R47H Variant of XXXX Associated With @entity195 in a Large Late-Onset Family: Clinical, Genetic, and Neuropathological Study.

@entity1 @entity70667 @entity16017 @entity2204 @entity16014 @entity303 @entity179 @entity460 @entity195 @entity529 @entity70668
IMPORTANCE: The @entity16017 variant in the triggering receptor expressed on myeloid cells 2 gene ( @entity16014 ), a modulator of the immune response of microglia, is a strong genetic risk factor for @entity195 ( @entity195 ) and possibly other @entity179 . OBJECTIVE: To investigate a large family with late-onset @entity195 (LOAD), in which @entity16017 cosegregated with 75% of cases. DESIGN, SETTING, AND @entity1 : This study includes genetic and pathologic studies of families with LOAD from 1985 to 2014. A total of 131 families with LOAD (751 individuals) were included from the University of Washington @entity195 Research Center. To identify LOAD genes/risk factors in the LOAD123 family with 21 affected members and 12 autopsies, we sequenced 4 exomes. Candidate variants were tested for cosegregation with the disease. @entity16014 @entity16017 was genotyped in an additional 130 families with LOAD. We performed clinical and neuropathological assessments of @entity1 with and without @entity16017 and evaluated the variant's effect on brain pathology, cellular morphology, and expression of microglial markers. MAIN OUTCOMES AND MEASURES: We assessed the effect of @entity16014 genotype on age at onset and disease duration. We compared Braak and Consortium to Establish a Registry for @entity195 scores, presence of a-synuclein and @entity529 aggregates, and additional vascular or Parkinson pathology in @entity16014 @entity16017 carriers vs noncarriers. Microglial activation was assessed by quantitative immunohistochemistry and morphometry. RESULTS: Twelve of 16 @entity1 with @entity195 in the LOAD123 family carried @entity16017 . Eleven @entity1 with @entity303 had @entity2204 ( @entity2204 ) and @entity16017 genotypes. We also found a rare missense variant, @entity70667 , in a nominated @entity195 risk gene, @entity70668 ( @entity70668 ), in 5 affected individuals in the LOAD123 family. @entity16017 carriers demonstrated a shortened disease duration (mean [SD], 6.7 [2.8] vs 11.1 [6.6] years; 2-tailed t test; P   =   .04) and more frequent a-synucleinopathy. The panmicroglial marker ionized @entity460 -binding adapter molecule 1 was decreased in all @entity195 cases and the decrease was most pronounced in @entity16017 carriers (mean [SD], in the hilus: 0.114 [0.13] for @entity16017 _AD vs 0.574 [0.26] for control individuals; 2-tailed t test; P   =   .005 and vs 0.465 [0.32] for @entity195 ; P   =   .02; in frontal cortex gray matter: 0.006 [0.004] for @entity16017 _AD vs 0.016 [0.01] for @entity195 ; P   =   .04 and vs 0.033 [0.013] for control individuals; P   <   .001). Major histocompatibility complex class II, a marker of microglial activation, was increased in all @entity1 with @entity195 ( @entity195 , @entity16017 _AD: 2.7, and control: 1.0; P   <   .01). CONCLUSIONS AND RELEVANCE: Our results demonstrate a complex genetic landscape of LOAD, even in a single pedigree with an apparent autosomal dominant pattern of inheritance. @entity2204 , @entity16014 @entity16017 , and rare variants in other genes, such as @entity70668 @entity70667 , are likely responsible for the notable occurrence of @entity195 in this family. Our findings support the role of the @entity16014 receptor in microglial clearance of aggregation-prone proteins that is compromised in @entity16017 carriers and may accelerate the course of disease.
