Genome-wide association study of rate of cognitive decline in Alzheimer's disease patients identifies novel genes and pathways

Introduction: Variability exists in the disease trajectories of Alzheimer's disease (AD) patients. We performed a genome-wide association study to examine rate of cognitive decline (ROD) in patients with AD. Methods: We tested for interactions between genetic variants and time since diagnosis to predict the ROD of a composite cognitive score in 3946 AD cases and performed pathway analysis on the top genes. Results: Suggestive associations (P < 1.0 × 10⁻⁶) were observed on chromosome 15 in DNA polymerase-γ (rs3176205, P = 1.11 × 10⁻⁷), chromosome 7 (rs60465337,P = 4.06 × 10⁻⁷) in contactin-associated protein-2, in RP11-384F7.1 on chromosome 3 (rs28853947, P = 5.93 × 10⁻⁷), family with sequence similarity 214 member-A on chromosome 15 (rs2899492, P = 5.94 × 10⁻⁷), and intergenic regions on chromosomes 16 (rs4949142, P = 4.02 × 10⁻⁷) and 4 (rs1304013, P = 7.73 × 10⁻⁷). Significant pathways involving neuronal development and function, apoptosis, memory, and inflammation were identified. Discussion: Pathways related to AD, intelligence, and neurological function determine AD progression, while previously identified AD risk variants, including the apolipoprotein (APOE) ε4 and ε2 variants, do not have a major impact.