Malia Rumbaugh

R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family Clinical, Genetic, and Neuropathological Study

IMPORTANCE The R47H variant in the triggering receptor expressed on myeloid cells 2 gene (TREM2), a modulator of the immune response of microglia, is a strong genetic risk factor for Alzheimer disease (AD) and possibly other neurodegenerative disorders. OBJECTIVE To investigate a large family with late-onset AD (LOAD), in which R47H cosegregated with 75% of cases. DESIGN, SETTING, AND PARTICIPANTS 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 Alzheimer Disease 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. TREM2 R47H was genotyped in an additional 130 families with LOAD. We performed clinical and neuropathological assessments of patients with and without R47H and evaluated the variants effect on brain pathology, cellular morphology, and expression of microglial markers. MAIN OUTCOMES AND MEASURES We assessed the effect of TREM2 genotype on age at onset and disease duration. We compared Braak and Consortium to Establish a Registry for Alzheimers Disease scores, presence of α-synuclein and TAR DNA-binding protein 43 aggregates, and additional vascular or Parkinson pathology in TREM2 R47H carriers vs noncarriers. Microglial activation was assessed by quantitative immunohistochemistry and morphometry. RESULTS Twelve of 16 patients with AD in the LOAD123 family carried R47H. Eleven patients with dementia had apolipoprotein E 4 (ApoE4) and R47H genotypes. We also found a rare missense variant, D353N, in a nominated AD risk gene, unc-5 homolog C (UNC5C), in 5 affected individuals in the LOAD123 family. R47H 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 α-synucleinopathy. The panmicroglial marker ionized calcium-binding adapter molecule 1 was decreased in all AD cases and the decrease was most pronounced in R47H carriers (mean [SD], in the hilus: 0.114 [0.13] for R47H_AD vs 0.574 [0.26] for control individuals; 2-tailed t test; P = .005 and vs 0.465 [0.32] for AD; P = .02; in frontal cortex gray matter: 0.006 [0.004] for R47H_AD vs 0.016 [0.01] for AD; 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 patients with AD (AD: 2.5, R47H_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. ApoE4, TREM2 R47H, and rare variants in other genes, such as UNC5C D353N, are likely responsible for the notable occurrence of AD in this family. Our findings support the role of the TREM2 receptor in microglial clearance of aggregation-prone proteins that is compromised in R47H carriers and may accelerate the course of disease.

Clinicopathological concordance and discordance in three monozygotic twin pairs with familial Alzheimer’s disease

Aim: Neuropathological examination of both individuals in a monozygotic (MZ) twin pair with Alzheimer’s disease (AD) is rare, especially in the molecular genetic era. We had the opportunity to assess the concordance and discordance of clinical presentation and neuropathology in three MZ twin pairs with AD. Methods: The MZ twins were identified and characterised by the University of Washington Alzheimer’s Disease Research Center. We reviewed the available clinical and neuropathological records for all six cases looking specifically for concordance and discordance of clinical phenotype, neuritic amyloid plaques (NP), neurofibrillary tangles (NFT) and Lewy related pathology (LRP). Results: Discordance in age of onset for developing AD in the MZ twins varied from 4 to 18 years. Clinical presentations also differed between twins. One twin presented with a dementia with Lewy Body clinical syndrome while the other presented with typical clinical AD. Neuropathology within the MZ twin pairs was concordant for NP and NFT, regardless of duration of disease, and was discordant for LRP. This difference was most marked in the late onset AD twin pair. One pair was found to have a mutation in presenilin-1 (PS1) (A79V) with remarkably late onset in a family member. Conclusions: MZ twins with AD can vary considerably in age of onset, presentation and disease duration. The concordance of NP and NFT pathological change and the discordance of LRP support the concept that, in AD, the former are primarily under genetic control whereas the latter (LRP) is more influenced by disease duration and environmental factors. The A79V mutation in PS1 can be associated with very late onset of dementia.

MAPT haplotypes modify the association between head injury and risk of Alzheimer’s disease

Background:Alzheimer’s disease (AD) is a complex disease in which the quest for causative genes has been challenging. In this search, genome-wide studies (GWAS) have been a valuable tool, being able to investigate, through thousands of markers, associations with the disease or with its endophenotypes. However, GWAS analyses almost always use cross-sectional data. Despite the adversities of obtaining and analyzing longitudinal data, the information about the disease progress can be of great importance. For this reason, we have searched for genetic markers associated with changes in brain amyloid (Ab) load and glucose uptake. Methods: [F]Florbetapir positron emission tomography (PET) imaging was employed to assess brain Ab levels in 412 participants from the Alzheimer’s Disease Neuroimaging Initiative, whilst glucose uptake was measured using [F]fludeoxyglucose PET (FDG) in 419 subjects from the same cohort. The genotypes were obtained with IlluminaHumanOmni2.5 beadchip. After quality control in both imaging and genetic data, a GWAS was performed. The phenotypes used were the differences between global SUVR in the baseline and 24 months follow-up of [F]florbetapir and FDG. Covariates as diagnostic status and baseline SUVR were added in the genetic analysis. The Bonferroni threshold of genome-wide significance is 3.9x10. Values higher then 3.9x10 but less then 10were considered trends of association. Results: None of the SNPs reached genome-wide significance, however trends of association are reported here (Figure 1). Ab accumulation shows a trend with 24 markers from 15 genes, in which probably the most relevant, and significant, is PLCH1. Brain hipometabolism indicate trend associations with 21 markers from 8 genes. The genes TTC39B and NRP1were the most significant. Conclusions: The major genes reported to be associated with AD were not found in the present study. Interestingly, Ab accumulation seems to be related to the PLCH1 gene, which encodes for a phospholipase-C family-member. Phospholipases are important enzymes with key roles in cell signaling. Another relevant result may be the association of hypometabolism with the TTC39B gene. Its function is not clear, however this gene has been related to lipid metabolism. Further studies with bigger sample size would be necessary to confirm present results.

Four siblings with Variable Clinical and Pathological Characteristics of Alzheimer's and Lewy Body Disease

that have been clinically, neuropathologically, and genetically studied. CERAD score and Braak stage have been assessed as previously described. For assessing CAA, we have investigated six brain regions using a four-step -grading system based on histological Congo red, confirmed by immunohistochemical Ab staining. Results: In the preliminary studies based on Congo red staining, we have detected CAA in 201/307 individuals (65%). 144 individuals out of those 201 with CAA (72%) and 51 out of the 106 without (48%) were demented (p 1⁄4 0.000047). Logistic regression showed that the association between CAA and dementia remained significant (p 1⁄4 0.041) when age, gender, Braak stage, and CERAD score were included in the analysis (p 1⁄4 0.000047), suggesting that CAA might have an indipendent effect in the development of dementia. Conclusions: The study offers the unique opportunity to investigate the relationships between several neuropathological and other variables that interact resulting in the development of clinical dementia.