Overwhelming Evidence for a Major Role for Herpes Simplex Virus Type 1 (HSV1) in Alzheimer’s Disease (AD); Underwhelming Evidence against

Abstract

This review describes investigations of specific topics that lie within the general subject of HSV1’s role in AD/dementia, published in the last couple of years. They include studies on the following: relationship of HSV1 to AD using neural stem cells; the apparent protective effects of treatment of HSV1 infection or of VZV infection with antivirals prior to the onset of dementia; the putative involvement of VZV in AD/dementia; the possible role of human herpes virus 6 (HHV6) in AD; the seemingly reduced risk of dementia after vaccination with diverse types of vaccine, and the association shown in some vaccine studies with reduced frequency of HSV1 reactivation; anti-HSV serum antibodies supporting the linkage of HSV1 in brain with AD in APOE-ε4 carriers, and the association between APOE and cognition, and association of APOE and infection with AD/dementia. The conclusions are that there is now overwhelming evidence for HSV1’s role—probably causal—in AD, when it is present in brain of APOE-ε4 carriers, and that further investigations should be made on possible prevention of the disease by vaccination, or by prolonged antiviral treatment of HSV1 infection in APOE-ε4 carriers, before disease onset.

The Role of Exposomes in the Pathophysiology of Autoimmune Diseases II: Pathogens

“…Autoimmune encephalitis HSV Molecular mimicry [213] Encephalitis (Human herpes encephalitis) HSV Molecular mimicry [214] Encephalitis and chronic neurological sequelae HSV Molecular mimicry? [215] Stromal keratitis HSV Bystander activation [216] Alzheimer's HSV Unknown [217] Multiple sclerosis VZV Unknown [218] Lupus erythematosus EBV Molecular mimicry [164] Autoimmune hepatitis EBV Molecular mimicry; Persistence of EBV in B cell [219,220] Graves' disease EBV EBV B-cell activation [221] Hashimoto's disease EBV Unknown [222] Multiple sclerosis EBV Molecular mimicry; Molecular mimicry; Activation of Th1, Th17, Th1/Th17 [176,223,224] Rheumatoid arthritis EBV Molecular mimicry [225] Sjögren's syndrome EBV B cell activation [220] Systemic sclerosis CMV Molecular mimicry; Induction of inflammation [226,227] Type 1 diabetes mellitus CMV Unknown [172] Systemic lupus erythematosus CMV Epitope spreading [209] Rheumatoid arthritis CMV Aggravation of inflammation [228] Endothelial cell autoimmunity CMV Molecular mimicry [229] Autoimmune thyroiditis HHV-6A NK cell killing of HHV-6 infected thyrocytes [230] Multiple sclerosis HHV-6A/6B; HHV-6…”

Key questions on the epigenetics of herpes simplex virus latency

“…Understanding how cellular epigenetic marks differ on latent HSV genomes between individuals could be important for understanding how HSV latency and reactivation can be heterogenous within a population and may result in more severe clinical phenotypes in certain individuals [ 25 ]. Numerous studies have linked HSV infection with the development of late onset Alzheimer disease, especially in individuals with the ApoE4 variant [ 25 – 27 ]. Recent evidence suggests that reactivation from latency occurs in waves [ 28 , 29 ], with the first wave being potentially reversible, raising the possibility of abortive reactivation events [ 30 ].…”

Bacillus Calmette–Guérin in Immuno-Regulation of Alzheimer’s Disease

“…In this framework BCG is an "Old Friend" which compensates for this "loss." Without "Old Friends, " pathogens such as herpes and Porphyromonas gingivalis can become risk factors of AD (Singhrao and Olsen, 2018;Itzhaki, 2021). Interestingly BCG has been reported to neutralize both the herpes virus and the periodontal bacterium (Hippmann et al, 1992;Kato and Mikami, 2011).…”