A new factor of genetic susceptibility to Alzheimer's disease

A large-scale international study involving French researchers from the Inserm-Institut Pasteur Lille-Université Lille Nord de France "Public health and molecular epidemiology of ageing-related diseases" joint research unit led by Philippe Amouyel, has just discovered a gene for susceptibility to a rare disease that causes susceptibility to a common one, Alzheimer's disease, providing evidence of the heterogeneous aetiology of Alzheimer's disease.
This whole-exome sequencing approach is explained in detail in The New England Journal of Medicine dated 14 November 2012.
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, or Nasu-Hakola disease, is a genetic disorder passed on by means of autosomal recessive transmission. The disease starts at the age of around 30 years with pains in the wrists or shoulders associated with swollen joints. Bone fractures can occur as a result of minor traumas. Bone x-rays show epiphyseal cysts. Slight personality changes then occur followed by frontal neurological signs (euphoria, loss of social inhibitions) evolving into early-onset dementia. The disorder has been associated with mutations of the TREM2 (Triggering Receptor Expressed on Myeloid cells 2) gene on chromosome 6.
British, American and French researchers have now shown that on this same region of chromosome 6, mutations of the TREM2 gene were associated with a five times greater risk of developing late-onset Alzheimer's disease. A complete sequencing was performed on 281 individuals with Alzheimer's disease and 504 controls. Analysis of the TREM2 gene showed excessive TREM2 mutations in those with the disease compared with the control subjects. Characterisation of one of these TREM2 mutations in very large sample populations of patients with Alzheimer's disease has allowed researchers to measure precisely the importance of this association between TREM2 mutations and the disease. Finally, a replication study was performed in another independent series of 1994 cases and 4602 controls, which confirmed this strong association (OR=4.97 CI 95% [2.42-10.21], P<6 .10-6=".10-6" p="p"> These results are also confirmed in the same edition of The New England Journal of Medicine by an Icelandic team, which also shows that this gene is a risk factor for Alzheimer's disease in the Finnish population and other European populations.
A pathological analysis of six individuals presenting variants of the TREM2 gene has revealed evidence of Alzheimer's-type brain lesions. The study of TREM2 gene expression in normal human brains has shown high levels in the white matter and in the hippocampus and cortex.
In a transgenic mouse model of Alzheimer's disease, an increase in TREM2 expression was observed in microglial cells surrounding the amyloid plaques and the neurons compared with normal mice. The TREM2 gene encodes a protein that participates in the activation of immune responses in macrophages and dendritic cells.
This discovery has two main consequences. Firstly, this observation provides a better understanding of the immune system's involvement in Alzheimer's disease in which the gene of complement receptor 1 (CR1) had already been implicated, in previous work by Inserm-Lille2-IPL UMR744 . Furthermore, this approach of whole-exome sequencing has allowed the discovery of a gene for susceptibility to a rare disease that causes susceptibility to a common disease, evidence of the heterogeneous aetiology of Alzheimer's disease. It is the loss of function of this gene in its homozygous or heterozygous variants that determines the nature of the disorder.
These results, which demonstrate how much progress has been made in understanding Alzheimer's disease, involved teams from LabEx DISTALZ, and were able to be produced partly through the support of the French Foundation for Scientific Cooperation on Alzheimer's and similar diseases, launched in February 2008.

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Ever-increasing longevity among the human population means the number of patients suffering from Alzheimer's disease is also on the rise in France and throughout the world. Alzheimer's is the leading cause of memory and intellectual function disorders among elderly people and represents a major public health issue.
Alzheimer's disease is one of the main causes of dependency among the elderly. It results from neurodegeneration in different areas of the brain. Its symptoms include increasing impairment of memory and cognitive functions, and behaviour disorders that lead to a progressive loss of independence. In France, Alzheimer's disease affects more than 850,000 people and represents major social and economic costs.
Alzheimer's disease is characterized by the development of two types of lesion in the brain: amyloid plaques and neurofibrillary tangles. Amyloid plaques originate from the extracellular accumulation of a peptide, the beta amyloid peptide, in specific areas of the brain. Neurofibrillary tangles are intraneuronal lesions caused by abnormal filamentary aggregation of a protein known as a tau protein.
Identifying the genes that participate in the incidence of Alzheimer's disease and its development will make it possible to tackle the physiopathological mechanisms behind this affliction more rapidly, to identify the target proteins and metabolic channels for new treatments, and to provide a means of identifying the individuals that are most at risk when effective preventive treatments become available.