Alzheimer’s Disease Genetics: From the Bench to the Clinic

Karch, Celeste M.; Cruchaga, Carlos; Goate, Alison M.

doi:10.1016/j.neuron.2014.05.041

Cited by 411 publications

(328 citation statements)

References 173 publications

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“…In addition, this study confirmed that APOEe4, CR1, BIN1, EPHA1, and CD33 were associated with LOAD in African Americans as previously confirmed in Caucasians, highlighting the importance of these variants in disease risk by replicating the associations in multiple ethnically diverse populations. These studies demonstrate that some AD risk loci appear to have similar effects among different populations while others seem to be population-specific [46].…”

Section: Finding Genetic Risk Factors In Diverse Ethnic Groupsmentioning

confidence: 67%

An Overview of Genome-Wide Association Studies in Alzheimer’s Disease

Shen

Jia

2016

Neurosci. Bull.

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Genome-wide association studies (GWASs) have revealed a plethora of putative susceptibility genes for Alzheimer's disease (AD). With the sole exception of the APOE gene, these AD susceptibility genes have not been unequivocally validated in independent studies. No single novel functional risk genetic variant has been identified. In this review, we evaluate recent GWASs of AD, and discuss their significance, limitations, and challenges in the investigation of the genetic spectrum of AD.

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Section: Finding Genetic Risk Factors In Diverse Ethnic Groupsmentioning

confidence: 67%

An Overview of Genome-Wide Association Studies in Alzheimer’s Disease

Shen

Jia

2016

Neurosci. Bull.

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“…These neuropathological hallmarks of AD include the extracellular deposition of neurotoxic amyloid-β (Aβ) in the form of amyloid plaques and an accumulation of intracellular neurofibrillary tangles composed of hyperphosphorylated tau 3 . Despite progress in understanding risk factors contributing to AD progression, the mechanisms involved in disease progression are not fully understood and long-term treatments, reversing the cellular disease process in the cortex, are elusive.There has been considerable success in identifying genetic risk factors for AD 4 . While autosomal dominant mutations in three genes (APP, PSEN1, and PSEN2) can explain earlyonset (< 65 years) familial AD, these account for only 1-5% of the total disease burden 5 .…”

mentioning

confidence: 99%

A histone acetylome-wide association study of Alzheimer’s disease: neuropathology-associated regulatory variation in the human entorhinal cortex

Marzi

Ribarska

Smith

et al. 2017

Preprint

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Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by the progressive accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles in the neocortex. Recent studies have implicated a role for regulatory genomic variation in AD progression, finding widespread evidence for altered DNA methylation associated with neuropathology. To date, however, no study has systematically examined other types of regulatory genomic modifications in AD. In this study, we quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) -a robust mark of active enhancers and promoters that is strongly correlated with gene expression and transcription factor binding -in entorhinal cortex samples from AD cases and matched controls (n = 47) using chromatin immunoprecipitation followed by highly parallel sequencing (ChIP-seq). Across ~182,000 robustly detected H3K27ac peak regions, we found widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (FDR < 0.05) between AD cases and controls. These differentially acetylated peaks are enriched in disease-specific biological pathways and include regions annotated to multiple genes directly involved in the progression of Aβ and tau pathology (e.g. APP, PSEN1, PSEN2, MAPT), as well as genomic regions containing variants associated with sporadic late-onset AD. This is the first study of variable H3K27ac yet undertaken in AD and the largest study investigating this modification in the entorhinal cortex. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease, integrating our data with results obtained from genome-wide association studies as well as other epigenetic marks profiled on the same samples.. CC-BY 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/183541 doi: bioRxiv preprint first posted online 3 Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by cognitive decline and memory loss that contributes substantially to the global burden of disease, affecting in excess of 26 million people worldwide 1 . The symptoms of AD are associated with progressive neuropathology in the neocortex, with regions surrounding the entorhinal cortex being particularly affected early in the disease 2 . These neuropathological hallmarks of AD include the extracellular deposition of neurotoxic amyloid-β (Aβ) in the form of amyloid plaques and an accumulation of intracellular neurofibrillary tangles composed of hyperphosphorylated tau 3 . Despite progress in understanding risk factors contributing to AD progression, the mechanisms involved in disease progression are not fully understood and long-term treatments, reversing the cellular disease process in the cortex, are elusive.The...

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“…A common emerging theme in the research field of age-related neurodegenerative diseases is that of endosomal dysfunction [1]. Specifically in Alzheimer's disease (AD), primary evidence pinpointing the endosome as the intracellular site of dysfunction was described in a seminal series of histological studies performed by Cataldo et al [2].…”

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confidence: 99%

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

et al. 2015

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The retromer is an evolutionary conserved multiprotein complex involved in the sorting and retrograde trafficking of cargo from endosomal compartments to the Golgi network and to the cell surface. The neuronal retromer traffics the amyloid precursor protein away from the endosomes, a site where amyloid precursor protein is enzymatically cleaved into pathogenic fragments in Alzheimer's disease. In recent years, deficiencies in retromer-mediated transport have been implicated in several neurological and non-neurological diseases, including Parkinson's disease, suggesting that improving the efficacy of the retromer trafficking pathway would result in decreased pathology. We recently identified a new family of small molecules that appear to stabilize the interaction between members of the retromer complex and enhance its function in neurons: the retromer pharmacological chaperones. Here we discuss the role of these molecules in the improvement of retromer trafficking and endosomal dysfunction, as well as their potential as therapeutics for neurological and non-neurological disorders.

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Alzheimer’s Disease Genetics: From the Bench to the Clinic

Cited by 411 publications

References 173 publications

An Overview of Genome-Wide Association Studies in Alzheimer’s Disease

An Overview of Genome-Wide Association Studies in Alzheimer’s Disease

A histone acetylome-wide association study of Alzheimer’s disease: neuropathology-associated regulatory variation in the human entorhinal cortex

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

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