Transcobalamin 766G Homozygosity, Raised Homocysteine, Raised Methylmalonic Acid and High Creatinine: A Dementia-predisposing Phenotype? Implications for Dementia and Alzheimer’s Disease

Raised homocysteine may be a weak, nutritionally modifiable risk factor for Alzheimer’s disease, an etiologically complex disorder likely consisting of subtypes. To further understanding of homocysteine in dementia, we evaluated a set of variables known to reflect/affect the metabolism of vitamin B12 as risk factors for dementia development in a pilot, exploratory nested case/control study. These included raised homocysteine, raised methylmalonic acid, high creatinine and the C766G alleles of transcobalamin II (TCN2), the major blood transporter of B12. High creatinine reflects kidney dysfunction, and can affect levels of homocysteine and methylmalonic acid. In the absence of kidney dysfunction, abnormally high homocysteine is a marker of B12 and/or folate deficiency while raised methylmalonic acid reflects B12 deficiency. Transcobalamin produced from 766G may differ functionally from that produced from 766C. Participants were stringently-selected, community volunteers who at study entry were >age 65 and had high cognitive function. Among those who developed dementia within 6.39 years, all with raised serum homocysteine (>15μmol/L) at study entry also had co-occurring raised methylmalonic acid (>350nmol/L), high creatinine (>87μmol/L) and transcobalamin II 766G homozygosity. The odds ratios of TCN2 766G homozygosity plus raised homocysteine, raised methylmalonic acid, or high creatinine at study entry for dementia were high compared to factors singly. We have tentatively dubbed this four-factor cluster “the TCN2 dementiapredisposing phenotype, TDPP”. These original findings warrant investigation in larger samples. New questions to ask are if TDPP heralds a distinct subtype of impending Alzheimer’s and if TDPP might distinguish a group to target with nutritional intervention before onset of cognitive impairment.