Search

INTRODUCTION: Altered immune signatures are emerging as a central theme in neurodegenerative disease, yet little is known about immune responses in early‐onset Alzheimer's disease (EOAD). METHODS: We examined single‐cell RNA‐sequencing (scRNA‐seq) data from peripheral blood mononuclear cells (PBMCs) and droplet digital polymerase chain reaction (ddPCR) data from CD4 T cells from participants with EOAD and clinically normal controls. RESULTS: We analyzed PBMCs from 16 individuals by scRNA‐seq and discovered increased interferon signaling‐associated gene (ISAG) expression and striking expansion of antiviral‐like ISAGhi T cells in EOAD. Isolating CD4 T cells from 19 individuals, including four cases analyzed by scRNA‐seq, we confirmed increased expression of ISAGhi marker genes. Publicly available cerebrospinal fluid leukocyte scRNA‐seq data from late‐onset mild cognitive impairment and AD also revealed increased expression of interferon‐response genes. DISCUSSION: Antiviral‐like ISAGhi T cells are expanded in EOAD. Additional research into these cells and the role of heightened peripheral IFN signaling in neurodegeneration is warranted. Highlights: Interferon‐responsive T cells expanded in early‐onset Alzheimer's disease (AD).Increased interferon‐associated gene expression present in early‐ and late‐onset AD.Peripheral immune changes in T and NK cells driven by females with early‐onset AD. [ABSTRACT FROM AUTHOR]

Background: Cross‐sectional studies suggest a limited but promising relationship between epigenetic clocks, estimated using DNA methylation patterns, and Alzheimer's disease (AD) pathophysiology and risk. However, prior analyses did not utilize longitudinal analyses or neuroimaging biomarkers of AD. Herein, we employed survival and structural neuroimaging analyses to test the hypothesis that DNA methylation age predicts AD progression. Method: Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we calculated two established epigenetic ages, 'DNAmPhenoAge' and 'DNAmGrimAge' which proxy biologic age and mortality risk, respectively. Using Cox proportional hazard regression analysis in normal controls (NC), we tested whether DNAmPhenoAge/DNAmGrimAge associated with progression to mild cognitive impairment (MCI) or AD. Structural magnetic resonance (MR) images were segmented using Freesurfer 5.1 and a previously described white matter hyperintensity (WMH) quantification pipeline. Multiple regression analysis was used to test whether DNAmPhenoAge/DNAmGrimAge predicted WMH volumes and cortical atrophy. Result: Replicating prior work, we found no significant differences in DNAmPhenoAge and DNAmGrimAge between NC (n = 128), MCI (n = 251), and AD (n = 50) diagnoses. Strikingly, however, in NC participants, both DNAmPhenoAge (p = 0.004) and DNAmGrimAge (p = 0.05) associated with progression to MCI or AD (Figure 1). Even after correction for chronologic age, DNAmPhenoAge remained significantly associated with progression to MCI or AD (p = 0.01). Utilizing samples from across the spectrum of normal aging to AD, DNAmPhenoAge and DNAmGrimAge strongly associated with WMH in all diagnoses (Table 1). Moreover, DNAmPhenoAge remained significantly associated with WMH in select groups after correction for chronologic age (Table 1). Finally, both DNAmPhenoAge and DNAmGrimAge predicted cortical thickness in multiple AD‐relevant regions (Figure 2). Conclusion: In contrast to earlier work suggesting limited applicability of blood‐based DNA methylation scores in the context of AD, our novel survival and neuroimaging analyses have revealed the broad utility of second‐generation epigenetic clocks not only in predicting progression to MCI and AD but also via their association with neuroimaging biomarkers of AD, including white matter disease burden and cortical atrophy in AD‐relevant regions. Easily accessible, blood‐based measures of biologic age therefore represent promising predictors of AD risk and pathophysiology. [ABSTRACT FROM AUTHOR]