Homocysteine and vascular morbidity and dementia in women. A prospective population study

Abstract: Homocysteine and cardiovascular morbidity and dementia in women - A prospective population study Dimitri Edin Zylberstein Institute of Medicine, The Sahlgrenska Academy, Department of Public Health and Community Medicine, Section of Primary Health Care, University of Gothenburg Abstract Purpose. The purpose of this thesis was to study cardiovascular morbidity and dementia in relation to homocysteine levels in women in a longitudinal, prospective population study over several decades. We also studied associations between methylenetetrahydrofolate reductase (MTHFR) genotypes and dementia. Methods. The Prospective Population Study of Women in Gothenburg started 1968/1969. A representative cohort of female population aged 38 to 60 years in Gothenburg was selected with assistance from the census register and invited. Of all invited 90.1% agreed to participate (1462). Blood and serum samples were drawn at baseline examination and at subsequent examinations. A fraction of blood and serum were stored at -200C. This thesis is based on 1368 women with available homocysteine data at baseline. Follow-up examinations were performed 1974/75, 1981/82, 1992/93 and 2000/01 (-03). The studied endpoints were myocardial infarctions (MI), lacunar infarcts in brain, white matter lesions in brain and dementia. The follow-up time was 24 years for myocardial infarctions, lacunar infarcts and white matter lesions. Follow-up time for dementia was 35 years. Homocysteine was analysed using stored samples from baseline examination. MTHFR genes were analysed in 2000/2001 Results. Belonging to the highest quintile of total homocysteine (tHcy) was associated with two-fold risk for developing MI and five-fold risk for dying due to MI, compared to the four lowest quintiles pooled, during 24 years of follow-up. HR=1.9 (95% CI 1.1-3.3) respective 5.1 (95% CI 2.2-11.9). The effect of elevated tHcy on MI was demonstrable after 15 years of follow-up. Belonging to the highest tertile of tHcy was associated with almost three-fold risk for developing lacunar brain infarcts after 24 years of follow-up. OR=2.82 (95% CI 1.34-5.93). Belonging to the highest tertile of tHcy was associated with risk for developing all dementia and especially Alzheimer’s Disease without cerebrovascular disease. HR=1.67 (95% CI 1.10-2.57) respective 2.43 (95% CI 1.25-4.71). The effect could not be seen until 22 years of follow-up. The C allele of MTHFR 1298A>C single nucleotide polymorphism is protective against all dementia and Alzheimer disease. HR=0.59 (95% CI 0.39-0.90) respective HR=0.56 (95% CI 0.33-0.93) Conclusions. Elevated midlife homocysteine is a risk factor for cardiovascular morbidity and dementia in women in extended time perspective. MTHFR 1298C allele is protective against all dementia and Alzheimer’s disease Keywords: Women, population study, dementia, Homocysteine, MTHFR, myocardial infarctions, lacunar infarcts, epidemiology ISBN 978-91-628-7879-5 Gothenburg 2009