It’s as if herpes were trying to push corona out of the limelight—it keeps popping up in the news. At the virtual AD/PD 2021 conference, Morgane Linard, University of Bordeaux, France, linked brain-tissue changes and a higher Alzheimer’s disease incidence to herpes simplex virus (HSV) infection, with ApoE4 carriers doing worse. Also at the meeting, Oliver Goldhardt, Technical University of Munich, tied AD biomarkers in the cerebrospinal fluid to herpes infection. Both teams measured herpes infection by detecting anti-HSV immunoglobulin G (IgG) in participants’ blood or CSF.

  • Herpes infection bumped AD risk 2.7-fold in ApoE4 carriers.
  • Links reported to white-matter damage, shrunken hippocampus.
  • Anti-herpes antibodies tied to CSF phospho-tau in mild AD.

These new studies join a growing list linking herpes infection to AD (Feb 2021 news; Jan 2021 news). The risk of memory decline and AD was higher in infected ApoE4 than ApoE3 or E2 carriers (Lövheim et al., 2019; Lopatko Lindman et al., 2019). 

How about populations in France? Last year, Linard and colleagues saw much the same when they calculated the 10-year risk of developing AD in 1,037 people 65 or older from the long-standing Three-City cohort, of whom 178 had at least one ApoE4 allele (3C Study Group, 2003). ApoE4 carriers who had had frequent herpes flare-ups, as measured by higher anti-HSV antibody titers in their blood, were 3.3 to 3.7 times more likely to develop AD, whereas the risk in noncarriers was unaffected by herpes infection (Linard et al., 2020). 

In her AD/PD presentation, Linard reported on the continuation of this work. Her team is probing whether herpes infection or ApoE status were associated with brain-tissue changes in old age. The scientists initially gathered data on 2,104 participants over 65 from the Bordeaux 3C cohort and 1,002 from the AMI cohort, a longitudinal study on elderly French farmers in rural areas (Pérès et al., 2012). Of those, they chose 1,599 on whom the study had collected both HSV serology and AD incidence data; 438 of those had had MRI scans. Half were women, 288 carried at least one ApoE4 allele, and the mean age was 77 years. The researchers corrected for confounding factors, such as age, sex, years of education, marital status, and cardiovascular risk factors.

Eighty-three percent of participants were infected with herpes, measured by the presence of HSV antibodies in the blood. Over an average follow-up time of 6.8 years, 293 participants developed dementia, of which 222 cases were AD.

Did herpes infection influence dementia development? In participants without an ApoE4 allele, it did not, Linard reported. However, infected ApoE4 carriers were 2.7-times more likely to develop AD than uninfected carriers. The risk correlated with antibody titers: Those with the lowest IgG concentrations were about twice as likely to develop AD, those with the highest IgG, four times as likely. Linard suspects that higher HSV antibody titers reflect more frequent viral reactivations over time.

What about brain tissue? The researchers extracted hippocampal volume in the scans of 330 participants, of whom 69 were ApoE4 carriers. Herpes infection itself did not affect hippocampal volume; however, the hippocampi of people with the highest herpes antibody titers were 1 percent smaller on average compared to the uninfected. This difference doubled in infected ApoE4 carriers compared to uninfected carriers, but hippocampal volume differs so much from person to person that this group difference was not statistically significant in this small sample. The scientists saw no links between herpes infection and hippocampal volume in noncarriers.

Linard and colleagues then checked the brain’s white matter. They used 243 participants in whom they had diffusion tensor imaging. DTI is an MRI method that tracks the direction and speed of water molecules moving through tissue as an indicator of the tissue’s microstructural integrity. Healthy white matter has high fractional anisotropy, a measurement of water molecules flowing along white-matter tracts, and low diffusivity, a measurement of the speed of water molecules diffusing locally. Compared to uninfected people, those with herpes infection had reduced fractional anisotropy and increased diffusivity in the cingulum and fornix, two axon bundles near the hippocampus.

DTI interpretation can be controversial (Wheeler-Kingshott et al., 2009). Still, Linard concluded from her data that infected people may have weakened white matter and she suspects that high diffusivity indicates neuronal damage. Participants’ herpes antibody titers did not track with DTI alterations, nor did their ApoE4 status.

If herpes simplex virus can distort brain tissue, does infection correlate with markers of brain damage in the CSF? At AD/PD, Goldhardt, of TU Munich, addressed this question using data from 117 older people with mild cognitive impairment or early AD, of whom 92 had herpes IgG antibodies in their CSF and 25 did not. The researchers measured Aβ40, Aβ42, the Aβ42/40 ratio, total tau, and p-tau in the participants’ CSF.

None of these biomarkers were different in infected people as a group versus uninfected people as a group. However, Goldhardt proposed that the ratio of herpes antibody titers in the CSF versus in the serum may be a way to gauge herpes virus activity in the central nervous system. A higher ratio would indicate more herpes antibodies in the CSF, possibly meaning more viral activity in the CNS than the periphery. Indeed, higher CSF-to-serum antibody ratios correlated with higher total tau and p-tau in the CSF. High CSF p-tau has previously been seen in older people with herpes encephalitis (Krut et al., 2013). 

The presence of brain amyloid influenced the p-tau/herpes antibody correlation. CSF p-tau and CSF-to-serum anti-herpes IgG ratio tracked closely in people who had lower Aβ42/40 ratios, while this correlation was absent in those with higher ratios. “The association of CSF p-tau and herpes antibody ratio is weakened by higher Aβ42/40, which supports the idea that Aβ inhibits HSV,” Goldhardt wrote to Alzforum.

Previous cell-culture studies show that adding Aβ40 and Aβ42 to fibroblasts and neuronal cells muted HSV infection (Bourgade et al., 2015; Bourgade et al., 2016). In a mouse model of amyloidosis, some—but not all—studies have painted Aβ as protective against herpes infection (Jun 2018 news; Jan 2021 news). 

Goldhardt hypothesized that HSV may more easily reactivate in people with AD pathology because they may have less soluble amyloid. Viral reactivation prompts a p-tau spike in the brain, perhaps reflecting a cycle of p-tau aggregation and inflammation. “I am not saying that HSV causes sporadic AD—we need herpes vaccination trials to clarify that,” Goldhardt noted in his presentation. Several treatment trials of valacyclovir are ongoing.—Chelsea Weidman Burke


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News Citations

  1. Herpes Update—Virus Increases Dementia Risk in Sweden
  2. New Data Questions Herpes-Alzheimer’s Connection
  3. Herpes Triggers Amyloid—Could This Virus Fuel Alzheimer’s?
  4. New Data Question Anti-Microbial Powers of Aβ

Therapeutics Citations

  1. Valacyclovir

Paper Citations

  1. . Herpes Simplex Virus, APOEɛ4, and Cognitive Decline in Old Age: Results from the Betula Cohort Study. J Alzheimers Dis. 2019;67(1):211-220. PubMed.
  2. . A genetic signature including apolipoprotein Eε4 potentiates the risk of herpes simplex-associated Alzheimer's disease. Alzheimers Dement (N Y). 2019;5:697-704. Epub 2019 Nov 4 PubMed.
  3. . Vascular factors and risk of dementia: design of the Three-City Study and baseline characteristics of the study population. Neuroepidemiology. 2003 Nov-Dec;22(6):316-25. PubMed.
  4. . Interaction between APOE4 and herpes simplex virus type 1 in Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):200-208. PubMed.
  5. . Health and aging in elderly farmers: the AMI cohort. BMC Public Health. 2012 Jul 27;12:558. PubMed.
  6. . About "axial" and "radial" diffusivities. Magn Reson Med. 2009 May;61(5):1255-60. PubMed.
  7. . Cerebrospinal fluid Alzheimer's biomarker profiles in CNS infections. J Neurol. 2013 Feb;260(2):620-6. Epub 2012 Oct 9 PubMed.
  8. . β-Amyloid peptides display protective activity against the human Alzheimer's disease-associated herpes simplex virus-1. Biogerontology. 2015 Feb;16(1):85-98. Epub 2014 Nov 7 PubMed.
  9. . Protective Effect of Amyloid-β Peptides Against Herpes Simplex Virus-1 Infection in a Neuronal Cell Culture Model. J Alzheimers Dis. 2016;50(4):1227-41. PubMed.

Further Reading

Primary Papers

  1. . Herpes simplex virus, early neuroimaging markers and incidence of Alzheimer's disease. Transl Psychiatry. 2021 Jul 31;11(1):414. PubMed.