Considerations for integrative multi‐omic approaches to explore Alzheimer's disease mechanisms

The past decade has seen the maturation of multiple different forms of high‐dimensional molecular profiling to the point that these methods could be deployed in initially hundreds and more recently thousands of human samples. In the field of Alzheimer's disease (AD), these profiles have been applied to the target organ: the aging brain. In a growing number of cases, the same samples were profiled with multiple different approaches, yielding genetic, transcriptomic, epigenomic and proteomic data. Here, we review lessons learned so far as we move beyond quantitative trait locus (QTL) analyses which map the effect of genetic variation on molecular features to integrate multiple levels of “omic” data in an effort to identify the molecular drivers of AD. One thing is clear: no single layer of molecular or “omic” data is sufficient to capture the variance of AD or aging‐related cognitive decline. Nonetheless, reproducible findings are emerging from current efforts, and there is evidence of convergence using different approaches. Thus, we are on the cusp of an acceleration of truly integrative studies as the availability of large numbers of well‐characterized brain samples profiled in three or more dimensions enables the testing, comparison and refinement of analytic methods with which to dissect the molecular architecture of the aging brain.