Plasma amyloid-β levels, cerebral atrophy and risk of dementia: a population-based study

Background: Plasma amyloid-beta (A beta) levels are increasingly studied as a potential accessible marker of cognitive impairment and dementia. However, it remains underexplored whether plasma A beta levels including the novel A beta peptide 1-38 (A beta(1-38)) relate to preclinical markers of neurodegeneration and risk of dementia. We investigated the association of plasma A beta(1-38), A beta(1-40), and A beta(1-42) levels with imaging markers of neurodegeneration and risk of dementia in a prospective population-based study. Methods: We analyzed plasma A beta levels in 458 individuals from the Rotterdam Study. Brain volumes, including gray matter, white matter, and hippocampus, were computed on the basis of 1.5-T magnetic resonance imaging (MRI). Dementia and its subtypes were defined on the basis of internationally accepted criteria. Results: A total of 458 individuals (mean age, 67.8 +/- 7.7 yr; 232 [50.7%] women) with baseline MRI scans and incident dementia were included. The mean +/- SD values of A beta(1-38), A beta(1-40), and A beta(1-42) (in pg/ml) were 19.4 +/- 4.3, 186.1 +/- 35.9, and 56.3 +/- 6.2, respectively, at baseline. Lower plasma A beta(1-42) levels were associated with smaller hippocampal volume (mean difference in hippocampal volume per SD decrease in A beta(1-42) levels, -0.13; 95% CI, -0.23 to -0.04; p = 0.007). After a mean follow-up of 14.8 years (SD, 4.9; range, 4.1-23.5 yr), 79 persons developed dementia, 64 of whom were diagnosed with Alzheimer's disease (AD). Lower levels of A beta(1-38) and A beta(1-42) were associated with increased risk of dementia, specifically AD (HR for AD per SD decrease in A beta(1-38) levels, 1.39; 95% CI, 1.00-2.16; HR for AD per SD decrease in A beta(1-42) levels, 1.35; 95% CI, 1.05-1.75) after adjustment for age, sex, education, cardiovascular risk factors, apolipoprotein E epsilon 4 allele carrier status, and other A beta isoforms. Conclusions: Our results show that lower plasma A beta levels were associated with risk of dementia and incident AD. Moreover, lower plasma A beta(1-42) levels were related to smaller hippocampal volume. These results suggest that plasma A beta(1-38) and A beta(1-42) maybe useful biomarkers for identification of individuals at risk of dementia.