Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease.

Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls.

Humanized Transgenic Mice Are Resistant to Chronic Wasting Disease Prions From Norwegian Reindeer and Moose.

Chronic wasting disease (CWD) is the transmissible spongiform encephalopathy or prion disease affecting cervids. In 2016, the first cases of CWD were reported in Europe in Norwegian wild reindeer and moose. The origin and zoonotic potential of these new prion isolates remain unknown.

Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: a genome-wide association study.

Background: Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms.

Desmin forms toxic, seeding-competent amyloid aggregates that persist in muscle fibers.

Desmin-associated myofibrillar myopathy (MFM) has pathologic similarities to neurodegeneration-associated protein aggregate diseases. Desmin is an abundant muscle-specific intermediate filament, and disease mutations lead to its aggregation in cells, animals, and patients. We reasoned that similar to neurodegeneration-associated proteins, desmin itself may form amyloid.

Early onset cerebral amyloid angiopathy following childhood exposure to cadaveric dura.

Amyloid-β transmission has been described in patients both with and without iatrogenic Creutzfeldt-Jakob disease; however, there is little information regarding the clinical impact of this acquired amyloid-β pathology during life. Here, for the first time, we describe in detail the clinical and neuroimaging findings in 3 patients with early onset symptomatic amyloid-β cerebral amyloid angiopathy following childhood exposure to cadaveric dura (by neurosurgical grafting in 2 patients and tumor embolization in a third). Our observations provide further in vivo evidence that cerebral amyloid angiopathy might be caused by transmission of amyloid-β seeds (prions) present in cadaveric dura and have diagnostic relevance for younger patients presenting with suspected cerebral amyloid angiopathy.

Clinical trials.

Arguably the most important goal of prion research is the discovery of a safe and effective treatment for the human diseases. The final stages of the pathway to develop a treatment require clinical trials. Choices about how a trial is designed and conducted have a large impact on the chances of success.