A Paradigm Shift: Does Herpes Simplex Virus Type 1 Play a Causal Role in the Progression of Late-Onset Alzheimer’s Disease?

In recent years accumulating evidence has suggested a causal role for latent herpes simplex virus type 1 (HSV1) infections of the central nervous system (CNS) in late-onset AD. Epidemiological studies have implicated the combination of latent CNS HSV1, and the major genetic risk factor for late-onset AD, the apolipoprotein E type 4 (APOE ε4) allele, in approximately 60% of late-onset AD cases. The major neuropathological features of AD include amyloid beta (Aβ) plaques and neurofibrillary tangles (NTFs); both have been shown to accumulate in in vitro and in vivo models of HSV1 infection. It has been hypothesized that a persistent mild form of herpes simplex encephalitis (HSE) acting through chronic neuroinflammation and oxidative stress induced recurrent reactivations of latent CNS HSV1, may contribute to the neurite and synaptic degeneration characteristic of AD. This article aims to provide an overview of the impacts of the co-occurrence of HSV1 and APOE ε4 genotype on the incidence of AD, systemic activities controlling latent HSV1 reactivation, molecular mechanisms involved in neuropathophysiology, and the potential for antiviral approaches for the treatment of AD.