Disentangling the biological pathways involved in early features of Alzheimer's disease in the Rotterdam Study

Introduction: Exploring the role of Alzheimer's disease (AD) implicated pathways in the predementia phase may provide new insight for preventive and clinical trials targeting disease specific pathways. Methods: We constructed weighted Genetic risk scores, first based on 20 genome-wide significant AD risk variants and second clustering these variants within pathways. Risk scores were investigated for their association with AD, mild cognitive impairment, and brain magnetic resonance imaging phenotypes including white matter lesions, hippocampal volume, and brain volume. Results: The risk score capturing endocytosis pathway was significantly associated with mild cognitive impairment (P = 1.44 × 10−4). Immune response (P =.016) and clathrin/AP2 adaptor complex pathway (P = 3.55 × 10−3) excluding apolipoprotein E also showed modest association with white matter lesions but did not sustain Bonferroni correction (P = 9.09 × 10−4). Discussion: Our study suggests that the clinical spectrum of early AD pathology is explained by different biological pathways, in particular, the endocytosis, clathrin/AP2 adaptor complex, and immune response pathways, that are independent of apolipoprotein E (APOE).