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Article ; Online: Key variants via the Alzheimer's Disease Sequencing Project whole genome sequence data.

Wang, Yanbing / Sarnowski, Chloé / Lin, Honghuang / Pitsillides, Achilleas N / Heard-Costa, Nancy L / Choi, Seung Hoan / Wang, Dongyu / Bis, Joshua C / Blue, Elizabeth E / Boerwinkle, Eric / De Jager, Philip L / Fornage, Myriam / Wijsman, Ellen M / Seshadri, Sudha / Dupuis, Josée / Peloso, Gina M / DeStefano, Anita L

Alzheimer's & dementia : the journal of the Alzheimer's Association

2024

Abstract: Introduction: Genome-wide association studies (GWAS) have identified loci associated with Alzheimer's disease (AD) but did not identify specific causal genes or variants within those loci. Analysis of whole genome sequence (WGS) data, which interrogates ...

Abstract	Introduction: Genome-wide association studies (GWAS) have identified loci associated with Alzheimer's disease (AD) but did not identify specific causal genes or variants within those loci. Analysis of whole genome sequence (WGS) data, which interrogates the entire genome and captures rare variations, may identify causal variants within GWAS loci. Methods: We performed single common variant association analysis and rare variant aggregate analyses in the pooled population (N cases = 2184, N controls = 2383) and targeted analyses in subpopulations using WGS data from the Alzheimer's Disease Sequencing Project (ADSP). The analyses were restricted to variants within 100 kb of 83 previously identified GWAS lead variants. Results: Seventeen variants were significantly associated with AD within five genomic regions implicating the genes OARD1/NFYA/TREML1, JAZF1, FERMT2, and SLC24A4. KAT8 was implicated by both single variant and rare variant aggregate analyses. Discussion: This study demonstrates the utility of leveraging WGS to gain insights into AD loci identified via GWAS.
Language	English
Publishing date	2024-03-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13705
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Article: Frequency of Variants in Mendelian Alzheimer's Disease Genes within the Alzheimer's Disease Sequencing Project (ADSP).

Wang, Dongyu / Scalici, Alexandra / Wang, Yanbing / Lin, Honghuang / Pitsillides, Achilleas / Heard-Costa, Nancy / Cruchaga, Carlos / Ziegemeier, Ellen / Bis, Joshua C / Fornage, Myriam / Boerwinkle, Eric / De Jager, Philip L / Wijsman, Ellen / Dupuis, Josée / Renton, Alan E / Seshadri, Sudha / Goate, Alison M / DeStefano, Anita L / Peloso, Gina M

medRxiv : the preprint server for health sciences

2024

Abstract: Background: Prior studies using the ADSP data examined variants within presenilin-2 ( : Objective: To characterize previously-reported clinically-relevant variants and DM variants in : Methods: We identified rare variants (MAF <1%) previously- ... ...

Abstract	Background: Prior studies using the ADSP data examined variants within presenilin-2 ( Objective: To characterize previously-reported clinically-relevant variants and DM variants in Methods: We identified rare variants (MAF <1%) previously-reported in Results: We detected 31 previously-reported clinically-relevant variants with alternate alleles observed within the ADSP: 4 variants in Conclusion: A small proportion of individuals in the ADSP are carriers of a previously-reported clinically-relevant variant allele for AD and these participants have significantly earlier age of AD onset compared to non-carriers.
Language	English
Publishing date	2024-03-29
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.24.23297227
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Article: Association analysis of mitochondrial DNA heteroplasmic variants: methods and application.

medRxiv : the preprint server for health sciences

2024

Abstract: We rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust ... ...

Abstract	We rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α=0.001. Notably, when 5% or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden test. Applying this framework, we conducted association analyses on whole-blood derived heteroplasmy in 17,507 individuals of African and European ancestries (31% of African Ancestry, mean age of 62, with 58% women) with whole genome sequencing data. We performed both cohort- and ancestry-specific association analyses, followed by meta-analysis on both pooled samples and within each ancestry group. Our results suggest that mtDNA-encoded genes/regions are likely to exhibit varying rates in somatic aging, with the notably strong associations observed between heteroplasmy in the
Language	English
Publishing date	2024-01-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.12.24301233
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Article ; Online: Serum NfL and GFAP are associated with incident dementia and dementia mortality in older adults: The cardiovascular health study.

Cronjé, Héléne T / Liu, Xiaojuan / Odden, Michelle C / Moseholm, Kristine F / Seshadri, Sudha / Satizabal, Claudia L / Lopez, Oscar L / Bis, Joshua C / Djoussé, Luc / Fohner, Alison E / Psaty, Bruce M / Tracy, Russell P / Longstreth, W T / Jensen, Majken K / Mukamal, Kenneth J

Alzheimer's & dementia : the journal of the Alzheimer's Association

2023 Volume 19, Issue 12, Page(s) 5672–5680

Abstract: Introduction: Circulating neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have been independently associated with dementia risk. Their additive association, and their associations with dementia-specific mortality, have not ... ...

Abstract	Introduction: Circulating neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have been independently associated with dementia risk. Their additive association, and their associations with dementia-specific mortality, have not been investigated. Methods: We associated serum NfL, GFAP, total tau ,and ubiquitin carboxyl-terminal hydrolase-L1, measured in 1712 dementia-free adults, with 19-year incident dementia and dementia-specific mortality risk, and with 3-year cognitive decline. Results: In adjusted models, being in the highest versus lowest tertile of NfL or GFAP associated with a hazard ratio (HR) of 1.49 (1.20-1.84) and 1.38 (1.15-1.66) for incident dementia, and 2.87 (1.79-4.61) and 2.76 (1.73-4.40) for dementia-specific mortality. Joint third versus first tertile exposure further increased risk; HR = 2.06 (1.60-2.67) and 9.22 (4.48-18.9). NfL was independently associated with accelerated cognitive decline. Discussion: Circulating NfL and GFAP may, independently and jointly, provide useful clinical insight regarding dementia risk and prognosis.
MeSH term(s)	Aged ; Humans ; Biomarkers ; Cognitive Dysfunction/epidemiology ; Dementia/epidemiology ; Glial Fibrillary Acidic Protein ; Intermediate Filaments
Chemical Substances	Biomarkers ; Glial Fibrillary Acidic Protein ; neurofilament protein L ; GFAP protein, human
Language	English
Publishing date	2023-07-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13367
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Article: Key variants via Alzheimer's Disease Sequencing Project whole genome sequence data.

medRxiv : the preprint server for health sciences

2023

Abstract	Introduction: Genome-wide association studies (GWAS) have identified loci associated with Alzheimer's disease (AD) but did not identify specific causal genes or variants within those loci. Analysis of whole genome sequence (WGS) data, which interrogates the entire genome and captures rare variations, may identify causal variants within GWAS loci. Methods: We performed single common variant association analysis and rare variant aggregate analyses in the pooled population (N cases=2,184, N controls=2,383) and targeted analyses in sub-populations using WGS data from the Alzheimer's Disease Sequencing Project (ADSP). The analyses were restricted to variants within 100 kb of 83 previously identified GWAS lead variants. Results: Seventeen variants were significantly associated with AD within five genomic regions implicating the genes OARD1/NFYA/TREML1, JAZF1, FERMT2, and SLC24A4. KAT8 was implicated by both single variant and rare variant aggregate analyses. Discussion: This study demonstrates the utility of leveraging WGS to gain insights into AD loci identified via GWAS.
Language	English
Publishing date	2023-08-29
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.28.23294631
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Article ; Online: Plasma Proteomic Associations With Incident Ischemic Stroke in Older Adults: The Cardiovascular Health Study.

Kalani, Rizwan / Bartz, Traci M / Psaty, Bruce M / Elkind, Mitchell S V / Floyd, James S / Gerszten, Robert E / Shojaie, Ali / Heckbert, Susan R / Bis, Joshua C / Austin, Thomas R / Tirschwell, David L / Delaney, Joseph A C / Longstreth, W T

Neurology

2023 Volume 100, Issue 21, Page(s) e2182–e2190

Abstract: Background and objectives: Plasma proteomics may elucidate novel insights into the pathophysiology of ischemic stroke (IS), identify biomarkers of IS risk, and guide development of nascent prevention strategies. We evaluated the relationship between the ...

Abstract	Background and objectives: Plasma proteomics may elucidate novel insights into the pathophysiology of ischemic stroke (IS), identify biomarkers of IS risk, and guide development of nascent prevention strategies. We evaluated the relationship between the plasma proteome and IS risk in the population-based Cardiovascular Health Study (CHS). Methods: Eligible CHS participants were free of prevalent stroke and underwent quantification of 1,298 plasma proteins using the aptamer-based SOMAScan assay platform from the 1992-1993 study visit. Multivariable Cox proportional hazards regression was used to evaluate associations between a 1-SD increase in the log Results: Of 2,983 eligible participants, the mean age was 74.3 (±4.8) years, 61.2% were women, and 15.4% were Black. Over a median follow-up of 12.6 years, 450 participants experienced an incident IS. N-terminal probrain natriuretic peptide (NTproBNP, adjusted HR 1.37, 95% CI 1.23-1.53, Discussion: In a cohort of older adults, NTproBNP and MMP12 were independently associated with IS risk. We identified plasma proteomic determinants of incident cardioembolic and noncardioembolic IS and found a novel protein associated with IS risk in those with left atrial dysfunction.
MeSH term(s)	Male ; Humans ; Female ; Aged ; Atrial Fibrillation/complications ; Ischemic Stroke/complications ; Proteomics ; Matrix Metalloproteinase 12 ; Stroke/complications ; Risk Factors ; Biomarkers ; Incidence
Chemical Substances	Matrix Metalloproteinase 12 (EC 3.4.24.65) ; Biomarkers
Language	English
Publishing date	2023-04-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000207242
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Article ; Online: Biomedical consequences of elevated cholesterol-containing lipoproteins and apolipoproteins on cardiovascular and non-cardiovascular outcomes.

Schmidt, Amand F / Joshi, Roshni / Gordillo-Marañón, Maria / Drenos, Fotios / Charoen, Pimphen / Giambartolomei, Claudia / Bis, Joshua C / Gaunt, Tom R / Hughes, Alun D / Lawlor, Deborah A / Wong, Andrew / Price, Jackie F / Chaturvedi, Nishi / Wannamethee, Goya / Franceschini, Nora / Kivimaki, Mika / Hingorani, Aroon D / Finan, Chris

Communications medicine

2023 Volume 3, Issue 1, Page(s) 9

Abstract: Background: Higher concentrations of cholesterol-containing low-density lipoprotein (LDL-C) increase the risk of cardiovascular disease (CVD). The association of LDL-C with non-CVD traits remains unclear, as are the possible independent contributions of ...

Abstract	Background: Higher concentrations of cholesterol-containing low-density lipoprotein (LDL-C) increase the risk of cardiovascular disease (CVD). The association of LDL-C with non-CVD traits remains unclear, as are the possible independent contributions of other cholesterol-containing lipoproteins and apolipoproteins. Methods: Nuclear magnetic resonance spectroscopy was used to measure the cholesterol content of high density (HDL-C), very low-density (VLDL-C), intermediate-density (IDL-C), as well as low-density lipoprotein fractions, the apolipoproteins Apo-A1 and Apo-B, as well as total triglycerides (TG), remnant-cholesterol (Rem-Chol) and total cholesterol (TC). The causal effects of these exposures were assessed against 33 outcomes using univariable and multivariable Mendelian randomization (MR). Results: The majority of cholesterol containing lipoproteins and apolipoproteins affect coronary heart disease (CHD), carotid intima-media thickness, carotid plaque, C-reactive protein (CRP) and blood pressure. Multivariable MR indicated that many of these effects act independently of HDL-C, LDL-C and TG, the most frequently measured lipid fractions. Higher concentrations of TG, VLDL-C, Rem-Chol and Apo-B increased heart failure (HF) risk; often independently of LDL-C, HDL-C or TG. Finally, a subset of these exposures associated with non-CVD traits such as Alzheimer's disease (AD: HDL-C, LDL-C, IDL-C, Apo-B), type 2 diabetes (T2DM: VLDL-C, IDL-C, LDL-C), and inflammatory bowel disease (IBD: LDL-C, IDL-C). Conclusions: The cholesterol content of a wide range of lipoprotein and apolipoproteins associate with measures of atherosclerosis, blood pressure, CRP, and CHD, with a subset affecting HF, T2DM, AD and IBD risk. Many of the observed effects appear to act independently of LDL-C, HDL-C, and TG, supporting the targeting of lipid fractions beyond LDL-C for disease prevention.
Language	English
Publishing date	2023-01-20
Publishing country	England
Document type	Journal Article
ISSN	2730-664X
ISSN (online)	2730-664X
DOI	10.1038/s43856-022-00234-0
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Article ; Online: Admixture mapping implicates 13q33.3 as ancestry-of-origin locus for Alzheimer disease in Hispanic and Latino populations

Horimoto, Andrea R.V.R. / Boyken, Lisa A. / Blue, Elizabeth E. / Grinde, Kelsey E. / Nafikov, Rafael A. / Sohi, Harkirat K. / Nato, Alejandro Q. / Bis, Joshua C. / Brusco, Luis I. / Morelli, Laura / Ramírez, Alfredo / Dalmasso, Maria Carolina / Temple, Seth / Satizabal, Claudia / Browning, Sharon R. / Sudha Seshadri / Wijsman, Ellen M. / Thornton, Timothy A.

Human Genetics and Genomics Advances. 2023 May 20, p.100207-

2023 , Page(s) 100207–

Abstract: Alzheimer disease (AD) is the most common form of senile dementia, with high incidence late in life in many populations including Caribbean Hispanic (CH) populations. Such admixed populations, descended from more than one ancestral population, can ... ...

Abstract	Alzheimer disease (AD) is the most common form of senile dementia, with high incidence late in life in many populations including Caribbean Hispanic (CH) populations. Such admixed populations, descended from more than one ancestral population, can present challenges for genetic studies, including limited sample sizes and unique analytical constraints. Therefore, CH populations and other admixed populations have not been well represented in studies of AD, and much of the genetic variation contributing to AD risk in these populations remains unknown. Here, we conduct genome-wide analysis of AD in multiplex CH families from the Alzheimer Disease Sequencing Project (ADSP). We developed, validated, and applied an implementation of a logistic mixed model for admixture mapping with binary traits that leverages genetic ancestry to identify ancestry-of-origin loci contributing to AD. We identified three loci on chromosome 13q33.3 associated with reduced risk of AD, where associations were driven by Native American (NAM) ancestry. This AD admixture mapping signal spans the FAM155A, ABHD13, TNFSF13B, LIG4, and MYO16 genes and was supported by evidence for association in an independent sample from the Alzheimer's Genetics in Argentina-Alzheimer Argentina consortium (AGA-ALZAR) study with considerable NAM ancestry. We also provide evidence of NAM haplotypes and key variants within 13q33.3 that segregate with AD in the ADSP whole-genome sequencing data. Interestingly, the widely used genome-wide association study approach failed to identify associations in this region. Our findings underscore the potential of leveraging genetic ancestry diversity in recently admixed populations to improve genetic mapping, in this case for AD-relevant loci.
Keywords	Alzheimer disease ; Latinos ; ancestry ; genetic variation ; genome-wide association study ; genomics ; haplotypes ; human genetics ; loci ; risk ; risk reduction ; statistical models ; Argentina ; Caribbean
Language	English
Dates of publication	2023-0520
Publishing place	Elsevier Inc.
Document type	Article ; Online
Note	Pre-press version ; Use and reproduction
ISSN	2666-2477
DOI	10.1016/j.xhgg.2023.100207
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Association of Plasma YKL-40 With MRI, CSF, and Cognitive Markers of Brain Health and Dementia.

Pase, Matthew P / Himali, Jayandra J / Puerta, Raquel / Beiser, Alexa S / Gonzales, Mitzi M / Satizabal, Claudia L / Yang, Qiong / Aparicio, Hugo J / Kojis, Daniel J / Decarli, Charles S / Lopez, Oscar L / Longstreth, Will / Gudnason, Vilmundur / Mosley, Thomas H / Bis, Joshua C / Fohner, Alison / Psaty, Bruce M / Boada, Mercè / García-González, Pablo /

Valero, Sergi / Marquié, Marta / Tracy, Russell / Launer, Lenore J / Ruiz, Agustín / Fornage, Myriam / Seshadri, Sudha

Neurology

2024 Volume 102, Issue 4, Page(s) e208075

Abstract: Background and objectives: Higher YKL-40 levels in the CSF are a known biomarker of brain inflammation. We explored the utility of plasma YKL-40 as a biomarker for accelerated brain aging and dementia risk.: Methods: We performed cross-sectional and ... ...

Abstract	Background and objectives: Higher YKL-40 levels in the CSF are a known biomarker of brain inflammation. We explored the utility of plasma YKL-40 as a biomarker for accelerated brain aging and dementia risk. Methods: We performed cross-sectional and prospective analyses of 4 community-based cohorts in the United States or Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, Atherosclerosis Risk in the Communities study, Coronary Artery Risk Development in Young Adults study, and Framingham Heart Study (FHS). YKL-40 was measured from stored plasma by a single laboratory using Mesoscale Discovery with levels log transformed and standardized within each cohort. Outcomes included MRI total brain volume, hippocampal volume, and white matter hyperintensity volume (WMHV) as a percentage of intracranial volume, a general cognitive composite derived from neuropsychological testing (SD units [SDU]), and the risk of incident dementia. We sought to replicate associations with dementia in the clinic-based ACE csf cohort, which also had YKL-40 measured from the CSF. Results: Meta-analyses of MRI outcomes included 6,558 dementia-free participants, and for analysis of cognition, 6,670. The blood draw preceded MRI/cognitive assessment by up to 10.6 years across cohorts. The mean ages ranged from 50 to 76 years, with 39%-48% male individuals. In random-effects meta-analysis of study estimates, each SDU increase in log-transformed YKL-40 levels was associated with smaller total brain volume (β = -0.33; 95% CI -0.45 to -0.22; Discussion: Higher plasma YKL-40 levels were associated with lower brain volume, poorer cognition, and incident dementia. Plasma YKL-40 may be useful for studying the association of inflammation and its treatment on dementia risk.
MeSH term(s)	Aged ; Female ; Humans ; Male ; Middle Aged ; Alzheimer Disease ; Biomarkers ; Brain/diagnostic imaging ; Chitinase-3-Like Protein 1 ; Cognition ; Cognitive Dysfunction ; Cross-Sectional Studies ; Dementia/diagnostic imaging ; Magnetic Resonance Imaging ; Prospective Studies
Chemical Substances	Biomarkers ; Chitinase-3-Like Protein 1 ; CHI3L1 protein, human
Language	English
Publishing date	2024-01-30
Publishing country	United States
Document type	Meta-Analysis ; Journal Article
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000208075
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Article ; Online: Proteome Network Analysis Identifies Potential Biomarkers for Brain Aging.

Journal of Alzheimer's disease : JAD

2023 Volume 96, Issue 4, Page(s) 1767–1780

Abstract: Background: Alzheimer's disease and related dementias (ADRD) involve biological processes that begin years to decades before onset of clinical symptoms. The plasma proteome can offer insight into brain aging and risk of incident dementia among ... ...

Abstract	Background: Alzheimer's disease and related dementias (ADRD) involve biological processes that begin years to decades before onset of clinical symptoms. The plasma proteome can offer insight into brain aging and risk of incident dementia among cognitively healthy adults. Objective: To identify biomarkers and biological pathways associated with neuroimaging measures and incident dementia in two large community-based cohorts by applying a correlation-based network analysis to the plasma proteome. Methods: Weighted co-expression network analysis of 1,305 plasma proteins identified four modules of co-expressed proteins, which were related to MRI brain volumes and risk of incident dementia over a median 20-year follow-up in Framingham Heart Study (FHS) Offspring cohort participants (n = 1,861). Analyses were replicated in the Cardiovascular Health Study (CHS) (n = 2,117, mean 6-year follow-up). Results: Two proteomic modules, one related to protein clearance and synaptic maintenance (M2) and a second to inflammation (M4), were associated with total brain volume in FHS (M2: p = 0.014; M4: p = 4.2×10-5). These modules were not significantly associated with hippocampal volume, white matter hyperintensities, or incident all-cause or AD dementia. Associations with TCBV did not replicate in CHS, an older cohort with a greater burden of comorbidities. Conclusions: Proteome networks implicate an early role for biological pathways involving inflammation and synaptic function in preclinical brain atrophy, with implications for clinical dementia.
MeSH term(s)	Humans ; Dementia/diagnostic imaging ; Proteome ; Proteomics ; Brain/diagnostic imaging ; Aging ; Alzheimer Disease ; Biomarkers ; Magnetic Resonance Imaging ; Inflammation
Chemical Substances	Proteome ; Biomarkers
Language	English
Publishing date	2023-11-24
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-230145
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