Table 1 Selected studies consistent with a contributory role of herpesviral infections to AD.

Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains (Jamieson et al., J Med Virol. 1991 [1])

HSV-1 DNA is present in the brains of the majority of both normal and AD patients.

Herpes simplex virus infection causes cellular β-amyloid accumulation and secretase upregulation (Wozniak et al., Neurosci Lett. 2007 [2])

HSV-1 induces Aβ production and secretion in cultured neuronal and glial cells and wild-type mice by upregulating the Aβ-producing enzymes β-secretase 1 and γ-secretase.

Neuronal cytoskeletal dynamic modification and neurodegeneration induced by infection with herpes simplex virus type 1 (Zambrano et al., J Alzheimers Dis. 2008 [4])

HSV-1 infection causes tau hyperphosphorylation in mouse neuronal cultures.

Herpes simplex virus type 1 DNA is located within Alzheimer’s disease amyloid plaques (Wozniak et al., J Pathol. 2009 [3])

HSV-1 DNA is present in the core of 90% of Aβ plaques in postmortem brains from AD patients, and 72% of HSV-1 DNA in the brain was found within these plaques.

β-Amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1 (Bourgade et al., Biogerontology. 2015 [5])

Aβ inhibits HSV-1 replication and viral entry in cell cultures.

Alzheimer’s disease-associated β-amyloid is rapidly seeded by Herpesviridae to protect against brain infection (Eimer et al., Neuron. 2018 [7])

Amyloid-β plaques form to entrap viruses in 5xFAD mice and are protective against herpes simplex encephalitis in 3D human neural cells.

Multiscale analysis of three independent Alzheimer’s cohorts reveals disruption of molecular, genetic, and clinical networks by Human herpesvirus (Readhead et al., Neuron. 2018 [9])

Increased HSV-1, HHV-6A, and HHV-7 viral RNA levels detected in postmortem brain samples of AD patients relative to controls. Herpesviruses predicted to modulate the expression of known AD-related genes.

The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease (Hur et al., Nature. 2020 [15])

Interferon-γ treatment induced Aβ production in mouse neural cultures. IFITM3, a target of interferon signaling, physically interacts with γ-secretase and IFITM3 knockout impairs Aβ production in 5xFAD mice.

A 3D human brain-like tissue model of herpes-induced Alzheimer’s disease (Cairns et al., Sci Adv. 2020 [13])

HSV-1 infection of a 3D brain tissue model led to the formation of Aβ plaque-like structures, tau hyperphosphorylation, astrogliosis, neuroinflammation, and disrupted neuronal electrical activity. The antiherpetic drug valacyclovir prevented these changes.

Interaction between APOE4 and herpes simplex virus type 1 in Alzheimer’s disease (Linard et al., Alzheimers Dement. 2020 [21])

APOE4 carriers with recent HSV-1 reactivation (IgG+ and IgM+, or elevated IgG) developed AD at about 3× the rate of those merely infected with HSV-1 (IgG+); APOE4 noncarriers showed no such association. This indicates a gene-by-environment interaction between APOE4 and HSV-1 reactivation on AD risk.