May 26, 2024

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Is herpes virus the cause of Alzheimer’s disease?

Is herpes virus the cause of Alzheimer’s disease?


Neurology: Is herpes virus the cause of Alzheimer’s disease?

Regarding the etiology of Alzheimer’s disease (AD), the current mainstream view is that abnormal deposition of amyloid-beta and hyperphosphorylation of tau protein synergistically lead to neuronal death, but with the development of drugs targeting amyloid-beta in clinical trials One by one, scientists have also tried to find the cause of AD from different perspectives.

Among them, the herpes virus seems to “stand out” [1].


Preclinical studies have shown that β-amyloid has similar or even higher antibacterial ability to antimicrobial peptides [2], providing strong evidence for the hypothesis that infection causes AD.

In animal studies, multiple groups have reported that herpesvirus infection increases the risk of dementia [3, 4].

At the same time, multiple large-scale cohort studies have also shown that herpesvirus infection is associated with an increased risk of dementia, while those receiving antiviral therapy have a reduced risk of dementia [5-7].

However, there are also many studies that do not support the conclusion that there is a correlation between herpes virus infection and dementia [8, 9], and we still know little about the impact of herpes virus infection on brain structure and brain cognition.


To investigate this question, Professor Keenan A.  Walker’s team from the National Institute on Aging analyzed longitudinal MRI data from participants in the Baltimore Longitudinal Study of Aging (BLSA) and found that a diagnosis of symptomatic human herpesvirus (sHHV, a Symptoms and diagnosis, including varicella-zoster virus, herpes simplex virus-1, or herpes simplex virus-2) infection is associated with decreased total white matter volume, especially in the temporal lobe, and occipital white matter reduction with antiviral therapy volume reduction .


At the same time, the researchers also found that although the sHHV group had higher cognitive scores at baseline, sHHV infection was associated with a year-on-year decline in attention span.

Furthermore, sHHV infection was associated with elevated plasma GFAP (reactive astrogliosis biomarker) , but not with Aβ42/40 (AD biomarker) and NfL (neurodegeneration biomarker) levels .


These findings suggest that although sHHV infection is associated with multiple neurocognitive features, such as white matter volume, attention, and astrocytosis, they do not suggest a specific link between sHHV infection and AD In the famous journal “Neurology” [10].


Is herpes virus the cause of Alzheimer's disease?



Data for the study came from the BLSA, a longitudinal study conducted in Baltimore to assess the physical and cognitive functioning of participants in the community.

A total of 1009 participants (mean age, 65.7 years, 54.8% female) were included in the study , who underwent MRI and cognitive function tests at an average of 3.4 and 8.6 years .


The primary objective of the study was to assess the relationship between sHHV infection and regional brain volume obtained from MRI, in addition to sHHV infection and cognitive function (attention, executive function, verbal fluency, verbal memory, and visuospatial abilities) and multiple correlation of biomarkers.


Is herpes virus the cause of Alzheimer's disease?Research flow chart


The 1009 participants were followed up for an average of 3.4 years, and a total of 119 participants were diagnosed with sHHV infection, of which 82 (68.9%) had varicella-zoster virus infection, and 37 (31.1%) had varicella-zoster virus infection. For HSV 1/2 infection, 30 (25.2%) received antiviral therapy.


At baseline, there was no significant difference in brain volume between participants in the sHHV-infected and non-sHHV-infected groups.

However, sHHV infection was associated with an accelerated decline in participants’ total white matter volume (-0.34 cm³ /year, p=0.035), most notably in temporal white matter volume (-0.08 cm³/year, p=0.034) .

For total brain volume, total gray matter volume, and AD characteristic volume, no correlation was found with the diagnosis of sHHV infection.



The researchers also found that in sHHV-infected participants, receiving antiviral therapy was associated with a slower decline in occipital white matter volume (p=0.036) .


Is herpes virus the cause of Alzheimer's disease?Relationship between sHHV infection and longitudinal changes in brain volume


These results are consistent with previous studies showing that HHV primarily affects the white matter of the brain, especially in the temporal lobe [11].


Next, the researchers assessed the link between sHHV infection and changes in cognitive function.

At baseline, the sHHV-infected group had better performance in attention, executive function, and verbal memory compared to the non-sHHV-infected group, but it had a greater decrease in longitudinal changes in attention (-0.01 Z-score /year, p=0.008), and this effect was stronger in younger participants .

No correlation was found between sHHV infection and other cognitive function changes.



Among sHHV-infected participants, antiviral treatment was not associated with changes in participants’ future cognitive function.


Is herpes virus the cause of Alzheimer's disease?Relationship between sHHV infection and longitudinal changes in cognitive function


Finally, we assessed the relationship between sHHV infection and AD markers Aβ42/40, reactive astrogliosis markers (GFAP), and neurodegeneration biomarkers (NfL).

The study showed that compared with non-sHHV-infected participants, sHHV-infected participants had higher GFAP levels (p=0.008), while Aβ42/40 and NfL were not significantly different between the two groups . At the same time, receiving antiviral therapy was not associated with biomarker levels.


Comparison of biomarker levels in patients with sHHV infection and those without sHHV infection


Overall, this study demonstrated that sHHV infection still has a certain impact on brain structure and cognitive function, with decreased white matter volume and attention, and increased plasma GFAP levels in sHHV-infected patients.

However, the results of this study do not support a direct relationship between sHHV infection and AD , and the longitudinal changes in total brain volume, gray matter volume, memory function, and Aβ42/40 ratio in sHHV-infected patients were not significantly different from those without sHHV infection.



The pathogenesis of AD is complex, and it is clear that the existing evidence cannot prove a direct causal relationship between sHHV and AD.

But in theory, inflammation caused by viral infection could synergize with other actions to cause neuronal death , and antiviral therapy has also been reported to reduce the risk of dementia.



But another real problem is that the infection rate of herpes virus is too high. 

There are not many people in the world who have not been infected with herpes virus, and there are too many types of herpes virus.

Do any of these subtypes have What about a higher risk of AD? This is also a question worth exploring.



Studies have shown that two herpesvirus subtypes, HHV-6A and HHV-7, are commonly found at high levels in the brains of AD patients, especially HHV-6A, which can participate in the regulation of host AD risk genes, such as BACE1, APBB2, etc. [7] .

After the classification of herpes virus subtypes, it seems necessary to study the relationship between the two, however, such studies are still rare.

Therefore, more and more in-depth studies are needed to reveal the relationship between herpes virus and AD.



Although the study did not reach the expected conclusions, it represents the efforts of the scientific community to explore the pathogenesis of AD in order to find a more effective way to treat AD.

It is hoped that one day, all AD patients can remember to go home The road, recalling every beautiful moment in life.










1. Tzeng NS, Chung CH, Lin FH, Chiang CP, Yeh CB, Huang SY, Lu RB, Chang HA, Kao YC, Yeh HW et al: Anti-herpetic Medications and Reduced Risk of Dementia in Patients with Herpes Simplex Virus Infections -a Nationwide, Population-Based Cohort Study in Taiwan. Neurotherapeutics 2018, 15(2):417-429.

2. Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, Lefkowitz A, McColl G, Goldstein LE, Tanzi RE et al: Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease . Sci Transl Med 2016, 8(340):340ra372.

3. Duggan MR, Torkzaban B, Ahooyi TM, Khalili K: Potential Role for Herpesviruses in Alzheimer’s Disease. J Alzheimers Dis 2020, 78(3):855-869.

4. Linard M, Baillet M, Letenneur L, Garrigue I, Catheline G, Dartigues JF, Peres K, Helmer C: Herpes simplex virus, early neuroimaging markers and incidence of Alzheimer’s disease. Transl Psychiatry 2021, 11(1):414.

5. Lopatko Lindman K, Hemmingsson ES, Weidung B, Brannstrom J, Josefsson M, Olsson J, Elgh F, Nordstrom P, Lovheim H: Herpesvirus infections, antiviral treatment, and the risk of dementia-a registry-based cohort study in Sweden . Alzheimers Dement (NY) 2021, 7(1):e12119.

6. Schnier C, Janbek J, Williams L, Wilkinson T, Laursen TM, Waldemar G, Richter H, Kostev K, Lathe R, J GH: Antiherpetic medication and incident dementia: Observational cohort studies in four countries. Eur J Neurol 2021, 28(6):1840-1848.

7. Readhead B, Haure-Mirande JV, Funk CC, Richards MA, Shannon P, Haroutunian V, Sano M, Liang WS, Beckmann ND, Price ND et al: Multiscale Analysis of Independent Alzheimer’s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus. Neuron 2018, 99(1):64-82 e67.

8. Allnutt MA, Johnson K, Bennett DA, Connor SM, Troncoso JC, Pletnikova O, Albert MS, Resnick SM, Scholz SW, De Jager PL et al: Human Herpesvirus 6 Detection in Alzheimer’s Disease Cases and Controls across Multiple Cohorts. Neuron 2020, 105(6):1027-1035e1022.

9. Kwok MK, Schooling CM: Herpes simplex virus and Alzheimer’s disease: a Mendelian randomization study. Neurobiol Aging 2021, 99:101 e111-101 e113.

10. Duggan MR, Peng Z, An Y, Kitner Triolo MH, Shafer AT, Davatzikos C, Erus G, Karikkineth A, Lewis A, Moghekar A et al: Herpes Viruses in the Baltimore Longitudinal Study of Aging: Associations With Brain Volumes, Cognitive Performance, and Plasma Biomarkers. Neurology 2022.

11. Boukhvalova MS, Mortensen E, Mbaye A, Lopez D, Kastrukoff L, Blanco JCG: Herpes Simplex Virus 1 Induces Brain Inflammation and Multifocal Demyelination in the Cotton Rat Sigmodon hispidus. J Virol 2019, 94(1).

Is herpes virus the cause of Alzheimer’s disease?

(source:internet, reference only)

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