Systems-level analysis of Alzheimer's disease genetics: A first attempt

In the next few posts, I will try to build the case for faulty phagocytic clearance of apoptotic cells or other lipid-rich cellular debris as the biological process that systems-level analysis of the currently available human genetic association data more strongly implicates in the etiology of Alzheimer's disease (AD). Here, I would like to start with what I consider to be a seminal first attempt to investigate the complex genetic architecture of Alzheimer's disease from a network (or better, gene set) perspective. This work authored by Lesley Jones, Peter Holmans, Julie Williams (Cardiff University) and others is titled "Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease" and it can be freely accessed here.

Vindicating the long-forgotten original neuropathological observations by Alois Alzheimer and Gaetano Perusini (see my previous post), the authors showed that genome-wide SNPs associated with AD risk cluster around genes that play a role in (1) lipid/cholesterol metabolism and (2) the innate immune system. Later, the same authors extended this work by incorporating data from the International Genomics of Alzheimer's Project (IGAP) [PMID:24162737] and, while confirming their earlier results, also implicated (3) endocytosis in the etiology of AD [PMID:25533204].

The scientific hypothesis that I propose here is that the three aforementioned biological processes are not distinct/independent causal drivers of AD but, on the contrary, three facets of a higher-order etiological mechanism that integrates them as interacting (dis)functional components. This complex, multi-step biological process that goes awry in AD is called efferocytosis or 'debris clearance' and (as illustrated in part by the figure below from this nice article in Nature Reviews Immunology) consists of how phagocytes (including the professionals of the innate immune system) sense, seek and react to apoptotic cells, how they recognize and ingest this or other unwanted cellular material, how they digest it, and how they maintain cellular homeostasis in spite of a flood of cell constituents (in particular cholesterol and other lipids) by storing, recycling and (most importantly) 'pooping' them.

Courtesy of Nature Publishing Group [DOI:10.1038/nri2214]

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