Interpreting Viral Associations in Neurodegenerative Diseases

Viral infections have been associated with multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), but the associations may reflect different relationships to the disease process. This review evaluates evidence for viral involvement in disease initiation, modification of established disease, impaired viral control secondary to disease or treatment, and incidental detection. The strongest temporal evidence concerns Epstein-Barr virus (EBV) and MS. Prospective data place EBV seroconversion before clinical onset and the first observed increase in serum neurofilament light chain, while mechanistic studies link EBV infection, B-cell biology, and CNS-directed immunity. However, evidence that ongoing EBV activity modifies established MS remains limited. In AD, experimental studies support interactions between herpesviruses and AD-associated proteins, while the reduced incidence of all-cause dementia after herpes zoster vaccination suggests that viral or immunological pathways may be modifiable, without establishing that a specific herpesvirus initiates AD. Viral associations in PD rely mainly on epidemiological, experimental, and postmortem findings. Human pegivirus detection in a subset of PD brains remains a candidate association requiring independent confirmation and evidence of biological activity. Evidence in ALS is similarly limited. Enterovirus detection has been inconsistent, and altered human endogenous retrovirus K (HERV-K) expression in postmortem tissue does not establish an acquired viral infection. Stronger inference across these diseases will require longitudinal studies relating viral activity and antiviral immunity to subsequent disease-related changes, together with intervention studies that document the intended effect on the implicated viral process and separately assess subsequent disease risk or progression.