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The Alzheimer's inheritance mystery

28 February 2011

An innovative genetic study has found further evidence for the role of a rare genetic variant in Alzheimer's disease. The findings, from researchers at the Institute of Psychiatry at King’s, and colleagues, shed further light on the mystery of how Alzheimer’s disease is passed on from generation to generation.

Alzheimer’s disease is the most common form of dementia, affecting over 35 million people worldwide. It is estimated that genetics accounts for 70 per cent of the risk of developing the disease, yet until recently only one major genetic risk factor has been established (variants of the APOE gene contributing to late-onset Alzheimer's disease). Recent large-scale genetic studies have identified new risk factors in other variants, but these only have a small effect on risk. A great deal of the genetic influence on Alzheimer's disease remains unaccounted for.

Dr Michelle Lupton and colleagues used a new approach to study the gene nicastrin. The gene produces a protein involved in the production of the amyloid-β peptide – the main constituent of the amyloid plaque deposits found in the brains of Alzheimer's patients.

The researchers sought to test whether the presence of rare genetic variation affecting the function of the nicastrin protein would influence a person’s risk of developing Alzheimer’s disease. They combined DNA samples from 311 Alzheimer’s patients and 360 normal individuals into two separate pools and then sequenced the protein coding regions. This innovative approach allowed them to sequence DNA samples from a large number of people at a minimal cost.

The analysis identified one variant that is found more frequently in Alzheimer's patients compared to normal individuals. It equates to a single base pair change that alters the Nicastrin protein. The variant has been linked to Alzheimer's disease before, and the association found is a modest one, but the researchers say it warrants further investigation.

Dr Michelle Lupton, who led the study, said: “Identifying genes that are associated with risk of developing Alzheimer’s disease and the exact mechanisms of these associations will improve our understanding of the initial causes of the disease process, leading to new drug targets.”

The findings also have implications for the wider area of complex disease genetics. There is increasing evidence that rare variation that cannot be identified through genome-wide association studies may explain the missing heritability in many disorders. Innovative approaches, such as the technique developed in this study, could help identify such rare variants.

Rebecca Wood, Chief Executive of Alzheimer’s Research UK, which part-funded the research, said: ‘These findings represent an important step forward in our understanding of the genetics of Alzheimer’s disease. Uncovering the genes involved in Alzheimer’s will be crucial for understanding the causes of the disease, giving us valuable clues in the search for an effective treatment.

‘Over 820,000 people are living with dementia in the UK, but research into the condition is desperately under-funded. We must invest in more research like this if we are to defeat dementia.’

The study was supported by the National Institute for Health Research Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London, the Medical Research Council though the PhD Studentship funding and the Alzheimer’s Research Trust, and the 7th framework programme of the European Union.

Reference: Lupton MK et al. Deep sequencing of the Nicastrin gene in pooled DNA, the identification of genetic variants that affect risk of Alzheimer's disease. PLoS ONE 2011.

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