Alzheimer’s disease genetics, a multiplex model

Statement of the Problem: As an aging population alzheimer’s disease (AD) is a growing world-wide public health concern, with 13.9 million people expected to be living with dementia by 2060. Familial forms of AD follow a Mendelian inheritance, with heritability estimates (58-79%) showing a strong genetic component to sporadic AD. Multiplex Model: Over 40 genetic loci are associated with AD, and with polygenic risk profiling we are now able to correctly predict disease status around 80% of the time. Our analyses identify six biological pathways (immunity, endocytosis, cholesterol transport, ubiquitination, amyloid-β and tau processing) as pivotal in disease development. Epidemiological research also highlights a significant vascular component to AD development. The multiplex model assumes that changes to some, or all, of these model components act together to trigger a disease cascade, which ultimately results in the cell/synaptic loss observed in AD. AD could be triggered by a number of different patterns of deficits that may differ between tissues and over the course of disease development. Multi-omics approaches (Figure 1) allowed the identification of a gene-network enriched for both common and rare variants in AD. Conclusion & Significance: Genetic and environmental studies have changed our perception of AD, highlighting its multifactorial complexity. Application of genetic data to future research may include selection/enrichment for clinical trials and precision medicine, understanding of early disease development through risk related epidemiology, selective biomarkers and induced pluripotent stem cell models for single cell, multi-tissue/organoid and whole system chimeric analyses.