| Summary: | Abstract Background Plasma amyloid-β (Aβ) levels are increasingly studied as a potential accessible marker of cognitive impairment and dementia. However, it remains underexplored whether plasma Aβ levels including the novel Aβ peptide 1–38 (Aβ1–38) relate to preclinical markers of neurodegeneration and risk of dementia. We investigated the association of plasma Aβ1–38, Aβ1–40, and Aβ1–42 levels with imaging markers of neurodegeneration and risk of dementia in a prospective population-based study. Methods We analyzed plasma Aβ 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 Aβ1–38, Aβ1–40, and Aβ1–42 (in pg/ml) were 19.4 ± 4.3, 186.1 ± 35.9, and 56.3 ± 6.2, respectively, at baseline. Lower plasma Aβ1–42 levels were associated with smaller hippocampal volume (mean difference in hippocampal volume per SD decrease in Aβ1–42 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 Aβ1–38 and Aβ1–42 were associated with increased risk of dementia, specifically AD (HR for AD per SD decrease in Aβ1–38 levels, 1.39; 95% CI, 1.00–2.16; HR for AD per SD decrease in Aβ1–42 levels, 1.35; 95% CI, 1.05–1.75) after adjustment for age, sex, education, cardiovascular risk factors, apolipoprotein E ε4 allele carrier status, and other Aβ isoforms. Conclusions Our results show that lower plasma Aβ levels were associated with risk of dementia and incident AD. Moreover, lower plasma Aβ1–42 levels were related to smaller hippocampal volume. These results suggest that plasma Aβ1–38 and Aβ1–42 maybe useful biomarkers for identification of individuals at risk of dementia.
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