The genetics and neuropathology of neurodegenerative disorders: perspectives and implications for research and clinical practice

Abstract

Twenty-one years ago in a paper on Alzheimer’s disease (AD) there was a statement that there is “growing evidence of genetic causes of AD” [8]. Before the 1990s Parkinson’s disease (PD) was widely considered to have no genetic contribution. We’ve come a long way since then. In 2012 not only are there confirmed hereditary causes of AD, PD, frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS), but also additional genetic risk factors identified for all these diseases. It took several years from the time tau was identified as the pathological hallmark aggregate in cases of FTLD for mutations in MAPT to be identified as the underlying genetic cause of disease. In contrast, with the advent of powerful new sequencing technologies at the exome or genome level, the current pace of genetic discoveries is very rapid. Many of the initial gene discoveries by either candidate gene or linkage analysis approaches were made by single or small research groups. In contrast, genome-wide association (GWA) studies of today require large consortia and collaborations to collect the large number of control and disease cases needed for success. Once considered distinct and unrelated diseases, we now know that many clinical, pathologic and genetic characteristics are shared between AD, FTLD, ALS, and PD. Dementia is not only a key feature of AD and FTLD, but also seen in conjunction with PD and ALS. FTD can occur alone, and also in combination with motor neuron disease or Parkinsonism. FTLD and ALS, both sharing TDP-43 pathology and C9orf72 expansion mutations, are now considered to be a part of a disease spectrum rather than two distinct diseases. Times have changed, the tools have changed, and our understanding of these diseases has improved greatly, leading us forward on the path to personalized medicine. In this issue of Acta Neuropathologica we present a cluster of articles that review the genetics and neuropathology of four neurodegenerative disorders: AD, FTLD, ALS, and PD. Each article in the series provides a summary of what is currently known about both Mendelian disease genes and susceptibility loci for each disease and correlates these genetic associations with clinical and neuropathologic features. Genetic discoveries for neurodegenerative diseases have been very helpful in delineating molecular mechanisms of disease. This knowledge in turn has had a huge impact in many areas of research and clinical medicine, and has spawned numerous clinical trials that provide a realistic hope for therapeutic advances in the not too distant future. Continued advances will not only require large consortia, but also the cooperation and collaboration of neuropathologists, geneticists, clinicians, basic scientists, and bioinformaticians as well as the support of patients, families and advocacy groups. However, to put these genetic advances into practice it is important to consider the significance and utility of the genetic information, the importance of the correct use of terminology and nomenclature, challenges in assessing the pathogenicity of identified variants, ethical issues that may arise with all this information, and resources that are available to access related information.