TREM2 and Parkinson’s Disease Benitez, Bruno A.; Cruchaga C, Carlos
The New England journal of medicine,
10/2013, Letnik:
369, Številka:
16
Journal Article
Abstract Background Single-nucleotide polymorphisms (SNPs) located in the gene encoding the regulatory subunit of the protein phosphatase 2B ( PPP3R1 , rs1868402) and the microtubule-associated ...protein tau ( MAPT , rs3785883) gene were recently associated with higher cerebrospinal fluid (CSF) tau levels in samples from the Knight Alzheimer's Disease Research Center at Washington University (WU) and Alzheimer's Disease Neuroimaging Initiative (ADNI). In these same samples, these SNPs were also associated with faster functional decline, or progression of Alzheimer's disease (AD) as measured by the Clinical Dementia Rating sum of boxes scores (CDR-sb). We attempted to validate the latter association in an independent, population-based sample of incident AD cases from the Cache County Dementia Progression Study (DPS). Methods All 92 AD cases from the DPS with a global CDR-sb ≤1 (mild) at initial clinical assessment who were later assessed on CDR-sb data on at least two other time points were genotyped at the two SNPs of interest (rs1868402 and rs3785883). We used linear mixed models to estimate associations between these SNPs and CDR-sb trajectory. All analyses were performed using Proc Mixed in SAS. Results Although we observed no association between rs3785883 or rs1868402 alone and change in CDR-sb ( P > .10), there was a significant association between a combined genotype model and change in CDR-sb: carriers of the high-risk genotypes at both loci progressed >2.9 times faster than noncarriers ( P = .015). When data from DPS were combined with previously published data from WU and ADNI, change in CDR-sb was 30% faster for each copy of the high-risk allele at rs3785883 ( P = .0082) and carriers of both high-risk genotypes at both loci progressed 6 times faster ( P < .0001) than all others combined. Conclusions We replicate a previous report by Cruchaga et al that specific variations in rs3785883 and rs1868402 are associated with accelerated progression of AD. Further characterization of this association will provide a better understanding of how genetic factors influence the rate of progression of AD and could provide novel insights into preventative and therapeutic strategies.
Pittsburgh Compound-B (
C-PiB) and
F-florbetapir are amyloid-β (Aβ) positron emission tomography (PET) radiotracers that have been used as endpoints in Alzheimer's disease (AD) clinical trials to ...evaluate the efficacy of anti-Aβ monoclonal antibodies. However, comparing drug effects between and within trials may become complicated if different Aβ radiotracers were used. To study the consequences of using different Aβ radiotracers to measure Aβ clearance, we performed a head-to-head comparison of
C-PiB and
F-florbetapir in a Phase 2/3 clinical trial of anti-Aβ monoclonal antibodies.
Sixty-six mutation-positive participants enrolled in the gantenerumab and placebo arms of the first Dominantly Inherited Alzheimer Network Trials Unit clinical trial (DIAN-TU-001) underwent both
C-PiB and
F-florbetapir PET imaging at baseline and during at least one follow-up visit. For each PET scan, regional standardized uptake value ratios (SUVRs), regional Centiloids, a global cortical SUVR, and a global cortical Centiloid value were calculated. Longitudinal changes in SUVRs and Centiloids were estimated using linear mixed models. Differences in longitudinal change between PET radiotracers and between drug arms were estimated using paired and Welch two sample t-tests, respectively. Simulated clinical trials were conducted to evaluate the consequences of some research sites using
C-PiB while other sites use
F-florbetapir for Aβ PET imaging.
In the placebo arm, the absolute rate of longitudinal change measured by global cortical
C-PiB SUVRs did not differ from that of global cortical
F-florbetapir SUVRs. In the gantenerumab arm, global cortical
C-PiB SUVRs decreased more rapidly than global cortical
F-florbetapir SUVRs. Drug effects were statistically significant across both Aβ radiotracers. In contrast, the rates of longitudinal change measured in global cortical Centiloids did not differ between Aβ radiotracers in either the placebo or gantenerumab arms, and drug effects remained statistically significant. Regional analyses largely recapitulated these global cortical analyses. Across simulated clinical trials, type I error was higher in trials where both Aβ radiotracers were used versus trials where only one Aβ radiotracer was used. Power was lower in trials where
F-florbetapir was primarily used versus trials where
C-PiB was primarily used.
Gantenerumab treatment induces longitudinal changes in Aβ PET, and the absolute rates of these longitudinal changes differ significantly between Aβ radiotracers. These differences were not seen in the placebo arm, suggesting that Aβ-clearing treatments may pose unique challenges when attempting to compare longitudinal results across different Aβ radiotracers. Our results suggest converting Aβ PET SUVR measurements to Centiloids (both globally and regionally) can harmonize these differences without losing sensitivity to drug effects. Nonetheless, until consensus is achieved on how to harmonize drug effects across radiotracers, and since using multiple radiotracers in the same trial may increase type I error, multisite studies should consider potential variability due to different radiotracers when interpreting Aβ PET biomarker data and, if feasible, use a single radiotracer for the best results.
ClinicalTrials.gov NCT01760005. Registered 31 December 2012. Retrospectively registered.
Objective
To identify rare causal variants underlying known loci that segregate with late‐onset Alzheimer's disease (LOAD) in multiplex families.
Methods
We analyzed whole genome sequences (WGS) from ...351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer's Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case‐control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene‐based associations with disease within LOAD GWAS loci.
Results
A variant in AKAP9, p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07–30.9, P = 0.041). In addition, missense mutations in MYRF and ASRGL1 under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow‐up genotyping both were nominally significant (P < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including CR1 (P = 0.049), BIN1 (P = 0.0098) and SLC24A4 (P = 0.040).
Conclusions and Relevance
Rare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.
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