Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment

Abstract

Is it possible to prevent atrophy of key brain regions related to cognitive decline and Alzheimer's disease (AD)? One approach is to modify nongenetic risk factors, for instance by lowering elevated plasma homocysteine using B vitamins. In an initial, randomized controlled study on elderly subjects with increased dementia risk (mild cognitive impairment according to 2004 Petersen criteria), we showed that high-dose B-vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 y. Here, we go further by demonstrating that B-vitamin treatment reduces, by as much as seven fold, the cerebral atrophy in those gray matter (GM) regions specifically vulnerable to the AD process, including the medial temporal lobe. In the placebo group, higher homocysteine levels at baseline are associated with faster GM atrophy, but this deleterious effect is largely prevented by B-vitamin treatment. We additionally show that the beneficial effect of B vitamins is confined to participants with high homocysteine (above the median, 11 µmol/L) and that, in these participants, a causal Bayesian network analysis indicates the following chain of events: B vitamins lower homocysteine, which directly leads to a decrease in GM atrophy, thereby slowing cognitive decline. Our results show that B-vitamin supplementation can slow the atrophy of specific brain regions that are a key component of the AD process and that are associated with cognitive decline. Further B-vitamin supplementation trials focusing on elderly subjets with high homocysteine levels are warranted to see if progression to dementia can be prevented.

Keywords: causal modeling; clinical trial; degeneration; hippocampus; structural neuroimaging.

Fig. 1.

Regional loss of GM volume in placebo and B-vitamin groups. Placebo- and B-vitamin–treated groups showed significant reduction of GM volume over the 2-y period in similar regions (in yellow, P < 0.001 FWE-corrected for multiple comparisons, overlaid onto the average of all 156 GM volume images; Montreal Neurological Institute (MNI) coordinates in mm: x = −12, y = 4, z = −18). The extent and significance of volume loss appeared markedly greater in the placebo group compared with the B-vitamin group and is confirmed by direct statistical comparison (text and Fig. 2).

Fig. 2.

B-vitamin treatment significantly reduces regional loss of GM (P < 0.05 FWE-corrected). (A) Brain regions in blue demonstrate where B-vitamin treatment significantly reduces GM loss over the 2-y period (x = 26 and −8, y = −34 and −52, z = 0 and −16). All blue areas correspond to regions of significant loss in placebo and known to be vulnerable in AD (Fig. 1). (B) Percentage of GM loss for the 156 participants over the 2-y period, averaged across those brain regions that showed significant effect of B vitamins: placebo group (red triangles) had an average loss of 3.7% (±3.7), whereas the B-vitamin group (green circles) showed a loss of 0.5% (±2.9).

Fig. 3.

B-vitamin treatment is only effective in participants with higher tHcy levels (P < 0.05 FWE-corrected). (A) Brain regions in green demonstrate where B-vitamin treatment significantly reduces GM loss in participants with high tHcy levels (>11.06 μmol/L) at baseline (x = 26 and −8, y = −34 and −52, z = 0 and −16). (B) Percentage of GM loss for each of the 77 participants with high tHcy level: placebo group (n = 35) showed an average loss of 5.2% (±3.4) of GM volume over 2 y, whereas B-vitamin group (n =42) showed an average loss of 0.6% (±2.1).

Fig. 4.

Directed acyclic graph analysis of treatment and changes (“delta”) in B vitamins, tHcy, GM volume, and cognitive performance over the 2-y period. Of all possible edges (gray, A), we found that the optimal Bayesian network explaining our data (with a very good model fit, χ² P = 0.64; SI Methods) identified nine statistical dependencies between variables (A, blue) and causality for each of these edges as presented in B (rearranged for clarity of display): treatment increases B vitamins' “delta” concentration, with B12 lowering tHcy “delta” concentration, which in turn slows grey matter atrophy (“gm”), which then delays cognitive decline over time (“sob” for CDR-SOB, “hvlt” for HVLT-R delayed recall, “flue\x{201d} for category fluency).