subfield is a major target of the input to the hippocampus from the entorhinal cortex, via the perforant path, which carries information reaching the entorhinal cortex frommany cortical regions (12). MRI studies have shown that the white matter carrying the perforant path is damaged in individuals with mild cognitive impairment and that this damage is associated with memory impairment (13). Thus, the microstructural changes in the gray matter of the hippocampal subfield CA4-DG observed by Köbe et al. could arise as a result of damage to the perforant path. The finding that this disconnection of the hippocampus from the entorhinal cortex, a characteristic feature of Alzheimer disease, may in part be determined by low vitamin B-12 status is therefore of great significance. The second scientific question is, how does low vitamin B-12 status lead to damage to the perforant path and/or to its target zone in the dentate gyrus? One possibility is that the low vitamin B-12 status leads to elevation of homocysteine, which is an established risk factor for Alzheimer disease that causes brain atrophy (reviewed in reference 14). But the authors found that the association of microstructural damage in CA4-DG with low-normal