Genetic Variation in the Ontario Neurodegenerative Disease Research Initiative

Abstract

ABSTRACT:Background/Objective:Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer’s disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson’s disease, and (5) vascular cognitive impairment.Methods:Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.Results:Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.Conclusion:This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.

Ontario Neurodegenerative Disease Research Initiative (ONDRI): Structural MRI methods & outcome measures

“…The Ontario Neurodegenerative Research Initiative (ONDRI) is a multi-site prospective cohort study following patients with neurodegenerative diseases including Alzheimer's disease (AD), mild cognitive impairment (MCI), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and a vascular patient cohort (VAS) (Farhan et al, 2017). Over the course of 3 years, multiple assessment platforms acquired comprehensive data from the 520 patients including, clinical and demographic assessments, neuroimaging, neuropsychology, genomics, eye movements, retinal layer morphology, gait performance, and neuropathology (Dilliott et al, 2019;Montero-Odasso et al, 2017;Wong et al, 2019). The multi-modal data collected from ONDRI will be used to explore earlier detection, guide development of novel therapy and improving patient care .…”

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative

“…As a general index of directionality, higher GFAP, NfL, and p‐tau181 are considered more pathological, while lower Aβ 42/40 is considered more pathological. Apolipoprotein E ( APOE ) genotypes for each participant were identified using the custom next‐generation sequencing‐based panel ONDRISeq 32,33 and used to determine APOE ε4 carrier status. Less than 3% of the ONDRI cohort had monogenic mutations in genes known to be drivers of neurodegenerative diseases 34 …”

“…Blood samples were drawn from all participants at baseline at the closest LifeLabs Medical Laboratory Services location to their residence, with standardized operating protocols for collection and storage (https://www.lifelabs.com/page-section/specimen-collectionhandling-section-hcp-requisitions-page/). Samples were collected and processed within 24 hours; they were shipped on ice pack (not frozen ONDRISeq 32,33 and used to determine APOE ε4 carrier status. Less than 3% of the ONDRI cohort had monogenic mutations in genes known to be drivers of neurodegenerative diseases.…”

Rare neurovascular genetic and imaging markers across neurodegenerative diseases

“…27,29 Generated VCF files for each ONDRI participant were annotated using VarSeq® (Golden Helix, Bozeman, MT, USA All ONDRI participants were also assessed for the APOE genotype using the ONDRISeq data by extracting calls for the APOE variants rs429358(CT):p.Cys130Arg and rs7412(CT):p.Arg176Cys and mapping to the respective genotype, as previously described. 31 Any participant carrying at least one copy of either the ε2 or ε4 genotype were considered APOE variant positive, as both variants have been previously shown to increase the presence of SVD markers, including WMH burden. 32-34…”