Midlife homocysteine and late-life dementia in women. A prospective population study

Abstract

Elevated serum total homocysteine (tHcy) is an established risk factor for cardiovascular disease. Its role in dementia is still controversial, and no study has examined the role of midlife tHcy, or reports longer than 8 years of follow-up. We examined the relation between midlife tHcy and late-life dementia in women followed for 35 years.

The Prospective Population Study of Women in Gothenburg began in 1968–1969, comprising a representative population of women aged 38–60 years. Four extensive follow-ups were conducted by 2003. Serum samples from 1968 to 1969 were analysed for tHcy in 1368 women. In total, 151 women developed dementia. The highest tHcy tertile was related to a hazard ratio of 1.7 (95% CI 1.1–2.6) for developing any dementia, 2.1 (95% CI 1.2–3.7, n = 100) for AD and 2.4 (95% CI 1.3–4.7, n = 68) for AD without cerebrovascular disease. Kaplan–Meier plots showed divergence with respect to dementia after 22 years of follow-up. In conclusion, high homocysteine in midlife is an independent risk factor for the development of late-life Alzheimer dementia in women.

Introduction

The number of people with dementia is increasing dramatically with global aging (Ferri et al., 2005). Vascular risk factors and disorders have been associated with the development of Alzheimer's disease (AD) (Mielke et al., 2007), a neurodegenerative disease and the most common form of dementia. The second most common form of dementia, vascular dementia, is caused by cerebrovascular disease (CeVD) (Vicenzini et al., 2007), and is thus also associated with vascular risk factors. Hyperhomocysteinemia is a recognized risk factor for vascular disorders, such as myocardial infarction (Zylberstein et al., 2004), and stroke (Srikanth et al., 2006), and recently lacunar infarcts (Zylberstein et al., 2008). A relation between homocysteine (Hcy) and dementia has therefore been hypothesised (Hogervorst et al., 2002).

The literature on Hcy and dementia is mixed. Four prospective studies conducted in elderly populations and with follow-ups ranging from 4 to 8 years have reported associations between high tHcy (total Hcy) and AD (Haan et al., 2007, McCaddon et al., 1998, Ravaglia et al., 2005, Seshadri et al., 2002), while others did not find an association (Luchsinger et al., 2004). Further support for an association between tHcy and dementia comes from studies showing associations between high tHcy and lower cognitive function among non-demented individuals as well as with increased conversion rate from mild cognitive impairment to AD (Blasko et al., 2008). Hcy has also been suggested to be directly associated with the pathogenesis of AD (Hogervorst et al., 2002). A recently published meta-analysis has confirmed the role of homocysteine as a risk factor for CVD (Humphrey et al., 2008). However, the role of tHcy in middle age for AD in late life has not been examined. Thus it is has not been easy to elucidate whether the association between homocysteine and dementia is a manifestation of early disease or a causal risk factor. The purpose of the present paper was to assess whether tHcy in blood samples drawn in 1968/1969 is associated to the development of dementia in a representative sample of 38–60 year old women who were followed 35 years.