Association Between Common Variants of APOE, ABCA7, A2M, BACE1, and Cerebrospinal Fluid Biomarkers in Alzheimer’s Disease: Data from the PUMCH Dementia Cohort

Dong, Liling; Mao, Chenhui; Liu, Caiyan; Li, Jie; Huang, Xin; Wang, Jie; Lei, Dan; Chu, Shanshan; Sha, Longze; Xu, Qi; Peng, Bin; Gao, Jing

doi:10.3233/jad-215067

Cited by 8 publications

(7 citation statements)

References 39 publications

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“…The current analysis corresponds to a similar examination of genes associated with AD and their variants, as summarized in earlier studies [19]. The present study also corroborated the association between AD and its comorbid diseases such as dementia, Parkinson's disease, and type 2 diabetes, as documented earlier [20][21][22][23][24][25][26].…”

Section: Discussionsupporting

confidence: 90%

Comorbidity-Guided Text Mining and Omics Pipeline to Identify Candidate Genes and Drugs for Alzheimer’s Disease

Oviya,

Sankar,

Manoharan

et al. 2024

Genes

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Alzheimer’s disease (AD), a multifactorial neurodegenerative disorder, is prevalent among the elderly population. It is a complex trait with mutations in multiple genes. Although the US Food and Drug Administration (FDA) has approved a few drugs for AD treatment, a definitive cure remains elusive. Research efforts persist in seeking improved treatment options for AD. Here, a hybrid pipeline is proposed to apply text mining to identify comorbid diseases for AD and an omics approach to identify the common genes between AD and five comorbid diseases—dementia, type 2 diabetes, hypertension, Parkinson’s disease, and Down syndrome. We further identified the pathways and drugs for common genes. The rationale behind this approach is rooted in the fact that elderly individuals often receive multiple medications for various comorbid diseases, and an insight into the genes that are common to comorbid diseases may enhance treatment strategies. We identified seven common genes—PSEN1, PSEN2, MAPT, APP, APOE, NOTCH, and HFE—for AD and five comorbid diseases. We investigated the drugs interacting with these common genes using LINCS gene–drug perturbation. Our analysis unveiled several promising candidates, including MG-132 and Masitinib, which exhibit potential efficacy for both AD and its comorbid diseases. The pipeline can be extended to other diseases.

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Section: Discussionsupporting

confidence: 90%

Comorbidity-Guided Text Mining and Omics Pipeline to Identify Candidate Genes and Drugs for Alzheimer’s Disease

Oviya,

Sankar,

Manoharan

et al. 2024

Genes

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“…Shortly, multiple genetic markers were associated with increased amyloid pathology, which has been replicated in several studies, 38,51–54 which could be indicative for a role of ABCA7 dysfunction in the amyloid pathway. Evidence for association with tau pathology has been more inconsistent 38,51,54,55 . Studies in different brain regions generally suggested association of risk alleles with either brain atrophy or altered functional connectivity 38,56–59 .…”

Section: Abca7 Ad‐associated Variantsmentioning

confidence: 83%

“…The abovementioned GWAS sentinel SNPs have also been studied for their association with AD endophenotypes, such as amyloid deposition, tau pathology, brain morphology, and various clinical symptoms, which has been extensively reviewed before 38,50 . Shortly, multiple genetic markers were associated with increased amyloid pathology, which has been replicated in several studies, 38,51–54 which could be indicative for a role of ABCA7 dysfunction in the amyloid pathway. Evidence for association with tau pathology has been more inconsistent 38,51,54,55 .…”

Section: Abca7 Ad‐associated Variantsmentioning

confidence: 99%

“…Evidence for association with tau pathology has been more inconsistent. 38 , 51 , 54 , 55 Studies in different brain regions generally suggested association of risk alleles with either brain atrophy or altered functional connectivity. 38 , 56 , 57 , 58 , 59 Finally, for association with different measures of cognitive decline and memory, mixed results have been found as well.…”

Section: Abca7 Ad‐associated Variantsmentioning

confidence: 99%

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The ABC's of Alzheimer risk gene ABCA7

Duchateau,

Wawrzyniak,

Sleegers

2024

Alzheimer's & Dementia

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Alzheimer's disease (AD) is a growing problem worldwide. Since ABCA7’s identification as a risk gene, it has been extensively researched for its role in the disease. We review its recently characterized structure and what the mechanistic insights teach us about its function. We furthermore provide an overview of identified ABCA7 mutations, their presence in different ancestries and protein domains and how they might cause AD. For ABCA7 PTC variants and a VNTR expansion, haploinsufficiency is proposed as the most likely mode‐of‐action, although splice events could further influence disease risk. Overall, the need to better understand expression of canonical ABCA7 and its isoforms in disease is indicated. Finally, ABCA7's potential functions in lipid metabolism, phagocytosis, amyloid deposition, and the interplay between these three, is described. To conclude, in this review, we provide a comprehensive overview and discussion about the current knowledge on ABCA7 in AD, and what research questions remain.Highlights Alzheimer's risk‐increasing variants in ABCA7 can be found in up to 7% of AD patients. We review the recently characterized protein structure of ABCA7. We present latest insights in genetics, expression patterns, and functions of ABCA7.

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“…Notably, A2M is markedly elevated in neuronal protrusions in senile plaques, neurofibrillary tangles, and atrophic neurons in Alzheimer’s disease patients’ brains ( 23 ). A2M is strongly associated with neurological disorders associated with dopaminergic neuronal dysfunction and cerebrospinal fluid (CSF) biomarkers within the coding region of Alzheimer’s disease (AD) susceptibility genes ( 22 , 24 ). This study indicates that A2M, in the XXZ group of patients with acute ischemic stroke, is primarily associated with “inflammatory response” and “response to lipid.” Decreasing A2M expression may influence sICAS through anti-inflammatory and lipid responses and may also contribute to improving neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Biomarker study of symptomatic intracranial atherosclerotic stenosis in patients with acute ischemic stroke

Ding,

Li,

Shan

et al. 2023

Front. Neurol.

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ObjectiveAcute ischemic stroke (AIS) is characterized by high rates of morbidity, disability, mortality, and recurrence, often leaving patients with varying degrees of sequelae. Symptomatic intracranial atherosclerotic stenosis (sICAS) is a significant contributor to AIS pathogenesis and recurrence. The formation and progression of sICAS are influenced by pathways such as lipid metabolism and inflammatory response. Given its high risk of clinical recurrence, timely assessment of intracranial vascular stenosis in AIS is crucial for diagnosing sICAS, treating stroke, and preventing stroke recurrence.MethodsFourteen AIS patients were divided into stenosis and control groups based on the presence or absence of intracranial vessel stenosis. Initially, 4D Label-free proteome quantification technology was employed for mass spectrometry analysis to identify differential proteins between the groups. Subsequently, functional enrichment analysis, including GO classification, KEGG pathway, and Domain, revealed trends related to differential proteins. The STRING (v.11.5) protein interaction network database was used to identify differential protein interactions and target proteins. Finally, parallel reaction monitoring (PRM) validated the selected target proteins.ResultsMass spectrometry identified 1,096 proteins, with 991 being quantitatively comparable. Using a p-value <0.05 and differential expression change thresholds of >1.3 for significant up-regulation and < 1/1.3 for significant down-regulation, 46 differential proteins were identified: 24 significantly up-regulated and 22 significantly down-regulated. PRM experiments validated five proteins related to lipid metabolism and inflammatory response: namely alpha-2-macroglobulin (A2M), lipopolysaccharide-binding protein (LBP), cathepsin G (CTSG), cystatin (CST)3, and fatty acid-binding protein (FABP)1.ConclusionThe detection of changes in these five proteins in AIS patients can aid in the diagnosis of sICAS, inform stroke treatment, and assist in preventing stroke recurrence. Moreover, it can contribute to the development of drugs for preventing AIS recurrence by integrating traditional Chinese and Western medicine.

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Association Between Common Variants of APOE, ABCA7, A2M, BACE1, and Cerebrospinal Fluid Biomarkers in Alzheimer’s Disease: Data from the PUMCH Dementia Cohort

Cited by 8 publications

References 39 publications

Comorbidity-Guided Text Mining and Omics Pipeline to Identify Candidate Genes and Drugs for Alzheimer’s Disease

Comorbidity-Guided Text Mining and Omics Pipeline to Identify Candidate Genes and Drugs for Alzheimer’s Disease

The ABC's of Alzheimer risk gene ABCA7

Biomarker study of symptomatic intracranial atherosclerotic stenosis in patients with acute ischemic stroke

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