Endophenotypes for Alzheimer’s disease – GWAS on CSF tau levels

Beneath the surface. Endophenotypes sound great on paper. As the actual disease phenotype is difficult to classify and complicated, a biomarker is used for genetic analysis that is assumed to be closer to the genetic underpinnings of a disease than the disease itself. A recent study in Cell now investigates the hunt for risk factors for Alzheimer’s disease using a well-established endophenotype. The results demonstrate the complexity of endophenotypes and the difficulties in interpretation. Continue reading

C9orf72 expansions and neurodegenerative disease

Out of my league. I must admit that I know very little about the genetics of neurodegenerative disorders, but a recent article in the American Journal of Human Genetics caught my interest. Massive expansions of a hexanucleotide repeat in the first intron of C9orf72 are a known cause of frontotemporal lobar degeneration (FTLD)  and Amyotrophic Lateral Sclerosis (ALS). With a novel method for rapid screening for these expansions, the authors investigate a large cohort of patients with neurodegenerative disorders and population controls, providing an interesting example of how seemingly clear-cut monogenic disorders acquire an unanticipated degree of complexity. Continue reading

Mutations don’t always cause disease, quite the opposite

A mutation in APP protecting against Alzheimer’s disease. Alzheimer’s disease is one of the leading causes of dementia in the Western world. In rare familial forms of Alzheimer’s disease, variants in the APP gene are well-known to be disease-causing. This led Jonnson and colleagues to search for additional rare variants in the APP gene that might be associated with further cases of Alzheimer’s disease. When they analysed their datasets, they stumbled across an associated APP variant. However, this variant does not increase the risk for Alzheimer’s, it reduces it… Continue reading