Genetic epistasis regulates amyloid deposition in resilient aging

Felsky, Daniel; Xu, Jishu; Chibnik, Lori B.; Schneider, Julie A.; Knight, Jo; Kennedy, James L.; Bennett, David A.; Jager, Philip L. De; Voineskos, Aristotle N.

doi:10.1016/j.jalz.2017.01.027

Cited by 8 publications

(5 citation statements)

References 57 publications

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“…A different mechanism was proposed for the action of the Val66Met polymorphism in BDNF, the protective activity of which is affected by variants in SORL1, an established AD risk allele [127]. In elderly without pathological AD, a SORL1 RNA transcript that strongly regulated the interaction between SORL1 and BDNF was strongly associated with diffuse rather than neuritic Ab plaques and significantly influenced Ab load [127]. These results implicate genetic epistasis affecting regulation of Ab deposition as a mechanism of resilient aging.…”

Section: Mechanisms Underlying Resilience To Admentioning

confidence: 96%

“…These variants may therefore act protectively against AD disease progression by increasing brain reserve in the posterior cingulate. A different mechanism was proposed for the action of the Val66Met polymorphism in BDNF, the protective activity of which is affected by variants in SORL1 , an established AD risk allele [127]. In elderly without pathological AD, a SORL1 RNA transcript that strongly regulated the interaction between SORL1 and BDNF was strongly associated with diffuse rather than neuritic Aβ plaques and significantly influenced Aβ load [127].…”

Section: Mechanisms Underlying Resilience To Admentioning

confidence: 99%

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Understanding disease progression and improving Alzheimer's disease clinical trials: Recent highlights from the Alzheimer's Disease Neuroimaging Initiative

Veitch

Weiner

Aisen

et al. 2018

Alzheimer's & Dementia

342

265

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Introduction The overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to validate biomarkers for Alzheimer's disease (AD) clinical trials. ADNI is a multisite, longitudinal, observational study that has collected many biomarkers since 2004. Recent publications highlight the multifactorial nature of late‐onset AD. We discuss selected topics that provide insights into AD progression and outline how this knowledge may improve clinical trials. Methods We used standard methods to identify nearly 600 publications using ADNI data from 2016 and 2017 (listed in Supplementary Material and searchable at http://adni.loni.usc.edu/news-publications/publications/). Results (1) Data‐driven AD progression models supported multifactorial interactions rather than a linear cascade of events. (2) β‐Amyloid (Aβ) deposition occurred concurrently with functional connectivity changes within the default mode network in preclinical subjects and was followed by specific and progressive disconnection of functional and anatomical networks. (3) Changes in functional connectivity, volumetric measures, regional hypometabolism, and cognition were detectable at subthreshold levels of Aβ deposition. 4. Tau positron emission tomography imaging studies detailed a specific temporal and spatial pattern of tau pathology dependent on prior Aβ deposition, and related to subsequent cognitive decline. 5. Clustering studies using a wide range of modalities consistently identified a “typical AD” subgroup and a second subgroup characterized by executive impairment and widespread cortical atrophy in preclinical and prodromal subjects. 6. Vascular pathology burden may act through both Aβ dependent and independent mechanisms to exacerbate AD progression. 7. The APOE ε4 allele interacted with cerebrovascular disease to impede Aβ clearance mechanisms. 8. Genetic approaches identified novel genetic risk factors involving a wide range of processes, and demonstrated shared genetic risk for AD and vascular disorders, as well as the temporal and regional pathological associations of established AD risk alleles. 9. Knowledge of early pathological changes guided the development of novel prognostic biomarkers for preclinical subjects. 10. Placebo populations of randomized controlled clinical trials had highly variable trajectories of cognitive change, underscoring the importance of subject selection and monitoring. 11. Selection criteria based on Aβ positivity, hippocampal volume, baseline cognitive/functional measures, and APOE ε4 status in combination with improved cognitive outcome measures were projected to decrease clinical trial duration and cost. 12. Multiple concurrent therapies targeting vascular health and other AD pathology in addition to Aβ may be more effective than single therapies. Discussion ADNI publications from 2016 and 2017 supported the idea of AD as a multifactorial disease and provided insights into the complexities of AD disease progression. These findings guided the development of novel biomarkers and suggested that su...

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Section: Mechanisms Underlying Resilience To Admentioning

confidence: 96%

Section: Mechanisms Underlying Resilience To Admentioning

confidence: 99%

Understanding disease progression and improving Alzheimer's disease clinical trials: Recent highlights from the Alzheimer's Disease Neuroimaging Initiative

Veitch

Weiner

Aisen

et al. 2018

Alzheimer's & Dementia

342

265

View full text Add to dashboard Cite

show abstract

“…Although the phenomenon of epistasis has been known for over 100 years, 9 there is a paucity of studies to detect possible epistatic interactions in human diseases. 10 It is hoped that results presented here will inspire further investigations on gene-gene interactions in AD and other complex polygenic/multifactorial diseases.…”

Section: Discussionmentioning

confidence: 77%

Interactive Effects of HLA and GM Alleles on the Development of Alzheimer Disease

Pandey

Nietert

Kothera³

et al. 2021

Neurol Genet

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ObjectiveWe investigated whether particular immunoglobulin GM (γ marker) alleles—individually or epistatically with a known human leukocyte antigen (HLA) risk allele—were associated with the development of Alzheimer disease (AD).MethodsUsing a prospective cohort study design, we genotyped DNA samples from 209 African American (AA) and 638 European American (EA) participants for IgG1 (GM 3 and GM 17), IgG2 (GM 23+ and GM 23−), and HLA-DRB1 rs9271192 (A/C) alleles by TaqMan and rhAMP genotyping assays.ResultsIn EA subjects, none of the GM or HLA alleles—individually or epistatically—were associated with time to development of AD. In AA subjects, GM and HLA alleles individually were not associated with time to development of AD. However, there was a significant interaction: In the presence of GM 3 (i.e., GM 3/3 and GM 3/17 subjects), the presence of the HLA-C allele was associated with a 4-fold increase in the likelihood of developing AD compared with its absence (hazard ratio [HR] 4.17, 95% CI, 1.28–13.58). In the absence of GM 3 (GM 17/17 subjects), however, the presence of the HLA-C allele was not associated with time to development of AD (HR 1.10, 95% CI, 0.50–2.41).ConclusionsThese results show that particular GM and HLA alleles epistatically contribute to the development of AD.

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“…The only gene attaining genome-wide level statistical significance (besides APOE ) was SORL1 (sortilin related receptor 1), encoding a preproprotein that, following proteolytic processing, generates a receptor that likely plays a role in protein endocytosis and sorting, possibly affecting the clearance of extracellular amyloid-β. 39 This finding awaits an independent validation.…”

Section: Dna Vs Rna Biomarkers For Early Alzheimer Disease Detectionmentioning

confidence: 90%

Peripheral transcriptomic biomarkers for early detection of sporadic Alzheimer disease?

Hadar

Genevieve

2018

Dialogues in Clinical Neuroscience

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Alzheimer disease (AD) is the major epidemic of the 21 st century, its prevalence rising along with improved human longevity. Early AD diagnosis is key to successful treatment, as currently available therapeutics only allow small benefits for diagnosed AD patients. By contrast, future therapeutics, including those already in preclinical or clinical trials, are expected to afford neuroprotection prior to widespread brain damage and dementia. Brain imaging technologies are developing as promising tools for early AD diagnostics, yet their high cost limits their utility for screening at-risk populations. Blood or plasma transcriptomics, proteomics, and/or metabolomics may pave the way for cost-effective AD risk screening in middle-aged individuals years ahead of cognitive decline. This notion is exemplified by data mining of blood transcriptomics from a published dataset. Consortia blood sample collection and analysis from large cohorts with mild cognitive impairment followed longitudinally for their cognitive state would allow the development of a reliable and inexpensive early AD screening tool.

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Genetic epistasis regulates amyloid deposition in resilient aging

Cited by 8 publications

References 57 publications

Understanding disease progression and improving Alzheimer's disease clinical trials: Recent highlights from the Alzheimer's Disease Neuroimaging Initiative

Understanding disease progression and improving Alzheimer's disease clinical trials: Recent highlights from the Alzheimer's Disease Neuroimaging Initiative

Interactive Effects of HLA and GM Alleles on the Development of Alzheimer Disease

Peripheral transcriptomic biomarkers for early detection of sporadic Alzheimer disease?

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