Virus exposure and neurodegenerative disease risk across national biobanks

Abstract

BACKGROUND With recent findings connecting Epstein-Barr virus to increased risk of multiple sclerosis and growing concerns regarding the potential neurological impact of the coronavirus pandemic, we surveyed biobank scale real-world data to identify potential links between viral exposures and neurodegenerative disease risks. METHODS To assess the potential increased risk of neurodegenerative diseases due to viral exposures, we mined time series data from FinnGen as a discovery dataset and cross-sectional data from the UK Biobank as a replication dataset for 73 pairs of common viral exposures and neurodegenerative disease outcomes. We investigated the impact of time span between viral exposure and disease risk using time series data from FinnGen at 1, 5, and 15 year intervals between exposure and disease onset. This analysis helped us to avoid the potential confounding of concurrent diagnosis due to hospitalization with viral infection. Further, to address the possible bias of reverse causality we examined risk for severe viral infections after NDD diagnosis. RESULTS We identified 45 viral exposures significantly associated with increased risk of post-exposure neurodegenerative disease onset after multiple test correction in the discovery phase using longitudinal data. 22 of these associations were replicated in cross sectional data from the UK Biobank. The largest effect association we saw replicated was between viral encephalitis exposure and Alzheimer's disease, with discovery hazard estimates of ~30 and a replication odds ratio of ~22. We also replicated the association between Epstein-Barr virus exposure and multiple sclerosis 5-15 years before diagnosis of multiple sclerosis. In total, 17 virus/neurodegeneration pairs were significant with 5-15 years between viral exposure and NDD diagnosis. In an investigation of potential confounding and reverse causality, we generally see larger hazard ratios associated with viruses preceding NDD diagnosis than viruses post NDD diagnosis. CONCLUSIONS Viral exposures contribute to later in life risk of neurodegenerative disease with increased risk of neurodegeneration still significant at up to 15 years between some events in this report.

An FDA-Approved Assay Platform Can Detect Biomarkers of Neuronal and Glial Injury in the Blood of COVID-19 Patients

“…Since the same assays used in this study could potentially detect neuronal and glial cell injury from infections by any systemic pathogens, this research can provide urgently needed technology to diagnose currently unrecognized increased risks for neurodegenerative diseases from numerous other infections. 36,37,56 SARS-CoV-2 can also potentially result in opportunistic infections by other neurotropic viruses such as the human herpes virus which has been reported in 79% of severe COVID-19 patients. 57 Thus, it could be important to screen for other neurotropic pathogens in COVID-19 patients with neurological deficits.…”

Oxidized MIF is an Alzheimer’s Disease drug target relaying external risk factors to tau pathology

“…4. The long-known epidemiological association between latent herpes virus reactivation and AD (Allnutt et al, 2020; Itzhaki et al, 2020; Lovheim et al, 2015; Readhead et al, 2018; Tzeng et al, 2018) (Allnutt et al, 2020; Itzhaki et al, 2020; Levine et al, 2023; Lovheim et al, 2015; Readhead et al, 2018; Tzeng et al, 2018) are opposed by much fewer studies unable to find this association in different cohorts (Murphy et al, 2021; Warren-Gash et al, 2022). The molecular mechanism of potentially triggering effects of herpes virus activation have remained unexplained, even though several molecular scenarios have been proposed such as a role for Aβ as a cellular defense (Eimer et al, 2018) or an interference of herpes virus with autophagy (Cirone, 2018; Orvedahl et al, 2007).…”

“…Among those risk factors are such diverse conditions as obesity, diabetes, trauma, chronic infections, inflammation or immune activations (Arnold et al, 2018; Itzhaki et al, 2020). Although known not to cause neurodegenerative diseases directly, the subchronic exposure to neurotropic viruses has been associated to the occurrence to, for example, Parkinson’s disease (PD) for influenza virus (Marreiros et al, 2020), Alzheimer’s disease (AD) for herpes viruses (Itzhaki et al, 1997), or others (Levine et al, 2023). Either direct effects of the virus on host factors also involved in critical molecular mechanisms of neurodegeneration or indirect effects of the virus through immune activation or its elicited cellular responses, are conceivable.…”