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Article ; Online: A Preliminary Comparison of the Methylome and Transcriptome from the Prefrontal Cortex Across Alzheimer's Disease and Lewy Body Dementia.

Fisher, Daniel W / Tulloch, Jessica / Yu, Chang-En / Tsuang, Debby

Journal of Alzheimer's disease reports

2023 Volume 7, Issue 1, Page(s) 279–297

Abstract: Background: Pathological amyloid-β and : Objective: In this preliminary study, we explore differences in DNA methylation and transcription in five neuropathologically defined groups: cognitively unimpaired controls, AD, pure DLB, DLB with concomitant ...

Abstract	Background: Pathological amyloid-β and Objective: In this preliminary study, we explore differences in DNA methylation and transcription in five neuropathologically defined groups: cognitively unimpaired controls, AD, pure DLB, DLB with concomitant AD (DLBAD), and PDD. Methods: We employed an Illumina Infinium 850k array and RNA-seq to quantify these differences in DNA methylation and transcription, respectively. We then used Weighted Gene Co-Network Expression Analysis (WGCNA) to determine transcriptional modules and correlated these with DNA methylation. Results: We found that PDD was transcriptionally unique and correlated with an unexpected hypomethylation pattern compared to the other dementias and controls. Surprisingly, differences between PDD and DLB were especially notable with 197 differentially methylated regions. WGCNA yielded numerous modules associated with controls and the four dementias: one module was associated with transcriptional differences between controls and all the dementias as well as having significant overlap with differentially methylated probes. Functional enrichment demonstrated that this module was associated with responses to oxidative stress. Conclusion: Future work that extends these joint DNA methylation and transcription analyses will be critical to better understanding of differences that contribute to varying clinical presentation across dementias.
Language	English
Publishing date	2023-04-20
Publishing country	Netherlands
Document type	Journal Article
ISSN	2542-4823
ISSN (online)	2542-4823
DOI	10.3233/ADR220114
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Article ; Online: APOE

Lee, Eun-Gyung / Leong, Lesley / Chen, Sunny / Tulloch, Jessica / Yu, Chang-En

International journal of molecular sciences

2023 Volume 24, Issue 13

Abstract: The Apolipoprotein E ( ...

Abstract	The Apolipoprotein E (
MeSH term(s)	Humans ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Apolipoproteins E/genetics ; Aging/genetics ; Aging/metabolism ; Genotype ; Mitochondria/genetics ; Mitochondria/metabolism ; Apolipoprotein E4/genetics
Chemical Substances	Apolipoproteins E ; Apolipoprotein E4
Language	English
Publishing date	2023-06-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241310440
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Article ; Online: Weight Loss Is a Strong Predictor of Memory Disorder Independent of Genetic Influences

Chen, Sunny / Sarasua, Sara M. / Davis, Nicole J. / DeLuca, Jane M. / Thielke, Stephen M. / Yu, Chang-En

Genes (Basel). 2023 July 31, v. 14, no. 8

2023

Abstract: Background: Past studies identified a link between weight loss and dementia, but lacked consistent conclusions. We sought to establish this link by examining the weight change profiles before and after dementia diagnosis. Methods: Using data from the ... ...

Abstract	Background: Past studies identified a link between weight loss and dementia, but lacked consistent conclusions. We sought to establish this link by examining the weight change profiles before and after dementia diagnosis. Methods: Using data from the Health and Retirement Study (1996–2020), we examined 13,123 participants. We conducted a nested case–control analysis to assess differences in biennial weight change profile while controlling for BMI, longevity polygenic risk scores, and APOE gene variants. Results: Participants with a memory disorder lost weight (−0.63%) biennially, whereas those without a diagnosis did not (+0.013%, p-value < 0.0001). Our case–control study shows a significant difference (p-value < 0.01) in pre-dementia % weight changes between the cases (−0.29%) and controls (0.19%), but not in post-dementia weight changes. The weight loss group have the highest risk (OR = 2.01; p-value < 0.0001) of developing a memory disorder compared to the stable weight and weight gain groups. The observations hold true after adjusting for BMI, longevity polygenic risk scores, and APOE variant in a multivariable model. Conclusions: We observe that weight loss in dementia is a physiological process independent of genetic factors associated with BMI and longevity. Pre-dementia weight loss may be an important prognostic criterion to assess a person’s risk of developing a memory disorder.
Keywords	case-control studies ; dementia ; genes ; longevity ; memory disorders ; multivariate analysis ; risk ; weight gain ; weight loss
Language	English
Dates of publication	2023-0731
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes14081563
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Article ; Online: Weight Loss Is a Strong Predictor of Memory Disorder Independent of Genetic Influences.

Chen, Sunny / Sarasua, Sara M / Davis, Nicole J / DeLuca, Jane M / Thielke, Stephen M / Yu, Chang-En

Genes

2023 Volume 14, Issue 8

Abstract	Background: Past studies identified a link between weight loss and dementia, but lacked consistent conclusions. We sought to establish this link by examining the weight change profiles before and after dementia diagnosis. Methods: Using data from the Health and Retirement Study (1996-2020), we examined 13,123 participants. We conducted a nested case-control analysis to assess differences in biennial weight change profile while controlling for BMI, longevity polygenic risk scores, and Results: Participants with a memory disorder lost weight (-0.63%) biennially, whereas those without a diagnosis did not (+0.013%, Conclusions: We observe that weight loss in dementia is a physiological process independent of genetic factors associated with BMI and longevity. Pre-dementia weight loss may be an important prognostic criterion to assess a person's risk of developing a memory disorder.
MeSH term(s)	Humans ; Case-Control Studies ; Memory Disorders/genetics ; Weight Loss/genetics ; Dementia/genetics ; Apolipoproteins E/genetics
Chemical Substances	Apolipoproteins E
Language	English
Publishing date	2023-07-31
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes14081563
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Article ; Online: A familial missense variant in the Alzheimer's disease gene SORL1 impairs its maturation and endosomal sorting.

Fazeli, Elnaz / Child, Daniel D / Bucks, Stephanie A / Stovarsky, Miki / Edwards, Gabrielle / Rose, Shannon E / Yu, Chang-En / Latimer, Caitlin / Kitago, Yu / Bird, Thomas / Jayadev, Suman / Andersen, Olav M / Young, Jessica E

Acta neuropathologica

2024 Volume 147, Issue 1, Page(s) 20

Abstract: The SORL1 gene has recently emerged as a strong Alzheimer's Disease (AD) risk gene. Over 500 different variants have been identified in the gene and the contribution of individual variants to AD development and progression is still largely unknown. Here, ...

Abstract	The SORL1 gene has recently emerged as a strong Alzheimer's Disease (AD) risk gene. Over 500 different variants have been identified in the gene and the contribution of individual variants to AD development and progression is still largely unknown. Here, we describe a family consisting of 2 parents and 5 offspring. Both parents were affected with dementia and one had confirmed AD pathology with an age of onset > 75 years. All offspring were affected with AD with ages at onset ranging from 53 years to 74 years. DNA was available from the parent with confirmed AD and 5 offspring. We identified a coding variant, p.(Arg953Cys), in SORL1 in 5 of 6 individuals affected by AD. Notably, variant carriers had severe AD pathology, and the SORL1 variant segregated with TDP-43 pathology (LATE-NC). We further characterized this variant and show that this Arginine substitution occurs at a critical position in the YWTD-domain of the SORL1 translation product, SORL1. Functional studies further show that the p.R953C variant leads to retention of the SORL1 protein in the endoplasmic reticulum which leads to decreased maturation and shedding of the receptor and prevents its normal endosomal trafficking. Together, our analysis suggests that p.R953C is a pathogenic variant of SORL1 and sheds light on mechanisms of how missense SORL1 variants may lead to AD.
MeSH term(s)	Humans ; Aged ; Alzheimer Disease/genetics ; Gene Frequency ; Genetic Predisposition to Disease ; Membrane Transport Proteins/genetics ; Mutation, Missense ; LDL-Receptor Related Proteins/genetics ; Polymorphism, Single Nucleotide
Chemical Substances	Membrane Transport Proteins ; LDL-Receptor Related Proteins ; SORL1 protein, human
Language	English
Publishing date	2024-01-20
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-023-02670-1
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Article ; Online: Erratum to

Yu Chang-En / Foraker Jessica

Biomolecular Concepts, Vol 6, Iss 3, Pp 235-

Epigenetic considerations of the APOE gene

2015 Volume 235

Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2015-06-01T00:00:00Z
Publisher	De Gruyter
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Epigenetic considerations of the APOE gene

Yu Chang-En / Foraker Jessica

Biomolecular Concepts, Vol 6, Iss 1, Pp 77-

2015 Volume 84

Abstract: The apolipoprotein E (APOE) gene is robustly linked with numerous physiological conditions, including healthy aging, altered cardiovascular fitness, and cognitive function. These connections have been established primarily by phenotype-genotype ... ...

Abstract	The apolipoprotein E (APOE) gene is robustly linked with numerous physiological conditions, including healthy aging, altered cardiovascular fitness, and cognitive function. These connections have been established primarily by phenotype-genotype association studies using APOE’s three common genetic variants (ε2, ε3, and ε4). These variants encode for the three apoE protein isoforms (E2, E3, and E4), which have slightly different structures and, consequently, distinct functions in lipid metabolism. However, the differential lipid binding and transferring properties of these isoforms cannot fully explain the association of APOE with such a wide range of physiological phenotypes. One potential explanation for APOE’s pleiotropic roles may lie in its unique epigenetic properties. In this article, we present a brief review of the APOE gene and protein, its disease associations, and epigenetic components, with a focus on DNA methylation. We close with a discussion of the prospective epigenetic implications of APOE in disease.
Keywords	apoe ; dna methylation ; disease ; epigenetics ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2015-03-01T00:00:00Z
Publisher	De Gruyter
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: TOMM40 RNA Transcription in Alzheimer’s Disease Brain and Its Implication in Mitochondrial Dysfunction

Lee, Eun-Gyung / Chen, Sunny / Leong, Lesley / Tulloch, Jessica / Yu, Chang-En

Genes. 2021 June 06, v. 12, no. 6

2021

Abstract: Increasing evidence suggests that the Translocase of Outer Mitochondria Membrane 40 (TOMM40) gene may contribute to the risk of Alzheimer’s disease (AD). Currently, there is no consensus as to whether TOMM40 expression is up- or down-regulated in AD ... ...

Abstract	Increasing evidence suggests that the Translocase of Outer Mitochondria Membrane 40 (TOMM40) gene may contribute to the risk of Alzheimer’s disease (AD). Currently, there is no consensus as to whether TOMM40 expression is up- or down-regulated in AD brains, hindering a clear interpretation of TOMM40’s role in this disease. The aim of this study was to determine if TOMM40 RNA levels differ between AD and control brains. We applied RT-qPCR to study TOMM40 transcription in human postmortem brain (PMB) and assessed associations of these RNA levels with genetic variants in APOE and TOMM40. We also compared TOMM40 RNA levels with mitochondrial functions in human cell lines. Initially, we found that the human genome carries multiple TOMM40 pseudogenes capable of producing highly homologous RNAs that can obscure precise TOMM40 RNA measurements. To circumvent this obstacle, we developed a novel RNA expression assay targeting the primary transcript of TOMM40. Using this assay, we showed that TOMM40 RNA was upregulated in AD PMB. Additionally, elevated TOMM40 RNA levels were associated with decreases in mitochondrial DNA copy number and mitochondrial membrane potential in oxidative stress-challenged cells. Overall, differential transcription of TOMM40 RNA in the brain is associated with AD and could be an indicator of mitochondrial dysfunction.
Keywords	brain ; humans ; membrane potential ; mitochondria ; mitochondrial DNA ; mitochondrial membrane ; pseudogenes ; risk
Language	English
Dates of publication	2021-0606
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes12060871
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Article ; Online: Association of Uncommon, Noncoding Variants in the APOE Region With Risk of Alzheimer Disease in Adults of European Ancestry.

Blue, Elizabeth E / Cheng, Anqi / Chen, Sunny / Yu, Chang-En

JAMA network open

2020 Volume 3, Issue 10, Page(s) e2017666

Abstract: Importance: The ε2 and ε4 alleles of the apolipoprotein E (APOE) gene are associated with Alzheimer disease (AD) risk. Although nearby genetic variants have also been shown to be associated with AD, including rs2075650 in the TOMM40 gene and rs4420638 ... ...

Abstract	Importance: The ε2 and ε4 alleles of the apolipoprotein E (APOE) gene are associated with Alzheimer disease (AD) risk. Although nearby genetic variants have also been shown to be associated with AD, including rs2075650 in the TOMM40 gene and rs4420638 near the APOC1 gene, it is unknown whether these associations are independent of the ε2 and ε4 alleles. Objective: To assess whether variants near APOE are associated with AD independently of the ε2/ε3/ε4 genotype. Design, setting, and participants: In this genetic association study of the Alzheimer's Disease Genetics Consortium imputed genotype at data, 14 415 variants near APOE (±500 kilobase) for 18 795 individuals with European ancestry were tested for association with AD using 4 logistic mixed models adjusting for sex, cohort, population structure, and relatedness. Model 1 had no APOE adjustment, and model 2 adjusted for the count of ε2 and ε4 alleles. Model 3 was restricted to ε3 homozygotes, and model 4 was restricted to ε4 homozygotes. Data were downloaded from May 31, 2018, to June 3, 2018, and analyzed from November 1, 2018, to June 24, 2020. Main outcomes and measures: Alzheimer disease affectation status was defined by clinicians using standard National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer Disease and Related Disorders Association criteria. Association was evaluated using Score tests; results with P < .05 divided by the number of independent tests per model were considered statistically significant. Results: Among the 18 795 individuals in the study, 9704 were affected by AD and 9066 were control individuals; the median age at onset/evaluation was 76 (interquartile range, 70-82) years; and 11 167 were female (59.4%). Associations with AD were found for rs2075650 (odds ratio [OR], 2.59; 95% CI, 2.45-2.75; P = 3.19 × 10-228) and rs4420638 (OR, 2.77; 95% CI, 2.62-2.94; P = 2.99 × 10-254) without APOE adjustment. Although rs2075650 was nominally associated with AD among the ε4 homozygotes (OR, 1.33; 95% CI, 1.00-1.77; P = .047), the association between rs4420638 and AD was eliminated by APOE adjustment (model 2 OR, 1.06 [95% CI, 0.96-1.18; P = .24]; model 3 OR, 1.13 [95% CI, 0.95-1.34; P = .18]; model 4 OR, 0.90 [95% CI, 0.56-1.45; P = .66]). There was a significant association between rs192879175 and AD among ε3 homozygotes (OR, 0.50; 95% CI, 0.37-0.68; P = 8.30 × 10-6). Conclusions and relevance: The results of this genetic association study suggest that ε2/ε3/ε4 alleles are not the only variants in the APOE region that are associated with AD risk. Additional work with independent data is needed to replicate these results.
MeSH term(s)	Aged ; Aged, 80 and over ; Alleles ; Alzheimer Disease/genetics ; Apolipoproteins E/genetics ; Case-Control Studies ; Cohort Studies ; Europe ; Female ; Genetic Variation ; Genotype ; Humans ; Logistic Models ; Male ; Risk Factors ; Whites/genetics
Chemical Substances	Apolipoproteins E
Language	English
Publishing date	2020-10-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2020.17666
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Article ; Online: Lack of APOE Christchurch variant in five age of onset outliers with PSEN1, PSEN2 Alzheimer's disease and MAPT frontotemporal dementia.

Yu, Chang-En / Chen, Sunny / Jayadev, Suman / Bird, Thomas

Journal of the neurological sciences

2020 Volume 418, Page(s) 117143

Abstract: Introduction: Age of onset modifiers are of considerable importance in Alzheimer's and related dementias. Arboleda-Valesquez et al., reporting on a single PSEN1 subject, suggested that homozygosity for the Christchurch variant of APOE could represent ... ...

Abstract	Introduction: Age of onset modifiers are of considerable importance in Alzheimer's and related dementias. Arboleda-Valesquez et al., reporting on a single PSEN1 subject, suggested that homozygosity for the Christchurch variant of APOE could represent such a modifier. Methods: We studied APOE Christchurch and Kloth-VS genotypes of five dementia age of onset outliers who carried their families' pathogenic variant, but were asymptomatic at ages beyond the families' average age of onset. Results: Four age of onset outliers with PSEN1/2 and MAPT mutations did not carry the Christchurch variant and a fifth individual was also determined to not be homozygous for this variant. Among them, only one subject (APOE ε3/ε3) carries the Klotho-VS heterozygous genotype. Discussion: From a small but informative sample of five age of onset outliers we show that neither the APOE Christchurch nor the Klotho-VS variant is a common age of onset modifier for three genetic forms of dementia. Larger studies of this association and further research is required to identify additional genetic modifiers.
MeSH term(s)	Age of Onset ; Alzheimer Disease/genetics ; Apolipoproteins E/genetics ; Frontotemporal Dementia/genetics ; Humans ; Mutation/genetics ; Presenilin-1/genetics ; Presenilin-2/genetics ; tau Proteins/genetics
Chemical Substances	Apolipoproteins E ; MAPT protein, human ; PSEN1 protein, human ; PSEN2 protein, human ; Presenilin-1 ; Presenilin-2 ; tau Proteins
Language	English
Publishing date	2020-09-18
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80160-4
ISSN	1878-5883 ; 0022-510X ; 0374-8642
ISSN (online)	1878-5883
ISSN	0022-510X ; 0374-8642
DOI	10.1016/j.jns.2020.117143
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