Fast track — ArticlesPlasma Aβ1–40 and Aβ1–42 and the risk of dementia: a prospective case-cohort study
Introduction
The presence of amyloid-containing senile plaques together with neurofibrillary tangles is a hallmark of Alzheimer's disease.1 Important components of these plaques are amyloid β1–40 (Aβ1–40) and amyloid β1–42 (Aβ1–42), derived from the Aβ precursor protein (APP).2 Previous reports suggest that in Alzheimer's disease brains Aβ1–42 is deposited first and constitutes the predominant form in senile plaques, whereas Aβ1–40 is deposited later in the disease process.3, 4 How Aβ deposition in the brain affects plasma concentrations of Aβ is unclear. A complex equilibrium exists between brain production and deposition of Aβ5, 6 as well as peripheral production by platelets.7
Plasma concentrations of both Aβ1–40 and Aβ1–42 increase with age over 65 years8, 9 and are increased in people who carry mutations that cause early-onset familial Alzheimer's disease10 and in patients with Down's syndrome who are at heightened risk of developing Alzheimer's disease.11 Also, plasma Aβ is increased in first degree relatives of people with Alzheimer's disease, who are at an increased risk of developing the disease.12
In a previous longitudinal study, higher baseline plasma Aβ1–40 and Aβ1–42 concentrations were reported in people who developed dementia 5 years later than in people who remained free of dementia, which suggests that increased plasma concentrations of Aβ are associated with the development of dementia.9 In the same study, plasma Aβ1–42 was shown to decrease over time with newly acquired Alzheimer's disease. Other studies provide evidence for a decline in plasma Aβ1–42 in the presymptomatic period of the disease. Graff-Radford and colleagues13 reported that plasma Aβ1–42 declines at an average rate of 12% per year in people with mild cognitive impairment, whereas plasma Aβ1–42 rises at an average rate of 9% per year in non-demented controls. Another longitudinal study showed that high baseline plasma Aβ1–42 concentrations and large reductions in Aβ1–42 concentrations were associated with reductions in cognitive scores.14 An explanation for this selective decrease could be that Aβ1–42 concentrations in both cerebral spinal fluid (CSF) and plasma decrease when Aβ1–42 is deposited in the brain.15
The relation of plasma Aβ1–42 concentrations with risk of dementia might therefore vary with time to onset. We sought to assess whether plasma concentrations of Aβ1–40 and Aβ1–42 were associated with risk of dementia and subtypes of dementia. We investigated this association in the Rotterdam Study, a prospective population-based cohort study of men and women aged 55 years and older.
Section snippets
Study population
The Rotterdam Study is an ongoing prospective population-based cohort study investigating incidence and risk factors of cardiovascular, neurodegenerative, locomotor, and ophthalmological diseases in elderly people.16 From 1990–93, all 10 275 residents aged 55 years or older of Ommoord, a district in the city of Rotterdam, were invited to participate in an extensive home interview and two visits to the research centre; 7983 (78%) of them agreed. The medical ethics committee of the Erasmus
Results
Baseline characteristics of the cohort at risk and the random cohort are shown in table 1. Those who developed dementia during follow-up had significantly higher baseline concentrations of plasma Aβ1–40 and a significantly lower ratio of Aβ1–42/Aβ1–40 than did those who remained free of dementia (webtable 1). Of the 392 patients with incident dementia 289 were diagnosed with Alzheimer's disease, of whom 31 had cerebrovascular disease; 54 with vascular dementia; 17 with dementia in Parkinson's
Discussion
We showed that high plasma concentrations of Aβ1–40 were associated with an increased risk of dementia, especially for people who have concomitant low concentrations of Aβ1–42. Individuals with high concentrations of Aβ1–40 combined with low concentrations of Aβ1–42 had an over 10-fold increased risk of dementia compared with people with low concentrations of both Aβ1–40 and Aβ1–42. These associations were independent of the presence of an APOE ɛ4 allele. Plasma concentrations of Aβ1–42 were
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