October 18, 2010 — Both serum homocysteine (tHcy), an amino acid associated with vitamin B12, and holotranscobalamin (holoTC), the biologically active fraction of vitamin B12, may have a role in the development of Alzheimer's disease (AD), the findings of a new Finnish study suggest.

Among a group of elderly subjects followed up for 7 years, elevated baseline serum tHcy concentrations were independently associated with an increased risk of developing AD, whereas higher baseline holoTC values were independently related to a reduced risk for incident AD. No association was observed with folate.

"Our results indicate that vitamin B12 and related metabolites may have a role in Alzheimer's disease, but more research is needed before we can get conclusion on the role of vitamin B12 supplements on neurodegenerative diseases such as Alzheimer's disease," first study author Babak Hooshmand, MD, MSc, of the Aging Research Center, Karolinska Institutet, Stockholm, Sweden, noted in an email to Medscape Medical News.

Their results are published October 19 in Neurology.

Cardiovascular Risk Factors, Aging and Dementia Study

"Most available studies have so far considered tHcy and its main determinants separately in relation to AD," Dr. Hooshmand and colleagues note in their report. Few studies, they add, have investigated the association between holoTC and AD.

Here, they investigated serum tHcy, holoTC, and folate levels simultaneously, as well as putative interactions between them, in relation to AD risk in a subsample of the population-based Cardiovascular Risk Factors, Aging and Dementia study.

The sample comprised 271 community-dwelling subjects, 65 to 79 years old, who were dementia free at baseline and were followed up for up to 7 years for incident AD. During that period, 17 (6.2%) developed the disease.

As expected, subjects who developed AD were older at baseline and had lower body mass index (BMI), lower blood pressure, and a higher frequency of the APOE ε4 allele than those who did not. They also had higher tHcy levels (14.9 vs 12.6 µmol/L) and lower holoTC levels (61.6 vs 93.3 pmol/L) compared with subjects who did not develop AD.

According to the investigators, for each 1-µmol/L increase in the baseline concentration of tHcy, the risk for AD increased by 16% (odds ratio [OR], 1.16; 95% confidence interval [CI], 1.04 – 1.31). On the other hand, for each 1-pmol/L increase in baseline holoTC, the risk for AD was reduced by 2% (OR, 0.980; 95% CI, 0.965 – 0.995).

The results held up in analyses adjusted for several potential confounding factors, including age, sex, education APOE e4 allele, body mass index, Mini-Mental State Examination score, smoking, stroke, and blood pressure.

Adjusting for holoTC attenuated the tHcy-AD link; the OR changed from 1.16 to 1.10 (95% CI, 0.96 – 1.25). The holoTC-AD relationship was less influenced by controlling for tHcy; the OR changed from 0.980 to 0.984 (95% CI, 0.986 – 1.000).

A significant interaction between holoTC and age was observed; the protective effect of holoTC became more pronounced with increasing age (adjusted OR for the interaction, 0.994; 95% CI, 0.989 – 0.998). Adding folate to the analysis did not change any of the results.

Important First Step

This study is "an important initial step relating plasma holoTC to risk of incident dementia and AD," Sudha Seshadri, MD, of Boston University School of Medicine in Massachusetts, writes in a commentary published with the study.

By way of background, Dr. Seshadri notes that, in the 1990s, several observational and cohort studies linked elevated tHcy level with an increased risk for stroke, cognitive decline, and dementia, including AD. Homocysteine can directly promote cerebrovascular disease and neuronal injury through a variety of mechanisms.

The associations with tHcy were "generally more robust than those for B12 levels (vitamin B12 levels indirectly elevating tHcy), so tHcy replaced B12 as the putative risk factor of greater interest," Dr. Seshadri explains.

However, it was subsequently found in clinical trials that lower tHcy levels (via folate administration) did not seem to have a beneficial effect on cognitive outcomes, whether assessed in healthy persons, those with mild cognitive impairment, or those with mild dementia. "Ironically, these results turned scientific interest back to a renewed emphasis on direct adverse effects of B12 deficiency, independent of plasma tHcy," Dr. Seshadri notes.

Going Forward

Dr. Hooshmand and Dr. Seshadri both agree that further study is needed to unravel the vitamin B12 story as it relates to AD, including clinical studies that directly relate holoTC to clinical AD or comprehensively address the relative importance of the interlinked players (B12, tHcy, holoTC, and folate).

"I think that it is an advantage if future studies on B12 and AD include other vitamin B12 indicators, including holotranscobalamin," Dr. Hooshmand told Medscape Medical News.

Dr. Seshadri thinks future vitamin B12 researchers should "either measure holoTC levels or store serum samples to permit this to be done," the researcher said. "I would support further observational studies and clinical trials that relate B12, folate to brain function and look comprehensively at possible intermediate metabolites."

The study was supported by the Karolinska Institutet, the Swedish Research Council for Medical Research, the European Commission Seventh Framework Programme, the Academy of Finland, the Ragnhild and Einar Lundströms Minne Lindhés Foundation, the Stohnes Foundation, the Gamla Tjanarinnor Foundation, and the Dementia Foundation of Sweden. Dr. Hooshmand has disclosed no relevant financial relationships. A complete list of disclosures for the other authors of the study are published with the original article. Dr. Seshadri discloses serving as an editor for the Journal of Alzheimer's Disease and on the editorial board of Stroke and receives research support from the National Institutes of Health.

Neurology. 2010;75:1408-1414.