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]


Back to the future: Alois Alzheimer's and Gaetano Perusini's initial reports

Even though nowadays AD is almost always described as dementia caused by progressive neurodegeneration that is characterized by two neuropathological hallmarks (amyloid plaques and neurofibrillary tangles, regarded by many as causative agents), this hasn't always been the case.

Courtesy of Alzheimer's Disease Research, a program of the BrightFocus Foundation.

Indeed, the neuropathologists that first described this disease at the turn of the last century, Alois Alzheimer and Gaetano Perusini, also reported two other prominent neuropathological features of AD, lipidosis and gliosis. Unfortunately, for the longest time, these two additional hallmarks have been either completely forgotten (lipidosis) or merely considered reactive changes (gliosis). It is kind of sad that it took 100 years and all the money, technology and scientific effort required to develop the capability of performing genome-wide association studies, to (re)discover that lipid/cholesterol metabolism and innate immune cell function are likely critical players in the etiology of AD [PMID:21085570].

In his famous one-case report of 1906/1911, Alois Alzheimer described the now homonymous disease as characterized by:
  • “minute miliary foci caused by deposition of a particular substance in the cortex” [amyloid plaques]
  • “quite striking changes of the neurofibrils” [neurofibrillary tangles]
  • “extraordinarily strong accumulation of lipoid material in the ganglion cells, glia and vascular wall cells” [lipidosis]
  • “particularly numerous fibril-forming glia cells” [gliosis]

and Gaetano Perusini shortly after (1909/1910) reported that the far more numerous cases he analyzed where “characterized anatomically by atrophy of the cerebral cortex of the most extreme degree, whereby massive cellular loss, a peculiar fibrillary disorder of the ganglion cells, strong proliferation of the fibril-producing glia, deposition of unusual metabolic products in the form of plaques in the cerebral cortex, moderate proliferative phenomena of the vasculature, and major accumulation of lipoid products in the ganglion cells, glia and vasculature occur.”

It is important to note that, at the time, neurons were referred to as "ganglion cells".

For a more thorough and extended historical account on the topic, the interested reader should refer to the nice review by Dr Paul Foley titled "Lipids in Alzheimer's disease: A century-old story" [PMID:20471492].

Welcome to "Alzheimer's disease genetics - A network perspective"!

I decided to finally start my own blog to help me crystallize and record my thinking about the genetics and biology of Alzheimer's disease from a systems perspective. Of course, I also hope that publicly sharing my rumblings could be helpful to somebody else (hence feedback is greatly appreciated).

Enjoy! :)