Association and Interaction of TOMM40 and PVRL2 with Plasma Amyloid-Β and Alzheimer's Disease Among Chinese Older Adults: A Population-Based Study

Background: Despite genetic studies have identified Alzheimer’s disease (AD)-associated SNPs in TOMM40 and PVRL2 genes, the underlying mechanisms have not yet been elucidated. We examined their associations and interactions with AD risk and plasma AD biomarkers among Chinese older adults. Methods: This population-based study included 4876 participants (age ≥65 years, 57.2% women) from the MIND-China study. TOMM40(rs2075650) and PVRL2(rs6859) polymorphisms were detected using multiple-polymerase chain reaction amplification. Plasma Aβ40, Aβ42, and t-tau concentrations were measured using SIMOA in a subsample (n=1257). Data was analyzed using multiple logistic and general linear regression models. Findings: AD was diagnosed in 182 participants. The multi-adjusted odds ratio of AD was 6.24(95%CI 1.73-22.48) for TOMM40GG (vs. AA), 1.47(0.89-2.42) for PVRL2AA (vs. GG), and 12.87(3.97-41.73) for having both risk alleles (P interaction =0.0003). In the plasma biomarker subsample, TOMM40GG was significantly associated with lower plasma Aβ42 and the Aβ42-to-Aβ40 ratio (p<0.05). Interpretation: TOMM40 and PVRL2 genes could interact to substantially increase the likelihood of AD, possibly through influencing Aβ metabolism. Funding Statement: MIND-China was supported from the National Key R&D Program of China (2017YFC1310100), the National Nature Science (81861138008, 82011530139), the Academic Promotion Program of Shandong First Medical University (2019QL020), and the Taishan Scholar Program of Shandong Province, China. C Qiu received grants from the Swedish Research Council (2017-00740, 2017-05819, and 2020-01574), the Swedish Foundation for International Cooperation in Research and Higher Education (STINT) (CH2019-8320) for the Joint China-Sweden Mobility program, and the Karolinska Institutet, Stockholm, Sweden. Declaration of Interests: All authors have declared that they have no competing interests. Ethics Approval Statement: The MIND-China project was approved by the Ethics Committee of Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong. All participants provided written informed consent for both study enrollment and blood sample collection, or in case of persons with severe cognitive impairment, their informants provided informed consent. Trial Registration: MIND-China was registered in the Chinese Clinical Trial Registry (registration no.: ChiCTR1800017758).