Overlap of Frailty and Depression and Its Association With Cardiovascular Disease: A Population-Based Study.

Understanding variation at the locus has been of great importance to the study of neurodegeneration as it strongly contributes to the pathogenesis of a myriad of disorders. Common variation defining the H1 extended haplotype is considered to be a major risk factor for frontotemporal lobar degeneration spectrum disorders (FTLD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). At the same time, the H1 haplotype and the common alleles that define it have been linked to an increased risk of other neurodegenerative diseases, including Parkinson’s disease (PD) and Alzheimer’s disease (AD). In addition, the less common H2 haplotype was recently associated with increased risk of Pick’s disease (PiD), another FTLD disorder with tau pathology. In addition to common variation, rare mutations have also been identified in families with FTLD with tau pathology (FTLD-tau). Since the discovery of the first missense and splice variants, there have been over 100 mutations identified that are predicted to have different levels of pathogenicity across the tauopathies. Some of the identified variants are highly penetrant, disease-causing mutations that account for 5–20% of FTLD-tau. Other variants have been identified in individuals with sporadic disease and have been shown to have intermediate effect size and act as risk factors or disease modifiers. One such example is the rare p.A152T variant located in exon 7 of the gene known to increase risk for both AD and FTLD as well as atypical tauopathies. As such, it is evident that harbours both Mendelian pathogenic variation and rare and common variants acting as disease risk factors. variants are linked to various phenotypic and neuropathological entities and are associated with distinct disease processes, including microtubule binding and assembly, alternative splicing and aggregation propensity. Moreover, variants have also been evaluated for their effect on tau isoform-specific aggregation since the tau protein exists in many different isoforms in the adult human brain. These isoforms are classified into 3-Repeat (3R) and 4-Repeat (4R) forms based on the number of repeat motifs present in the microtubule-binding domain of the protein. This domain is encoded by four highly similar exons (9, 10, 11 and 12) with the splicing of exon 10 at the mRNA level differentiating 3R (exclusion) and 4R (inclusion) tau isoforms. Tauopathies, a group of neurodegenerative disorders characterized by tau aggregation, follow a similar classification (3R, 4R) based on the predominance of a specific tau isoform in the pathogenic aggregates that define each pathology. As such, disorders such as CBD and PSP are classified as 4R tauopathies, while PiD represents a 3R tauopathy. Interestingly, the majority of familial, rare pathogenic variants identified have been shown to be associated with phenotypes consistent with PSP, CBD or globular glial tauopathy, as well as an increase in either 4R or 3R + 4R tau expression. Less frequently, familial variants have been linked to Pick-like 3R pathology. Similarly, there have been no rare, intermediate-effect-size, disease-modifying variants identified for PiD.