Development of dementia in mild cognitive impairment (MCI) patients with focus on B-vitamins

Abstract: This thesis focused on the importance of low B-vitamins, hyperhomocysteinemia and the development of dementia and Alzheimer´s disease (AD) in patients with mild cognitive impairment (MCI). The relation between vitamin B12 /folate and dementia has been extensively investigated, but the results are inconsistent. The connection of thyroid stimulating hormone (TSH) and dementia is also explored in a lot of studies but neither here is a consensus found. The active fraction of vitamin B12, holo-Transcobalamin (holo-TC), is less studied. The first three studies this thesis were using data from the Geriatric Department of Karolinska University Hospital, Huddinge, Stockholm; the first study also from the Geriatric Department of Falun Hospital. In the fourth study survey data was used from the Kungsholmen Project, a longitudinal population-based study on aging and degenerative disorders in Stockholm. In paper I, we compared the serum levels of vitamin B12, folate and homocysteine in 120 persons with MCI, living either single or in a family setting. We found a higher level of serum homocysteine in men living single compared to men living in a family. In paper II, we investigated the association of homocysteine levels and the development of AD in 136 MCI patients over a three-year period. The percentage of persons who converted to AD was 31%. For the women we found that 45% with Hcy levels >16mumol/L converted to AD compared to 21% with Hcy levels <16mumol/L. Of the men 33% with Hcy levels >20mumol/L, 50% with Hcy levels 20-17mumol/L and none of those with levels<17mumol/L converted. In paper III, we studied predictive factors for the development of AD over a six-year period in 93 subjects with MCI. The percentage of persons converting to AD was 34%. The most important predictive factors were low TSH levels and hyperhomocysteinemia together with low Mini Mental State Examination (MMSE) and age. The importance of Hcy declined with higher age. In paper IV, we investigated the association between total plasma homocysteine (tHcy) and holo-TC and the subsequent development of dementia and AD in 228 persons in a prospective study with a mean follow-up time of 6.7 years. 41% developed dementia of which 31% AD. Subjects with high tHcy (the 4th quartile) had more than twice as high risk of developing AD than persons with low tHcy (the 1st quartile). The 3rd quartile of holo-TC was associated with a reduced risk of AD. In conclusion the results of our studies suggest that hyperhomocysteinemia may be a risk marker for dementia and AD. This finding can only be confirmed in intervention clinical trials showing a prevention of the development of dementia by lowering of homocysteine. It is not possible to rule out the importance of TSH for the development of dementia from our results, and we found no clear association between dementia and holo-TC.