CSF biomarkers of immune activation and Alzheimer’s disease for predicting cognitive impairment risk in the elderly

Shue, Francis; White, Launia J.; Hendrix, Rachel; Ulrich, Jason; Henson, Rachel L.; Knight, William; Martens, Yuka A.; Wang, Ni; Roy, Bhaskar; Starling, Skylar C.; Ren, Yingxue; Xiong, Chengjie; Asmann, Yan W.; Syrjanen, Jeremy A.; Vassilaki, Maria; Mielke, Michelle M.; Timsina, Jigyasha; Sung, Yun Ju; Cruchaga, Carlos; Holtzman, David M.; Bu, Guojun; Petersen, Ronald C.; Heckman, Michael G.; Kanekiyo, Takahisa

doi:10.1126/sciadv.adk3674

Cited by 5 publications

References 61 publications

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APOE ε4–associated downregulation of the IL‐7/IL‐7R pathway in effector memory T cells: Implications for Alzheimer's disease

Zhang,

Cheng,

Tang

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONThe apolipoprotein E (APOE) ε4 allele exerts a significant influence on peripheral inflammation and neuroinflammation, yet the underlying mechanisms remain elusive.METHODSThe present study enrolled 54 patients diagnosed with late‐onset Alzheimer's disease (AD; including 28 APOE ε4 carriers and 26 non‐carriers). Plasma inflammatory cytokine concentration was assessed, alongside bulk RNA sequencing (RNA‐seq) and single‐cell RNA sequencing (scRNA‐seq) analysis of peripheral blood mononuclear cells (PBMCs).RESULTSPlasma tumor necrosis factor α, interferon γ, and interleukin (IL)‐33 levels increased in the APOE ε4 carriers but IL‐7 expression notably decreased. A negative correlation was observed between plasma IL‐7 level and the hippocampal atrophy degree. Additionally, the expression of IL‐7R and CD28 also decreased in PBMCs of APOE ε4 carriers. ScRNA‐seq data results indicated that the changes were mainly related to the CD4+ Tem (effector memory) and CD8+ Tem T cells.DISCUSSIONThese findings shed light on the role of the downregulated IL‐7/IL‐7R pathway associated with the APOE ε4 allele in modulating neuroinflammation and hippocampal atrophy.Highlights The apolipoprotein E (APOE) ε4 allele decreases plasma interleukin (IL)‐7 and aggravates hippocampal atrophy in Alzheimer's disease. Plasma IL‐7 level is negatively associated with the degree of hippocampal atrophy. The expression of IL‐7R signaling decreased in peripheral blood mononuclear cells of APOE ε4 carriers Dysregulation of the IL‐7/IL‐7R signal pathways enriches T cells.

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APOE ε4–associated downregulation of the IL‐7/IL‐7R pathway in effector memory T cells: Implications for Alzheimer's disease

Zhang,

Cheng,

Tang

et al. 2024

Alzheimer's & Dementia

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Neuronal APOE4-induced Early Hippocampal Network Hyperexcitability in Alzheimer’s Disease Pathogenesis

Tabuena,

Jang,

Grone

et al. 2023

Preprint

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The impact of apolipoprotein E4 (apoE4), the strongest genetic risk factor for Alzheimer’s disease (AD), on neuronal function remains unclear. We investigated this by examining excitatory neurons in the hippocampus of young and aged human apoE4 knock-in (apoE4-KI) and apoE3-KI mice using electrophysiology and single-nucleus RNA-sequencing (snRNA-seq). In young apoE4-KI mice, we identified region-specific subpopulations of excitatory neurons with hyperexcitability underlain by reduced cell size, which were eliminated by selective removal of neuronal apoE4. Aged apoE4-KI mice showed an increased fraction of hyperexcitable granule cells, a pronounced inhibitory deficit, and E/I imbalance in the dentate gyrus, contributing to network dysfunction. snRNA-seq analysis revealed neuron type-specific and age-dependent transcriptomic changes, identifying Nell2 overexpression in apoE4-KI mice. Reducing Nell2 expression in specific neuronal types of apoE4-KI mice with CRISPRi rescued their morphological and excitability phenotypes, supporting Nell2 overexpression as a cause for apoE4-induced neuronal dysfunction. Our findings highlight the early transcriptomic and morpho-electric alterations behind the apoE4-induced neuronal dysfunction in AD.HIGHLIGHTSApoE4 causes hyperexcitability of select hippocampal neurons in young apoE4 mice.ApoE4 causes dentate hyperexcitability and inhibitory deficit in aged apoE4 mice.snRNA-seq reveals apoE genotype-, cell type-, and age-dependent transcriptomic changes.Nell2 overexpression identified as a cause of apoE4-induced neuronal hyperexcitability.

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Changes in the Public IgM Repertoire and its Idiotypic Connectivity in Alzheimer’s Disease and Frontotemporal Dementia

Pashova-Dimova,

Petrov,

Karachanak-Yankova

et al. 2024

Preprint

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Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are prevalent neurodegenerative disorders. Early diagnosis is challenging due to the lack of definitive biomarkers and reliance on invasive procedures. Immune biomarkers, particularly those reflecting the interaction between the central nervous system (CNS) and the peripheral immune system, have shown promise for non-invasive detection through blood samples. This study investigates the reactivity of serum IgM and IgG from AD and FTD patients against a library of mimotopes representing public IgM reactivities in healthy donors. Serum samples from AD, FTD, and other neurodegenerative dementias (ND), and controls were tested on peptide microarrays. The samples were pooled to mitigate individual variability. The reactivity data were analyzed using graphs to represent the cross-reactivity networks. The analysis revealed distinct reactivity patterns for the studied groups. Public IgM reactivities showed significant correlations with neurodegenerative conditions, with AD and FTD exhibiting loss or gain of specific IgM reactivities. Graph analysis highlighted significant differences in graph density, clustering, and assortativity parameters between disease and control groups. Idiotypic reactivities, particularly in IgM, were more connected in healthy controls compared to those with neurodegenerative diseases. Furthermore, clusters of reactivities showed significant distinctions between AD and FTD, with IgG reactivities providing additional differentiation. A number of self proteins related to neurodegeneration proved to have sequences homologous to disease associated mimotopes. Thus, the public IgM repertoire, characterized by its broad reactivity and inherent autoreactivity, offers valuable insights into the immunological alterations in neurodegenerative diseases. The study supports the potential of IgM and IgG reactivity profiles as another compartment of non-invasive biomarkers for early diagnosis and differentiation of AD and FTD.

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CSF biomarkers of immune activation and Alzheimer’s disease for predicting cognitive impairment risk in the elderly

Cited by 5 publications

References 61 publications

APOE ε4–associated downregulation of the IL‐7/IL‐7R pathway in effector memory T cells: Implications for Alzheimer's disease

APOE ε4–associated downregulation of the IL‐7/IL‐7R pathway in effector memory T cells: Implications for Alzheimer's disease

Neuronal APOE4-induced Early Hippocampal Network Hyperexcitability in Alzheimer’s Disease Pathogenesis

Changes in the Public IgM Repertoire and its Idiotypic Connectivity in Alzheimer’s Disease and Frontotemporal Dementia

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