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Review
, 12 (1), 43

Late Onset Alzheimer's Disease Genetics Implicates Microglial Pathways in Disease Risk

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Review

Late Onset Alzheimer's Disease Genetics Implicates Microglial Pathways in Disease Risk

Anastasia G Efthymiou et al. Mol Neurodegener.

Abstract

Alzheimer's disease (AD) is a highly heritable complex disease with no current effective prevention or treatment. The majority of drugs developed for AD focus on the amyloid cascade hypothesis, which implicates Aß plaques as a causal factor in the disease. However, it is possible that other underexplored disease-associated pathways may be more fruitful targets for drug development. Findings from gene network analyses implicate immune networks as being enriched in AD; many of the genes in these networks fall within genomic regions that contain common and rare variants that are associated with increased risk of developing AD. Of these genes, several (including CR1, SPI1, the MS4As, TREM2, ABCA7, CD33, and INPP5D) are expressed by microglia, the resident immune cells of the brain. We summarize the gene network and genetics findings that implicate that these microglial genes are involved in AD, as well as several studies that have looked at the expression and function of these genes in microglia and in the context of AD. We propose that these genes are contributing to AD in a non-Aß-dependent fashion.

Keywords: Alzheimer’s disease; Genetics; Microglia; Myeloid.

Figures

Fig. 1
Fig. 1
Framework of support for microglia involvement in LOAD. Findings from gene network analysis and disease genetics converge to show enriched immune and myeloid contributions in AD. These findings are verified through functional genomics using cell and animal models to determine the contribution of these genes to LOAD pathology
Fig. 2
Fig. 2
Efferocytosis model of microglia in LOAD. Microglia contain multiple receptors that can recognize cellular distress signals and other ligands on apoptotic or necrotic cells, including lipids, C1q, and APOE. Propagation of downstream signals activate the transcription factor PU.1, which transcribes the majority of the genes involved in these pathways

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