AD is characterised by the coexistence of two main pathological lesions: (1) intraneuronal neurofibrillary tangles composed of abnormally modified Tau proteins and (2) parenchymal amyloid deposits centred around β-amyloid (Aβ) peptides. Preceding neuronal death, synaptic dysfunction and synapse loss have been observed in post-mortem AD brains and are correlated with cognitive decline.

Hippocampal atrophy due to neuronal death is one of the earliest hallmarks of AD. AD causes memory loss and cognitive impairment, which are invariant early signs of the disease. Genetically driven synaptic failure hypothesis will need to be further tested experimentally within the general AD framework.Īlzheimer’s disease (AD) is the most common neurodegenerative disorder and constitutes a major public health problem worldwide (with 35.6 million sufferers). 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. 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. 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.

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. 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 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. A strong genetic predisposition (60–80% of attributable risk) is present in Alzheimer’s disease (AD).

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