Genome-wide association study identifies CBFA2T3 affecting the rate of CSF Aβ₄₂ decline in non-demented elders

Brain amyloid deposition is an early pathological event in Alzheimer's disease (AD), and abnormally low levels amyloid-β₄₂ peptide (Aβ₄₂) in cerebrospinal fluid (CSF) can be detected in preclinical AD. To identify the genetic determinants that regulate the rate of CSF Aβ₄₂ decline among non-demented elders, we conducted a genome-wide association study involved 321 non-demented elders from Alzheimer's Disease Neuroimaging Initiative (ADNI) 1/GO/2 cohorts restricted to non-Hispanic Caucasians. A novel genome-wide significant association of higher annualized percent decline of CSF Aβ₄₂ in the gene CBFA2T3 (CBFA2/RUNX1 translocation partner 3; rs13333659-T; p = 2.24 × 10^-9) was identified. Besides displaying abnormal CSF Aβ₄₂ levels, rs13333659-T carriers were more likely to exhibit a greater longitudinal cognitive decline (p = 0.029, β = 0.097) and hippocampal atrophy (p = 0.029, β = -0.160) in the non-demented elders, especially for the participants who were amyloid-positive at baseline. These findings suggest rs13333659 in CBFA2T3 as a risk locus to modulate the decline rate of CSF Aβ₄₂ preceding the onset of clinical symptoms.