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Annals of Medicine and Surgery logoLink to Annals of Medicine and Surgery
. 2023 Jul 26;85(10):5060–5074. doi: 10.1097/MS9.0000000000000951

Herpes simplex virus infection and the risk of dementia: a systematic review and meta-analysis

Rowan H Elhalag a, Karam R Motawea a, Nesreen E Talat a, Samah S Rouzan a, Nada Mahmoud a, Elsayed M Hammad a, Sarraa M Reyad a, Mai S Mohamed a, Jaffer Shah b,*
PMCID: PMC10552998  PMID: 37811098

Abstract

Aim:

The authors aimed to perform a meta-analysis to evaluate the association between herpes simplex virus (HSV) infection and the risk of developing dementia.

Methods:

The authors searched the following databases: PubMed, Scopus, Cochrane Library, and Web of Science. The authors included any randomized control trials and controlled observational studies that investigated the prevalence of dementia in HSV-infected patients and HSV-free control group. Also, if the studies measured the levels of HSV antibodies and incidence of these antibodies in patients with dementia compared with a healthy control group.

Results:

After a comprehensive literature search, 19 studies were included in the meta-analysis with 342 535 patients included in the analysis. The pooled analysis showed a statistically significant association between Alzheimer’s disease (AD), mild cognitive impairment (MCI), and increased levels of IgG titer group [mean difference (MD) = 0.99, 95% confidence interval (CI) = 0.36–1.63, P-value = 0.002], (MD = 0.80, 95% CI = 0.26–1.35, P-value = 0.004), respectively. Additionally, the generic inverse variance showed a statistically significant association between the HSV group and increased incidence of dementia compared with the no HSV control group [risk ratio (RR) = 2.23, 95% CI = 1.18–2.29, P-value <0.00001]. Moreover, this analysis showed no statistically significant difference between the AD group and the control group in anti-HSV IgM titer n (%) outcome (RR = 1.35, 95% CI = 0.91–2.01, P-value = 0.14), respectively.

Conclusion:

This study revealed that AD and MCI patients have increased levels of IgG antibodies titer against HSV infection. The study showed a significant association between HSV infection and increased incidence of dementia. Thus, regular follow-up of HSV patients’ IgG titer levels could be useful in the prevention of dementia in these patients.

Keywords: AD, dementia, HSV, MCI, meta-analysis

Introduction

Highlights

  • We aimed to perform a meta-analysis to evaluate the association between herpes simplex virus (HSV) infection and the risk of developing dementia.

  • The pooled analysis showed a statistically significant association between Alzheimer’s disease (AD), mild cognitive impairment (MCI), and increased levels of IgG titer, respectively. Additionally, the generic inverse variance showed a statistically significant association between HSV group and increased incidence of dementia compared with no HSV control group.

  • Our study revealed that AD and MCI patients have increased levels of IgG antibodies titer against HSV infection. The study showed a significant association between HSV infection and increased incidence of dementia. Thus, regular follow-up of HSV patients IgG titer levels could be useful in prevention of dementia in these patients.

Dementia is described by the World Health Organization and Alzheimer’s Disease International as ‘a syndrome that results from a brain disease – mostly chronic or progressive in nature – in which there is multiple higher cortical functions disturbance, including memory, thinking, comprehension, orientation, calculation, language, learning capacity, and judgment’1. According to statistics from the World Health Organization, dementia is the main cause of dependency and disability among older people globally and the largest contributor to disease burden in advanced market economies1. Currently, 5% of adults over 65 years have dementia, and that number rises to nearly 50% for those over 901. More than 90% of dementia cases present after the age of 65, making aging the most significant risk factor for dementia. The incidence and prevalence of dementia continue to rise progressively over the world as the average population age rises2. According to the World Alzheimer Report, a thorough meta-analysis of population-based studies, there are currently 46.8 million dementia sufferers worldwide, and that number is predicted to rise to 131.5 million by the year 20503. By 2030, it is expected that the total cost of dementia-related medical expenses and lost wages, which is currently $81 billion (USD) annually, will reach $2 trillion3. An intervention that delayed dementia onset by 5 years in the USA alone would save Medicare costs by $283 billion in the year 20504.

Alzheimer’s disease (AD), vascular dementia (VaD), frontotemporal dementia and associated syndromes, Lewy body dementias, and prion disorders are the most prevalent dementia subtypes2. Up to 80% of dementia diagnoses are due to AD, which is by far the most frequent cause of dementia5. Between 2000 and 2014, there was an 89% increase in mortality attributed to AD6. The estimated yearly cost of healthcare linked to AD, including direct and indirect costs, is close to $500 billion7.

Mild cognitive impairment (MCI) is subjective and objective deterioration in cognition and function that does not fulfill the criteria for a diagnosis of dementia but is higher than what would be expected given an individual’s age and level of education8–10. Thus, it represents the preclinical, transitional stage between healthy aging and dementia11. Around 10–15% of those with amnestic MCI develop AD annually, as opposed to 1–2% of the population of healthy older adults8,12. Histopathologically, AD is distinguished by two features, the presence of intracellular neurofibrillary tangles (NFT), consisting of hyperphosphorylated aggregates of the microtubule-associated protein tau, and extracellular amyloid plaques, consisting of an amyloid beta (Aβ) protein core13; however, both MCI and AD pathogenesis show early cognitive changes14. Researchers and physicians consider MCI as a ‘window’ in which it may be feasible to intervene and prevent the progression to dementia11.

Herpes simplex virus (HSV) type 1 and type 2 are human neurotropic, host-adapted viruses that can cause both lytic and latent infections15, and infect a relatively large portion of the human population with rates of seropositivity for HSV-1 and HSV-2 being in the order of 67% and 11%, respectively16,17. Although the precise causes of dementia are not known, immunity and inflammation have been suggested as potential development pathways for this illness18. HSV-1 is a potential pathogen for raising the risk of dementia since it is a neuroinvasive and neurotoxic virus that can reach the brain through peripheral nerves19,20. Moir et al. explained HSV-1’s potential role in dementia development by triggering an innate immunological response that causes Aβ formation18, which results in Aβ accumulation causing neuroinflammation. Chronic inflammation causes brain cell destruction (neurodegeneration), which may eventually cause dementia. However, some recent studies found that HSV could be a substantial risk factor for AD21–24; additionally, they discovered that using antiherpetic drugs cut the risk by roughly 90%24, other studies did not detect a link between HSV infection and an elevated risk of dementia25.

Due to this conflict in results, we aimed to perform a meta-analysis to evaluate the association between HSV infection and the risk of developing dementia.

Methods

The Cochrane Handbook of Systematic Reviews26, the PRISMA (Preferred Reporting Items of Systematic Reviews and Meta-Analyses) 2020 Update, the MOOSE Guidelines, and the standards for PRISMA were all followed when conducting this review. A PRISMA 2020 Checklist completed form was submitted27,28.

Search strategy

We searched four databases: PubMed, Scopus, Web of Scopus, and Cochrane Library from inception to 11 September 2022, using MeSH terms to form the following search strategy: (Human Herpes Simplex Virus) AND (“Dementia” OR “Alzheimer’s disease” OR “Mild cognitive impairment”). As a secondary check, two authors manually searched the references of the included studies.

Study selection

Our inclusion criteria were: (1) any randomized control trials and (2) controlled observational studies as cross-sectional, prospective, or retrospective cohort and case–control studies that investigated the prevalence of dementia in HSV-infected patients and HSV-free control group. Also, if the studies measured the levels of HSV antibodies and incidence of these antibodies in patients with dementia compared with a healthy control (HC) group.

Exclusion criteria: (1) animal studies, (2) brain specimen-based studies of dead patients, (3) case reports, (4) case series, (5) editorials, and (6) reviews.

We divided the authors into two groups. Each group conducted the screening and data collection individually. Screening passed by two processes: (1) Title and abstract screening and (2) full-text screening. Two authors from each group performed title and abstract screening of each study using the Covidence platform; the study was included if it seemed eligible for inclusion according to our inclusion criteria, then the two authors performed full-text screening of each study included from the title and abstract screening phase. The first author resolved the disputes and compared the results from the two groups. The study was finally included in our analysis at this phase if it met our inclusion criteria.

Data extraction

Two Excel sheets were created from the data we extracted from the included studies; in the first one, one author extracted baseline characteristics: age, sex, study arms, study design, and the number of patients in each group, and the other contained outcomes: anti-HSV IgG titer, seropositive/prevalence of IgG n (%), anti-HSV IgM titer n (%), HSV DNA n (%), the incidence of dementia, prevalence of dementia after antiherpetic medication, HSV-1-specific IgG3 n (%), and HSV-1 avidity.

Quality assessment

Newcastle–Ottawa Scale (NOS) tool was used to assess the quality of the included observational studies. Each study was ranked as good, fair, or poor quality.

Data analysis

Review Manager Software version 5.4 was used to perform the meta-analysis; the continuous outcomes were measured as mean difference (MD) and standard deviation (SD), and the dichotomous outcomes as risk ratios (RR) with a 95% confidence interval (CI). In case of heterogeneity (χ 2 P-value <0.1), a random effect model was adopted, otherwise, a fixed-effect model was employed, in general; the results were considered significant if the P-value was less than 0.05.

Results

Summary of studies

After a search of the literature, 553 studies resulted, and then 413 were eligible for the title and abstract screening after duplicate removal. Of the 413, 329 were irrelevant and 84 studies were eligible for full-text screening. Finally, 19 studies15,24,25,29–42 were included in the meta-analysis after the full-text screening, as shown in the PRISMA in Figure 1.

Figure 1.

Figure 1

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PRISMA (Preferred Reporting Items of Systematic Reviews and Meta-Analyses) flow diagram.

The overall quality was good in 12 studies and fair in seven studies, as shown in Table 1.

Table 1.

Quality assessment

Selection Exposure
Case definition Representativeness Selection of controls Definition of controls Comparability Ascertainment Same method Non-response rate Total score AHRQ standards
NOS scale risk of bias assessment
1 1 0 1 2 1 1 1 8 Good
1 0 0 1 2 1 1 1 7 Good
1 0 0 1 2 1 1 1 7 Good
1 0 1 1 2 1 1 1 8 Good
1 1 1 1 1 1 1 1 8 Good
0 1 1 0 1 1 1 0 5 Fair
1 0 1 1 1 1 1 1 7 Good
1 0 1 1 1 1 1 1 7 Good
1 0 1 0 1 1 1 1 6 Fair
1 0 0 1 1 1 1 0 5 Fair
1 0 0 0 2 1 1 0 5 Fair
1 0 1 1 2 1 1 0 7 Good
1 1 1 1 2 1 1 0 8 Good
1 1 1 1 2 1 1 1 9 Good
1 1 0 1 2 1 1 0 7 Good
1 0 0 1 1 1 1 1 6 Fair
1 0 1 1 1 1 1 0 6 Good
1 0 0 1 2 1 1 0 6 Fair
1 0 0 1 2 1 1 0 6 Fair
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AHRQ, Agency for Health Research and Quality.

The total number of patients included in the study is 342 535 patients, 96 049 patients in the HSV group and 242 981 in the no HSV control group. In addition to 2011 patients in the AD group and MCI group, and 1494 patients in the control group, other baseline data are shown in Table 2.

Table 2.

Baseline characteristics

Study design Arms of the study Number of patients in each group Age (years) Sex (n)
Case Control Case Control Case Control
Retrospective cohort HSV patients, healthy control group 87 687 217 895 50–80 50–80 Males = 81893 Males = 206 032
Case–control study Alzhiemer’s disease (AD), healthy controls (HC) 365 365 55–65 55–65 N/A N/A
Case–control study AD, MCI, healthy controls 81 67 70–80 70–80 AD (M:F) = (28:42), MCI (30:31) M:F = (28:39)
Case–control study AD, MCI, HC AD = 56, MCI = 48 37 75–85 75–85 AD (M:F) = (24:32), MCI (74.1:5.7) M:F = (14:23)
Retrospective cohort HSV patients, healthy control group 8362 25 086 50–65 50–65 Males = 3638 Males = 14 172
Case–control study AD, MCI, HC AD = 67, MCI = 58 61 70–80 70–80 AD (M:F) = (29:38), MCI (26:32) M:F = (27:34)
Case–control study AD, MCI, HC AD = 79, MCI = 57 81 70–80 70–80 AD (M:F) = (32:47), MCI (22:35) (34:47)
Case–control study AD, HC 128 135 70–80s 70–80 Males = 65 Males = 66
Case–control study AD, HC 338 324 60–70 60–70 Males = 83 Males = 77
Case–control study AD, MCI, HC AD = 83, MCI = 68 74 65–80 65–80 AD (M:F) = (33:50), MCI (31:37) M:F= (32:42)
Case–control study AD, MCI, HC AD = 85, MCI = 34 34 70–85 66, 67 Males: AD = 28.4%, MCI = 44.1% Males = 57.1%
Case–control study AD, HC 83 51 70–80 70–80 (M:F) = 33:50 M:F = 20:31
Case–control study AD, HC 27 13 52–91 62 –87 (15 males, 12 females) (7 males, 6 females)
Case–control study AD, HC 46 44 54–96 58–95 10 males 25 males
Case–control study AD, HC 19 21 64–92 64–92 2 males 7 males
Case–control study AD, HC 33 28 64–92 59–85 10 males 13 males
Retrospective cohort study AD, MCI, HC AD = 43, MCI = 36 25 M = 74.97, SD = 5.49 N/A (M:F) = 15:21 N/A
Case–control study AD, HC 34 40 64–94 64–89 (M:F) = 8:26 (M:F) = 20:20
Case–control study AD, HC 53 39 45–96 58–95 (M:F) = 12:41 (M:F) = 23:16
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F, females; HSV, herpes simplex virus; M, males; M, mean; MCI, mild cognitive impairment; SD, standard deviation.

Outcomes

We have summarized all the results of the outcomes in Table 3.

Table 3.

Summary of outcomes

Outcome Risk ratio Mean difference Confidence interval (CI) P
Anti-HSV IgG titer (AD) 1.16 0.78−54 <0.00001
Anti-HSV IgG titer (MCI) 1.05 0.71−1.39 <0.00001
Anti-HSV IgG titer (AD and MCI) −0.10 −0.27 to 0.07 0.23
Seropositive/prevalence of IgG n (%) (AD) 1.01 0.94−1.08 0.78
Seropositive/prevalence of IgG n (%) (MCI) 1.05 0.94–1.16 0.40
Seropositive/prevalence of IgG n (%) (AD and MCI) 0.98 0.93–1.03 0.37
Anti-HSV IgM titer n (%) 1.35 0.91–2.01 0.14
HSV DNA n (%) (AD) 0.42 0.05–3.75 44
Incidence of dementia 2.23 1.18–2.29 <0.00001
Prevalence of dementia after antiherpetic medication 0.45 0.10–2.07 =0.30
HSV-1-specific IgG3 n (%) (AD) 1.16 0.99–1.35 0.07
HSV-1-specific IgG3 n (%) (MCI) 1.36 1.18–1.56 <0.0001
HSV-1-specific IgG3 n (%) (AD and MCI) 0.85 0.76–0.95 0.006
HSV-1 avidity (AD) 2.26 −0.36 to 4.88 0.09
HSV-1 avidity (MCI) 6.07 −3.65 to 15.70 0.22
HSV-1 avidity (AD and MCI) −4.07 −13.48 to 5.34 0.07
AD IgG titer less than 65 years subgroup 1.89 1.15–2.64 <0.00001
AD IgG titer equal to or more than 65 years subgroup 1 0.66–1.34 <0.00001
MCI IGg titer less than 65 years subgroup 1.44 0.47–2.41 0.004
MCI IGg titer equal to or more than 65 years subgroup 1 0.64–1.36 <0.00001
AD and MCI IgG titer less than 65 years subgroup 0.41 −0.61 to 1.43 0.43
AD and MCI IgG titer equal to or more than 65-year subgroup −0.03 −0.40 to 0.33 0.86
AD IgG prevalence less than 65 years subgroup 1.04 1.00–1.08 0.02
AD IgG prevalence equal to or more than 65-year subgroup 1.01 0.97–1.04 0.66
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Anti-HSV IgG titer (AD), (MCI), and (AD and MCI), respectively

The pooled analysis showed a statistically significant association between the AD group and increased levels of IgG titer compared with the control group (MD = 0.99, 95% CI = 0.36–1.63, P-value = 0.002). We observed a significant heterogeneity among studies (P<0.00001, I 2 = 84%). It was solved by leave-one-out test by removing Kobayashi, 2014 (P = 0.23, I 2 = 26%), and the analysis showed a statistically significant association between the AD group and increased levels of IgG titer compared with the control group (MD = 1.16, 95% CI = 0.78–1.54, P-value <0.00001), Figure 2. The pooled analysis showed a statistically significant association between the MCI group and increased levels of IgG titer compared with the control group (MD = 0.80, 95% CI = 0.26–1.35, P-value = 0.004). We observed a significant heterogeneity among studies (P = 0.001, I 2 = 77%). It was solved by leave-one-out test by removing Kobayashi, 2014 (P= 0.54, I 2 = 0%), and the analysis showed a statistically significant association between the AD group and increased levels of IgG titer compared with the control group (MD = 1.05, 95% CI = 0.71–1.39, P-value <0.00001), Figure 3. The pooled analysis showed no statistically significant difference between the AD group and the MCI group (MD = −0.10, 95% CI = −0.27 to 0.07, P-value = 0.23). We observed no significant heterogeneity among studies (P = 0.12, I 2 = 43%), Figure 4.

Figure 2.

Figure 2

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Anti-HSV IgG titer (AD).

Figure 3.

Figure 3

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Anti-HSV IgG titer (MCI).

Figure 4.

Figure 4

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Anti-HSV IgG titer (AD and MCI).

Seropositive/prevalence of IgG n (%) (AD), (MCI), and (AD and MCI), respectively

The pooled analysis showed a statistically significant association between the AD group and increased IgG prevalence compared with the control group (RR = 1.04, 95% CI = 1.01–1.07, P-value = 0.01). We observed no significant heterogeneity among studies (P = 0.23, I 2 = 24%), Figure 5. The pooled analysis showed no statistically significant difference between the MCI group and the control group (RR = 1.05, 95% CI = 0.94–1.16, P-value = 0.40). We observed a significant heterogeneity among studies (P = 0.006, I 2 = 76%). It was solved by leave-one-out test by removing Kobayashi, 2014 (P = 0.14, I 2 = 50%), and the analysis showed no statistically significant difference between the MCI group and the control group (RR = 1.01, 95% CI = 0.94–1.08, P-value = 0.78), Figure 6. The pooled analysis showed no statistically significant difference between the AD group and the MCI group (RR = 0.98, 95% CI = 0.93–1.03, P-value = 0.37). We observed no significant heterogeneity among studies (P = 0.33, I 2 = 13%), Figure 7.

Figure 5.

Figure 5

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Seropositive/prevalence of IgG n (%) (AD).

Figure 6.

Figure 6

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Seropositive/prevalence of IgG n (%) (MCI).

Figure 7.

Figure 7

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Seropositive/prevalence of IgG n (%) (AD and MCI).

Anti-HSV IgM titer n (%) and HSV DNA n (%) (AD)

The pooled analysis showed no statistically significant difference between the AD group and the control group in anti-HSV IgM titer n (%) outcome (RR =1.35, 95% CI = 0.91–2.01, P-value = 0.14), with no heterogeneity between the two studies (P = 1.00, I 2 = 0%) and HSV DNA n (%) (AD) outcome (RR = 0.42, 95% CI = 0.05–3.75, P-value = 0.44), respectively. We observed a significant heterogeneity between the two studies (P = 0.03, I 2 = 79%), Figures. 8 and 9, respectively.

Figure 8.

Figure 8

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Anti-HSV IgM titer n (%) (AD).

Figure 9.

Figure 9

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HSV DNA n (%) (AD).

Incidence of dementia

The generic inverse variance showed a statistically significant association between the HSV group and increased incidence of dementia compared with no HSV control group (RR = 2.23, 95% CI = 1.18–2.29, P-value <0.00001). We observed a significant heterogeneity between two studies (P<0.00001, I 2 = 100%), Figure 10.

Figure 10.

Figure 10

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Incidence of dementia.

Prevalence of dementia after antiherpetic medication

The pooled analysis showed no statistically significant difference between patients who received antiherpetic medication and patients who did not receive antiherpetic medication (RR = 0.45, 95% CI = 0.10–2.07, P-value = 0.30). We observed a significant heterogeneity between two studies (P<0.00001, I 2 = 100%), Figure 11.

Figure 11.

Figure 11

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Prevalence of dementia after antiherpetic medication.

HSV-1-specific IgG3 n (%) (AD), (MCI), and (AD and MCI), respectively

The pooled analysis showed no statistically significant difference between the AD group and the control group (RR = 1.16, 95% CI = 0.99–1.35, P-value = 0.07). We observed no significant heterogeneity between the two studies (P = 0.84, I 2 = 0%), Figure 12. The pooled analysis showed a statistically significant association between the MCI group and the increased prevalence of IgG3 compared with the control group (RR = 1.36, 95% CI = 1.18–1.56, P-value <0.0001). We observed no significant heterogeneity among two studies (P = 0.92, I 2 = 0%), Figure 13. The pooled analysis showed a statistically significant association between the MCI group and decreased prevalence of IgG3 compared with the AD group (RR = 0.85, 95% CI = 0.76–0.95, P-value = 0.006). We observed no significant heterogeneity between the two studies (P = 0.69, I 2 = 0%), Figure 14.

Figure 12.

Figure 12

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HSV-1-specific IgG3 n (%) (AD).

Figure 13.

Figure 13

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HSV-1-specific IgG3 n (%) (MCI).

Figure 14.

Figure 14

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HSV-1-specific IgG3 n (%) (AD and MCI).

HSV-1 avidity (AD), (MCI), and (AD and MCI), respectively

The pooled analysis showed no statistically significant difference between the AD group and the control group (MD = 2.26, 95% CI = −0.36 to 4.88, P-value = 0.09). We observed no significant heterogeneity between the two studies (P = 0.93, I 2 = 0%), Figure 15. The pooled analysis showed no statistically significant difference between the MCI group and the increased level of HSV-1 avidity compared with the control group (MD = 6.07, 95% CI = −3.65 to 15.70, P-value = 0.22). We observed a significant heterogeneity between the two studies (P = 0.006, I 2 = 87%), Figure 16. The pooled analysis showed no statistically significant difference between the AD group and the MCI group (MD = −4.07, 95% CI = −13.48 to 5.34, P-value = 0.07). We observed a significant heterogeneity between the two studies (P = 0.0007, I 2 = 91%), Figure 17.

Figure 15.

Figure 15

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HSV-1 avidity (AD).

Figure 16.

Figure 16

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HSV-1 avidity (MCI).

Figure 17.

Figure 17

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HSV-1 avidity (AD and MCI).

AD IgG titer

Less than 65 years subgroup

The pooled analysis showed a statistically significant association between the AD group and increased IgG titer compared with the control group in the subgroup of less than 65 years (MD = 1.89, 95% CI = 1.15–2.64, P-value <0.00001). We observed no significant heterogeneity between the two studies (P = 0.44, I 2 = 0%), Figure 18.

Figure 18.

Figure 18

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Subgroups of less than 65 years and equal to or more than 65 years in the outcome of AD IgG titer.

Equal to or more than 65 years subgroup

The pooled analysis showed a statistically significant association between the AD group and increased IgG titer compared with the control group in the subgroup of equal to or more than 65 years (MD = 0.76, 95% CI = 0.17–1.36, P-value = 0.01). We observed a significant heterogeneity among studies (P<0.0001, I 2 = 81%). It was solved by leave-one-out test by removing Kobayashi, 2014 (P = 0.57, I 2 = 0%), and the analysis showed a statistically significant association between the AD group and increased IgG titer compared with the control group (MD = 1.00, 95% CI = 0.66–1.34, P-value <0.00001), Figure 18.

MCI IgG titer

Less than 65 years subgroup

The pooled analysis showed a statistically significant association between the MCI group and increased IgG titer compared with the control group in the subgroup of less than 65 years (MD = 1.44, 95% CI = 0.47–2.41, P-value = 0.004), Figure 19.

Figure 19.

Figure 19

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Subgroups of less than 65 years and equal to or more than 65 years in the outcome of MCI IgG titer.

Equal to or more than 65 years subgroup

The pooled analysis showed a statistically significant association between the MCI group and increased IgG titer compared with the control group in the subgroup of equal to or more than 65 years (MD = 0.69, 95% CI = 0.13–1.25, P-value = 0.02). We observed a significant heterogeneity among studies (P = 0.003, I 2 = 78%). It was solved by leave-one-out test by removing Kobayashi, 2014 (P = 0.48, I 2 = 0%), and the analysis showed a statistically significant association between the MCI group and increased IgG titer compared with the control group (MD = 1.00, 95% CI = 0.64–1.36, P-value <0.00001), Figure 19.

AD and MCI IgG titer

Less than 65 years subgroup

The pooled analysis showed no statistically significant difference between the AD group and the MCI group in the subgroup of less than 65 years (MD = 0.41, 95% CI = −0.61 to 1.43, P-value = 0.43), Figure 20.

Figure 20.

Figure 20

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Subgroups of less than 65 years and equal to or more than 65 years in the outcome of AD and MCI IgG titer.

Equal to or more than 65 years subgroup

The pooled analysis showed no statistically significant difference between the AD group and the MCI group in the subgroup of equal to or more 65 years (MD = −0.03, 95% CI = −0.40 to 0.33, P-value = 0.86). We observed no significant heterogeneity among studies (P = 0.17, I 2 = 38%), Figure 20.

AD IgG prevalence

Less than 65 years subgroup

The pooled analysis showed a statistically significant association between the AD group and increased IgG prevalence compared with the control group in the subgroup of less than 65 years (RR = 1.04, 95% CI = 1.01–1.08, P-value = 0.02). We observed no significant heterogeneity among studies (P = 0.83, I 2 = 0%), Figure 21.

Figure 21.

Figure 21

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Subgroups of less than 65 years and equal to or more than 65 years in the outcome of AD IgG prevalence.

Equal to or more than 65 years subgroup

The pooled analysis showed no statistically significant difference between the AD group and the control group in the subgroup of equal to or more than 65 years (RR = 1.01% CI = 0.97–1.04, P-value = 0.66). We observed no significant heterogeneity among studies (P = 0.26, I 2 = 21%), Figure 21.

Discussion

Our analysis of 19 studies with 342 535 patients revealed a statistically significant association between the AD and MCI groups and elevated anti-HSV IgG titer compared to the control group. There is no statistically significant difference in anti-HSV IgG titer between the AD group and the MCI group. Some studies agree with our findings. For example, Agostini et al., Lövheim et al., and Mancuso et al.29,35,42. While others contradict these findings as presented in Renvoize et al.43. On the other hand, when compared to the control group, a significant association between increased IgG prevalence and the AD group, but not the MCI group, is seen. But no significant difference between the AD group and the MCI group is detected regarding the prevalence of IgG. This finding was similarly presented in some studies including Wozniak et al., Agostini et al., Mancuso et al., and Bu et al.29,30,40,42. Moreover, a subgroup analysis for age is performed. It shows a statistically significant association between the AD and MCI groups and increased IgG titer compared with the control group in all subgroups, those of less than, equal to, or more than 65 years of age. There is no statistically significant difference between the AD group and the MCI group in the subgroups of less than, equal to, or more than 65 years old. Instead, the analysis showed a statistically significant association between the AD group and increased IgG prevalence compared with the control group in the subgroup of fewer than 65 years but not in those equal to or more than 65 years of age.

Furthermore, in contrast to the control group, the pooled analysis uncovers a statistically significant association between the MCI group, but not the AD group, and a higher prevalence of IgG3 according to the results of two studies by Agostini et al. published in 2018 and Mancuso et al. published in 202029,42. Also, a statistically significant association between the MCI group and a lower frequency of IgG3 than the AD group was reported. A non-statistically significant association between the MCI group and AD, and higher HSV-1 avidity is noted. Nevertheless, no statistically significant difference is detected between the two groups regarding HSV-1 avidity.

Our analysis also shows no statistically significant differences in HSV DNA or anti-HSV IgM titer between the AD and control groups. We noticed that Hemling et al.32 support our findings regarding HSV DNA while Lin et al.34 contradict them. The latter has noted the substantial overlap between HSV-1 but not HSV-2 and being present in AD brains. It has been proposed that the significant difference between the proportion of elder brains harboring HSV-1 and HSV-2 may be due to the latter’s lower prevalence among infected individuals or the two viruses’ different susceptibilities to the frontotemporal areas. Additionally, anti-HSV IgM titer was presented in two studies: Lövheim et al. and Agostini et al. published in 201635,41. However, in Lövheim et al.35, the study’s large number of clearly defined cases of AD may have made it possible to confirm an association between the presence of anti-HSV IgG antibodies, while the study’s small number of individuals who tested positive for anti-HSV IgM may have made it difficult to identify any potential associations. Also, Letenneur et al.44 reported that individuals had anti-HSV-1 IgM antibodies before the start of AD, showing that HSV reactivation is a risk factor for the development of AD.

Lastly, we find that on comparing the HSV group to the control group with no HSV infection, a statistically significant association between the HSV group and an increased risk of dementia is revealed. However, patients who used antiherpetic medication did not exhibit a significant decline in dementia prevalence compared to those who did not receive antiherpetic medication. This assumption is based entirely on the results of two studies Tzeng et al. and Young-Xu et al.24,25. Where Tzeng et al. supported our findings, Young-Xu et al. contradicted them.

Moreover, the adjusted hazard ratio (HR) for the group of HSV-infected patients receiving antiherpetic medications was 0.092. Thus, they demonstrated a lower risk of developing any dementia, including AD, VaD, or other dementia, when compared to the group not receiving antiherpetic medications indicating that antiherpetic therapies could minimize the risk of dementia in patients with HSV infections by nearly 90.8%. Although one study claimed that antiviral drugs in neurodegenerative illnesses could be a new paradigm for treating AD45, the role of antiherpetic medications for AD prevention has not previously been investigated. However, according to Shen et al.46, who investigated the seroprevalence of HSV-1 and HSV-2, no significant association between sex and HSV-1 seropositivity was detected, but females had higher rates of HSV-2 seropositivity. Contrarily, Mancuso et al.42 established a correlation between the damage seen in the brains of AD and MCI patients and serum HSV-1-specific IgG3 antibodies. Additionally, Schnier et al.’s study47 summarized the findings of four sizable national cohorts. They looked into how the herpes subtype altered the relationship between antiherpetic drugs and incident dementia. They performed a subset analysis that excluded Coinfections and only included people with a diagnosis of Herpes simplex or Herpes zoster. They prescribed acyclovir, its prodrug valacyclovir, famciclovir, and brivudine for medication-specific analyses. According to Schnier et al., those with H. zoster diagnoses who were not subjected to any antiherpetic drugs had a higher rate of dementia compared to the control group, whereas those with H. simplex diagnosis and the control group had no change in dementia incidence. People subjected to antiherpetic medicine similarly showed this trend toward higher HRs in those with H. zoster diagnoses and lower HRs in those with H. simplex diagnoses; however, these differences were not statistically significant.

The examined groups all have similar HSV-1 seroprevalence rates, although AD and MCI patients had higher serum concentrations of HSV-1-specific IgG antibodies than controls. HC, AD patients, and MCI individuals had similar serum concentrations of HSV-1-specific IgG3. However, MCI individuals had a higher detection rate for this subclass of antibodies. Results from MCI patients revealed a negative correlation between HSV-1-specific IgG3 serum concentrations as well as the volumes of the cingulum, right superior temporal gyrus, and transverse temporal cortex, areas that have been associated with dementia as shown by Frisoni et al. and Rathore et al.48,49, but not to HSV-1 encephalitis as illustrated by Esiri et al., Damasio et al., Baringer et al., and Agostini et al.41,50–52. In line with the presented results, higher IgG3 titers are linked to more severe brain damage in AD but not in MCI. Together, these findings imply that as the disease progresses from MCI to AD, IgG3’s capacity to combat HSV-1 decreases.

In addition to proving that the frequency of HSV-1 IgG3 was significantly greater in MCI compared to AD and HC, Agostini et al. published in 201829 also made a crucial observation that, whereas total IgG and IgG1 were positively correlated in serum in AD and HC, this correlation was absent in MCI and that total IgG was significantly linked with IgG3, not IgG1. This outcome was unexpected given that IgG1, which is frequently induced by viral infections, is the IgG subclass that is primarily prevalent in human serum53. According to these findings, when HC, AD, and MCI people are compared to each other, there is a unique distribution of HSV-1-specific IgG subclasses. Even though IgG1 subclass response to HSV-1 predominates in all groups studied, MCI patients exhibit the IgG3 response far more frequently than the other groups do. These results are intriguing since different IgG subclasses have different structural and functional characteristics, and in the context of HSV-1 infection, HSV-1 is unable to hinder IgG3 function as part of its innate defense strategy. Surprisingly, AD sera have a diminished capacity to neutralize HSV-1, regardless of IgG3 or C3 titers. Therefore, additional research is required to comprehend the possible biological significance of these findings.

Lastly, the HSV-1 Avidity Index is an interesting finding that we also attempt to explore. It was presented by three studies Agostini et al., Mancuso et al., and Kobayashi et al.36,41,54, which assessed the prevalence of the HSV-1 avidity index in AD and MCI patients. Avidity, which quantifies an antibody’s affinity for a particular antigen, is defined as the strength with which antibodies attach to antigens. This parameter distinguishes between primary and secondary infections; as a result, the avidity of antibodies in primary infections is typically lower than 35%, whereas the avidity of antibodies in subsequent infections can range from 30 to 45%55. According to the assumption of Agostini et al.41, people with aMCI showed extremely high levels of HSV-1 avidity (>85%). Similarly, Kobayashi et al.54 claimed that MCI patients have higher levels of HSV-1-specific IgG than HC or AD patients do. Thus, it is evident that the aMCI group (the prodromal stage of AD) experiences HSV-1 reactivation more frequently than the HC and AD groups. Both the anti-HSV-1 IgG avidity index and anti-HSV-1 IgG antibody titer were different between the HC and aMCI groups. This comprehensively supports the idea of HSV-1 engagement as people move from a healthy state to the onset of aMCI. Also, given that it can be easily tested using peripheral blood, anti-HSV-1 IgG avidity index – a sign of HSV-1 reactivation – could be a promising biomarker for the early identification of aMCI and AD. Additionally, the study suggested administering antiviral medications to guard against reactivation and hence avoid AD development. Conversely, Mancuso et al.36 did not find any variations in the avidity of these antibodies among AD, MCI, or HC groups.

To draw attention to the assorted studies on the development of dementia in HSV patients, we came across numerous studies attempting to determine the root cause of HSV patients developing AD. Although the underlying mechanisms of aberrant tau phosphorylation and NFT in AD are unknown, Wozniak et al.56 studied whether HSV-1 may cause these effects. They discovered that HSV promotes AD-specific tau phosphorylation at amino acids T212 and S214. Increased phosphorylation was also seen at S396, S404, and S202, as well as an increase in a structurally aberrant type of tau. The total tau level was also raised. Thus, HSV-1 could cause aberrant tau phosphorylation by either raising or lowering the activity of the relevant kinases and phosphatases. Wozniak et al.57 also demonstrated that the infected cultured neuronal and glial cells with HSV-1 increase intracellular levels of amyloid (A) 1-40 and 1-42 while decreasing levels of amyloid precursor protein (APP). A1-42 deposits were also found in the mouse brain after HSV-1 infection. The method in cultured cells requires increased A production rather than simply increased cellular A retention, as levels of site APP-cleaving enzyme (BACE-1) and nicastrin, a component of gamma-secretase, both increase in HSV-1-infected cells. These new findings indicate that HSV-1 can directly contribute to the formation of senile plaques.

Future implications

Regular follow-up after HSV infection must be done to guard against the development of AD or MCI. This can be achieved in various ways including MRI imaging or calculating the anti-HSV IgG avidity index, a marker of HSV-1 reactivation, which can be quickly assessed using peripheral blood and employed as a biomarker for the early detection of aMCI and AD. Moreover, the use of antiherpetic medications as a protective method to guard against the development of dementia or MCI after HSV infection should be further investigated.

Strengths and limitations

The overall quality is good in most of the studies included in our analysis. A good number of studies were subjected to analysis as 19 studies were included. Along with a decent sample size, 342 535 patients were included in our analysis. Our study shows some limitations. For, example all the studies included were non-randomized observational, not randomized clinical trials, and hence might be subjected to bias. Prospective multicenter studies are needed to further evaluate the relationship between HSV and AD development. Moreover, significant heterogeneity was detected in some outcomes, including the incidence of dementia and HSV avidity, which is demonstrated as a primary limitation of our analysis. It could not be solved by the leave-one-out test owing to the few studies discussing these outcomes.

Conclusion

Our study revealed a significant association between HSV and an increased risk of dementia. Our findings thus pave the way for the development of new AD treatments. It is necessary to undertake future clinical trials examining antiherpetic medications and assess the HSV avidity index as a biomarker for AD and MCI. In the future, their usage in high-risk AD patients might be promising as a primary or secondary prophylaxis.

Ethical approval

Not applicable.

Consent

Not applicable.

Sources of funding

The authors declare they received no fund for this study.

Author contribution

R.H.E.: study design and writing; K.R.M.: supervision and writing; N.E.T.: analysis and writing; S.R.: writing; N.M., E.M.H., S.M.R., M.M., and J.S.: screening, data extraction, and quality assessment. All authors approved the manuscript.

Conflicts of interest disclosure

The authors declare that they have no conflicts of interest.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Karam R. Motawea and Jaffer Shah.

Data availability statement

Data and materials are available within the manuscript.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Acknowledgements

Not applicable.

Footnotes

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Published online 26 July 2023

Contributor Information

Rowan H. Elhalag, Email: rawan.fathy1801@alexmed.edu.eg.

Karam R. Motawea, Email: karam.Ahmed1650@alexmed.edu.eg.

Nesreen E. Talat, Email: talatnesreen@gmail.com.

Samah S. Rouzan, Email: samahsabry277@gmail.com.

Nada Mahmoud, Email: nadahisham095@gmail.com.

Elsayed M. Hammad, Email: Hmad41337@gmail.com.

Sarraa M. Reyad, Email: sarraareyad@gmail.com.

Mai S. Mohamed, Email: mai.saad.mohamed@gmail.com.

Jaffer Shah, Email: jaffer.shah@kateb.edu.af.

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