Abstract
A strong genetic predisposition (60–80% of attributable risk) is present in Alzheimer’s disease (AD). In view of this major genetic component, identification of the genetic risk factors has been a major objective in the AD field with the ultimate aim to better understand the pathological processes. In this review, we present how the genetic risk factors are involved in APP metabolism, β-amyloid peptide production, degradation, aggregation and toxicity, innate immunity, and Tau toxicity. In addition, on the basis of the new genetic landscape, resulting from the recent high-throughput genomic approaches and emerging neurobiological information, we propose an over-arching model in which the focal adhesion pathway and the related cell signalling are key elements in AD pathogenesis. The core of the focal adhesion pathway links the physiological functions of amyloid precursor protein and Tau with the pathophysiological processes they are involved in. This model includes several entry points, fitting with the different origins for the disease, and supports the notion that dysregulation of synaptic plasticity is a central node in AD. Notably, our interpretation of the latest data from genome wide association studies complements other hypotheses already developed in the AD field, i.e., amyloid cascade, cellular phase or propagation hypotheses. Genetically driven synaptic failure hypothesis will need to be further tested experimentally within the general AD framework.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and constitutes a major public health problem worldwide
We present the latest advances in AD genetics and in the post-genome wide association studies (GWASs) era, and discuss how these information might change our understanding of the AD pathophysiological processes
Therapeutic approaches based on the classical amyloid cascade hypothesis have mostly failed, suggesting that our understanding of AD is far from being complete
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and constitutes a major public health problem worldwide (with 35.6 million sufferers). Several genomic analyses suggest the involvement of microglia in AD: (1) the first reports on pathway enrichment analyses indicated the involvement of innate immunity in AD [81]; (2) as previously mentioned, these analyses highlighted the regulation of endocytosis (which is essential for phagocytosis) [64, 81]; (3) a large part of GWAS-define genes are expressed in microglia [45] (Fig. 1); and (4) a major genetic discovery indicated that non-synonymous variants in TREM2, ABI3 and PLCγ2 were associated with AD risk [40, 65, 120].
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