Cognitve Decline and B12 Marker Sensitivity

The US population is aging. Cognitive problems and dementia cause much limitation in daily life, and often lead to nursing home and other life disrupting placement. B12 deficiency is one of the more common reversible causes of cognitive impairment and dementia, especially among older patients. It is likely that folate supplementation masks B12 deficiency in some older persons. Further complicating matters is the probably insufficient sensitivity of standard laboratory cutoff values for B12 assays.

Tangey and colleagues prospectively studied a subset of 6,158 community dwelling older persons in Chicago over a 6 year interval. Covariates evaluated included age, gender, race, education, vitamin supplementation, smoking, ethanol intake, and certain dietary specifics, among other variables. Serum homocysteine, B12 and methylmalonic acid, creatinine and other markers were assayed. However, importantly, serum folate was not. 19.2% of persons studied had elevated serum homocysteine, but a larger subset, 36.4%, had elevated methylmalonic acid assays. Only 1% of the study population met their stringent criteria for definite B12 deficiency; 14.2% of the sample was classified as probable B12 deficiency.

In a complex multifactorial analysis, only methylmalonic acid was correlated with cognitive function in both mixed effects models used. Higher methylmalonic acid levels correlated with cognitive decline over the study period. Homocysteine did not. Higher B12 levels were associated with slower decline, but the effect was much less robust when all markers were combined in a single model.

The implications of this study are quite significant. Almost 1/6 of the study population had probable B12 deficiency. Conventional laboratory studies would have missed a large fraction of these persons. Homocysteine has been rather in vogue as a method of identifying persons at risk, but was not correlated with cognitive decline in this large, prospective study. Methylmalonic acid assays were considerably more specific for clinically significant B12 deficiency in this study. The big issue with the routine use of this marker, however, is cost. Their discussion also highlights the masking effect of folate, and a higher rate of decline in B12 deficient persons with high folate levels compared with normal levels. The authors do indicate that their study is limited by the absence of folate assays.

Mild cognitive impairment is not uncommon in older people, and the number of people with dementia is rising quickly. We have an obligation to seek out reversible causes of such impairments. The question, at least with regard to vitamin deficiencies, is how. Subtle B12 deficiencies likely cause cognitive impairment in a significant fraction of community dwelling older persons. Homocysteine and B12 levels may well be normal in many of them. Methylmalonic acid assays appear to be a considerably more sensitive marker. However, this assay is not routinely used, and is expensive compared with more conventional laboratory procedures. So, it's not clear that we should be using this as a screen in persons with cognitive decline, but it at least warrants serious consideration.