Genomics of Alzheimer’s disease implicates the innate and adaptive immune systems

Li, Yihan; Laws, Simon M.; Miles, Luke A.; Wiley, James S.; Huang, Xianming; Masters, Colin L.; Gu, Ben

doi:10.1007/s00018-021-03986-5

Cited by 37 publications

(40 citation statements)

References 187 publications

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“…None of the 10 most significantly enriched pathways with genetically defined AD genes (by GWAS or monogenic AD) are in the top 50 literature-ranked pathways; instead, they represent a number of immune KEGG pathways as well as type I diabetes mellitus. There is emerging evidence that AD, indeed, has a strong immune system component (Li et al, 2021), but other aspects of the disease were not enriched in this gene list. The KEGG Alzheimer's disease pathway, which was updated in October 2020 (Kanehisa et al, 2021), contains a small number of the early genetic loci associated with AD and was developed to include processes that are impacted in AD.…”

Section: Discussionmentioning

confidence: 99%

Most Pathways Can Be Related to the Pathogenesis of Alzheimer’s Disease

Morgan

Yeganeh

Koler

et al. 2022

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a complex neurodegenerative disorder. The relative contribution of the numerous underlying functional mechanisms is poorly understood. To comprehensively understand the context and distribution of pathways that contribute to AD, we performed text-mining to generate an exhaustive, systematic assessment of the breadth and diversity of biological pathways within a corpus of 206,324 dementia publication abstracts. A total of 91% (325/335) of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways have publications containing an association via at least 5 studies, while 63% of pathway terms have at least 50 studies providing a clear association with AD. Despite major technological advances, the same set of top-ranked pathways have been consistently related to AD for 30 years, including AD, immune system, metabolic pathways, cholinergic synapse, long-term depression, proteasome, diabetes, cancer, and chemokine signaling. AD pathways studied appear biased: animal model and human subject studies prioritize different AD pathways. Surprisingly, human genetic discoveries and drug targeting are not enriched in the most frequently studied pathways. Our findings suggest that not only is this disorder incredibly complex, but that its functional reach is also nearly global. As a consequence of our study, research results can now be assessed in the context of the wider AD literature, supporting the design of drug therapies that target a broader range of mechanisms. The results of this study can be explored at www.adpathways.org.

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Section: Discussionmentioning

confidence: 99%

Most Pathways Can Be Related to the Pathogenesis of Alzheimer’s Disease

Morgan

Yeganeh

Koler

et al. 2022

Front. Aging Neurosci.

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“…Recent genome-wide association studies (GWAS) of AD have discovered over 130 genomic loci associated with AD, demonstrating their roles in microglial phagocytosis of Aβ, particularly phagocytic receptors and endolysosomal network of the innate immune system [ 4 , 7 ]. In addition to the interaction between Aβ, tau, and glial cells in AD brain, new evidence demonstrates the crosstalk between the central nervous system (CNS) and the peripheral blood and immune system in AD.…”

Section: Introductionmentioning

confidence: 99%

“…Cerebral Aβ can be transported into the peripheral pool via BBB, cerebrospinal fluid (CSF), arachnoid villi, and glymphatic-lymphatic system [ 10 ]. Nearly half of cerebral Aβ can be exported into the peripheral circulation to be cleared by enzymes, immune cells, tissues, or organs [ 4 ]. The genomic studies of AD have demonstrated monocyte-specific enrichment of AD risk variants, indicating that AD risk variants may locate in the regulatory regions to modulate monocytic function [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…Nearly half of cerebral Aβ can be exported into the peripheral circulation to be cleared by enzymes, immune cells, tissues, or organs [ 4 ]. The genomic studies of AD have demonstrated monocyte-specific enrichment of AD risk variants, indicating that AD risk variants may locate in the regulatory regions to modulate monocytic function [ 4 ]. Our group also reported the first human evidence that the basal phagocytic ability of monocytes was associated positively with cerebral Aβ burden in AD patients [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…Our group has studied P2X purinoceptor 7 (P2X7) for decades, which is a dual-functional purinergic receptor that acts as an ATP-induced pro-inflammatory ion channel and a scavenger receptor responsible for phagocytosing apoptotic cells and debris [ 13 ]. Additionally, recent AD GWAS has nominated many microglial-specific risk genes, including CD11b (integrin alpha M, ITGAM , or α M ) and CD11c (integrin alpha X, ITGAX , or α X ), which are integrins responsible for phagocytosis mediated by complement system and the recruitment and migration of monocytes [ 4 ]. Given that AD GWAS and functional studies all indicate the role of phagocytosis in AD, the performance of P2X7, CD11b, and CD11c on professional phagocytes was the primary aim of this study, including monocytes and neutrophils.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Identification of Leukocyte Surface P2X7 as a Biomarker Associated with Alzheimer’s Disease

Huang

Fowler

et al. 2022

IJMS

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Alzheimer’s disease (AD) has shown altered immune responses in the periphery. We studied P2X7 (a proinflammatory receptor and a scavenger receptor) and two integrins, CD11b and CD11c, on the surface of circulating leukocytes and analysed their associations with Aβ-PET, brain atrophy, neuropsychological assessments, and cerebrospinal fluid (CSF) biomarkers. Total 287 age-matched, sex-balanced participants were recruited in a discovery cohort and two validation cohorts through the AIBL study and studied using tri-colour flow cytometry. Our results demonstrated reduced expressions of P2X7, CD11b, and CD11c on leukocytes, particularly monocytes, in Aβ +ve cases compared with Aβ −ve controls. P2X7 and integrin downregulation was observed at pre-clinical stage of AD and stayed low throughout disease course. We further constructed a polygenic risk score (PRS) model based on 12 P2RX7 risk alleles to assess the genetic impact on P2X7 function in AIBL and ADNI cohorts. No significant association was identified between the P2RX7 gene and AD, indicating that P2X7 downregulation in AD is likely caused by environmental changes rather than genetic factors. In conclusion, the downregulation of P2X7 and integrins at pre-clinical stage of AD indicates altered pro-inflammatory responses, phagocytic functions, and migrating capabilities of circulating monocytes in early AD pathogenesis. Our study not only improves our understanding of peripheral immune involvement in early stage of AD but also provides more insights into novel biomarker development, diagnosis, and prognosis of AD.

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Genetic Phenotypes of Alzheimer’s Disease: Mechanisms and Potential Therapy

et al. 2023

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Years of intensive research has brought us extensive knowledge on the genetic and molecular factors involved in Alzheimer's disease (AD). In addition to the mutations in the three main causative genes of familial AD (FAD) including presenilins and amyloid precursor protein genes, studies have identified several genes as the most plausible genes for the onset and progression of FAD, such as triggering receptor expressed on myeloid cells 2, sortilin-related receptor 1, and adenosine triphosphate-binding cassette transporter subfamily A member 7. The apolipoprotein E ε4 allele is reported to be the strongest genetic risk factor for sporadic AD (SAD), and it also plays an important role in FAD. Here, we reviewed recent developments in genetic and molecular studies that contributed to the understanding of the genetic phenotypes of FAD and compared them with SAD. We further reviewed the advancements in AD gene therapy and discussed the future perspectives based on the genetic phenotypes.

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Genomics of Alzheimer’s disease implicates the innate and adaptive immune systems

Cited by 37 publications

References 187 publications

Most Pathways Can Be Related to the Pathogenesis of Alzheimer’s Disease

Most Pathways Can Be Related to the Pathogenesis of Alzheimer’s Disease

Identification of Leukocyte Surface P2X7 as a Biomarker Associated with Alzheimer’s Disease

Genetic Phenotypes of Alzheimer’s Disease: Mechanisms and Potential Therapy

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