Midlife homocysteine and late-life dementia in women. A prospective population study
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.
Section snippets
Subjects
The study is part of the Prospective Population Study of Women in Gothenburg (Bengtsson et al., 1973, Lissner et al., 2003) which was initiated in 1968. Women born in 1908, 1914, 1918, 1922 and 1930 were systematically sampled from the census register based on specific birth dates in order to yield a representative sample at the ages studied. Among those sampled, 1462 women were examined (participation rate 90%). Baseline tHcy data are available for 1368 of those examined in 1968. The baseline
Results
The baseline characteristics of the sample in 1968 stratified by later development of dementia are shown in Table 1. In total, 151 individuals developed dementia, 100 any AD (68 pure AD, i.e. without known cerebrovascular disease (CeVD), and 32 AD with CeVD), 37 pure VaD, and 14 other types of dementia. None of the variables differ significantly between the stratified groups.
The hazard ratios for dementia and its subtypes in relation to tHcy in 1968 are shown in Table 2. The results are
Discussion
To the best of our knowledge, this is the first study to examine the association between tHcy in midlife and development of dementia in late life. We found that elevated tHcy levels in middle aged women followed for 35 years were related to an increased risk of dementia and AD in late life. The results were consistent irrespective of whether analysing tertiles of tHcy or tHcy as a continuous variable, and the results were not attenuated by inclusion in the models of covariates otherwise
Conflict of interest statement
None of the authors has conflict of interest. The corresponding author (DEZ) had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Acknowledgements
The authors thank The Swedish Research Council (11267, 2003-4443, 2005-8460, 2006-2782, 825-2007-7462), Swedish Council for Working Life and Social Research (no 2001-2835, 2001-2646, 2003-0234, 2004-0150, 2006-0020, 2004-0145, 2006-0596, 2008-1229, EpiLife), The Alzheimer's Association Zenith Award (ZEN-01-3151), The Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159), The Bank of Sweden Tercentenary Foundation, Swedish Brain Power, Stiftelsen Söderström-Königska Sjukhemmet,
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