Anti-herpetic treatment reduces dementia risk: A systematic review and meta-analysis

Abstract

Background

Human herpesvirus (HHV) infections, particularly for herpes simplex virus (HSV) and varicella-zoster virus (VZV), may increase dementia risk, yet the protective effects of anti-herpetic medications remained unclear.

Objective

This systematic review and meta-analysis of observational studies aimed to examine the association between anti-herpetic medications and dementia, focusing on HSV or VZV-related infections.

Methods

This study followed PRISMA guidelines (CRD42022368318). Cohort or nested case-control studies published from databases’ inception to December 2024 were systematically searched in PubMed, MEDLINE, Embase, Cochrane Library, PsycINFO, and Web of Science. Eligible studies evaluated anti-herpetic medications (e.g., acyclovir, famciclovir, ganciclovir, valacyclovir, valganciclovir) and dementia risk in non-demented adults aged ≥50. Pooled adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) were analyzed using random-effects models. Subgroup and meta-regression analyses were performed to explore potential sources of heterogeneity and effect modifiers.

Results

Fourteen cohort studies involving more than 10 million older adults were included. To demonstrate the effects of anti-herpetic medications in various clinical scenarios, the meta-analysis compared: diagnosed and treated versus diagnosed but untreated (aHR=0.77, 95% CI: 0.67–0.89); treated versus untreated regardless of diagnosis (aHR=0.90, 95% CI: 0.87–0.94); and diagnosed and treated versus neither diagnosed nor treated (aHR=0.87, 95% CI: 0.78–0.97). Subgroup analysis and meta-regression identified infection severity as a significant modifier (p < 0.0001), explaining 89.01% of heterogeneity.

Conclusions

This systematic review and meta-analysis reveals notable protective effect of anti-herpetic medication usage on dementia, and the effect is especially pronounced in patients with severe alpha herpesvirus infections.

Keywords

Alzheimer's disease anti-herpetic medication dementia meta-analysis

Introduction

Dementia is a neurodegenerative syndrome characterized by gradual decline in cognitive function that ultimately affects daily living activities. The 2015 World Alzheimer Report predicted that the worldwide prevalence of individuals with dementia will increase to 131 million by 2050.¹ Given the lack of an effective treatment, the discovery of preventive measures or reversible risk factors for dementia has become exceptionally important. The etiology of dementia is still unknown; however, numerous studies have suggested that it may result from complex interactions among lifestyle factors, infections, inflammation, and genetic predisposition.² Unfortunately, while dementia is expected to cause increasingly enormous burden on the society, there remains no cure for dementia.³ Identifying pharmacological treatments that can slow neurodegeneration in the early stages holds promise for altering the disease's course, as brain pathology develops years before symptoms appear.⁴

Recently, there has been a growing focus on the “infection hypothesis”, which proposes that pathogen load and the interaction between an individual's immune system and infectious agents could contribute to the development of dementia.^5,6 Viral infections, especially those caused by the Human Herpesviridae (HHV) family, have been proposed as potential risk factors for dementia. The HHV family consists of viruses that are prevalent in the environment and establish a persistent latent phase within the nervous system following primary infection, such as herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), and varicella-zoster virus (VZV), which exhibit rapid replication and a distinct propensity to establish latency in sensory ganglia. These neurotrophic viruses are called alpha herpes viruses. Researchers have observed memory loss in survivors of herpes simplex encephalitis, which resembles the symptoms seen in those with Alzheimer's disease (AD).⁷ Wozniak et al.⁸ first detected HSV-1 DNA within amyloid plaques in postmortem brains of AD patients, finding that 90% of plaques contained HSV-1 DNA, and 72% of the total HSV-1 DNA in the brain was associated with these plaques. Supporting findings have also been demonstrated in previous meta-analyses of observational studies, indicating that individuals with HSV-1 infections are at a higher risk of developing AD compared to uninfected individuals.^9–11 Although the HHV family includes other subfamilies—such as beta herpesviruses (e.g., cytomegalovirus, CMV) and gamma herpesviruses (e.g., Epstein-Barr virus, EBV)—most studies have concentrated on alpha herpesvirus infections, as these viruses often reactivate in clinically evident ways that may necessitate medical treatment.

Theoretically, if herpesvirus infections contribute to dementia risk, antiviral treatment may serve as a potential preventive strategy. Some epidemiological studies have indicated that individuals with alpha herpesvirus infections, particularly HSV and VZV, who receive anti-herpetic medications may have a lower risk of dementia.^12–14 However, separate studies have reported conflicting findings, showing no significant link between antiviral treatment and a higher risk of dementia.^15,16 Previous systematic reviews^17,18 combined studies with heterogeneous methodologies and mainly focused on case-control studies; therefore, the clarity and reliability of their conclusions regarding the association were limited. This systematic review and meta-analysis of both cohort and nested case-control studies aims to update previous reviews^17,18 and comprehensively evaluate the association between anti-herpetic medications and dementia risk in non-demented older adults.

Methods

Registration

Our study was registered in PROSPERO (registration number: CRD42022368318). This systematic review and meta-analysis adhered to the reporting guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA).¹⁹

Data sources and searches

We conducted a comprehensive search and review of medical electronic databases, including PubMed, MEDLINE, Embase, Cochrane Library, PsycINFO, CINAHL, and Web of Science, to identify relevant studies published from the databases’ beginnings date to December 2024. Keywords were organized using Medical Subject Headings (MeSH) to incorporate synonyms and specific terms while excluding irrelevant content, ensuring a precise search process. The expected MeSH terms will include “Herpesviridae,” “Antiviral agents,” and “Dementia” and these keywords will be combined using Boolean logic (AND/OR) (as detailed in Supplemental Table 1). Furthermore, we searched the reference lists of included studies and used database automatic alerts until December 2024 to increase the retrieval of studies.

Study selection

Studies meeting the following criteria were included: (1) studies investigating the association between dementia and anti-herpetic medications; (2) study population comprising individuals aged 50 years or older; (3) exposure defined as use of anti-herpetic medications including acyclovir, famciclovir, ganciclovir, valacyclovir, and valganciclovir; (4) comparator group consisting of individuals who did not use anti-herpetic medications during the study period; (5) primary outcome of dementia diagnosis (e.g., all cause dementia, AD or vascular dementia (VaD)) using adjusted hazard ratio (aHR), adjusted risk ratio (aRR) or adjusted odds ratio (aOR) as the effect measures; and (6) study design being cohort studies or nested case-control study.

If any of the following criteria were met, studies were excluded: (1) animal or in vitro studies, preclinical studies, case reports, meta-analyses, reviews, duplicate articles, or guidelines; (2) non-English publications; (3) inaccessible full-text documents; (4) studies that did not meet clinical diagnostic criteria for dementia; or (5) studies where individuals in the population were diagnosed with dementia before using anti-herpetic medications or before being infected with herpesvirus.

Data extraction and quality assessment

Initially, literature obtained from electronic databases and other sources was imported into the Endnote reference management software. After eliminating duplicates using Endnote's built-in functions, two reviewers (STC and YFC) independently evaluated the literature based on the inclusion and exclusion criteria mentioned above. Following the screening process, data to be extracted from the selected documents included the following points: (1) study information: author, year of publication, study design, initial setting of the study population, and source of data; (2) characteristics of study populations: herpesvirus subtypes, key demographic variables such as age, gender and follow-up duration, as well as details about the source of recruitment and sampling methods, including inclusion and exclusion criteria; (3) Definition of exposure and comparator groups and their corresponding number of subjects; (5) Outcomes: clinical diagnostic criteria for dementia and outcome measures of interest (aOR or aHR with the corresponding 95%CI).

The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to evaluate the quality of the included observational studies. The assessment covered three main domains: selection of the study population, comparability, and assessment of exposure or outcome, and included eight items. A median or mean follow-up of more than 3 years or a maximum follow-up of more than 5 years was considered sufficient long enough to detect dementia onset. Scores of 0–3 indicate low-quality evidence, scores of 4–6 indicate moderate-quality evidence, and scores of 7–9 indicate high-quality evidence.

The quality of evidence for the pooled results in the meta-analysis was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method.

Data synthesis and analysis

The synthesis and analysis of all data in this study was conducted using STATA 18, R version 4.4.2, and RevMan 5.4. The association between dementia and anti-herpetic medications was analyzed using a random-effects model, with results presented as pooled aHR with 95% confidence intervals (CIs). The meta-analysis will be divided into three comparison groups: treated subjects versus untreated subjects (T + versus T-) (regardless of infection diagnosis); diagnosed and treated subjects versus diagnosed but untreated subjects (D + T + versus D + T-); and diagnosed and treated subjects versus undiagnosed and untreated subjects (D + T + versus D-T-). Statistical significance was considered when the p-value<0.05. Heterogeneity among studies was evaluated through the Q-test and I² statistic, with p-value < 0.05 or I² > 50% indicating high heterogeneity.

If significant heterogeneity was detected among the studies, subgroup analyses would be conducted to identify potential sources of this heterogeneity and to determine whether the effects varied across subgroups. Subgroup analyses were conducted based on variables that may contribute to heterogeneity, such as different follow-up time (median or mean follow-up times ≥5 years or <5 years), baseline age (≥70 years old or < 70 years old), study setting (serology or registry-based study), study quality (NOS score ≥7 or <7) and severity of herpesvirus infection in study populations. If significant, a mixed effect meta-regression analysis using the metafor package in R was conducted to assess whether the effects tend to be modified by the subgroup variables.

In addition, sensitivity analyses were performed to assess the robustness of the findings. A leave-one-out sensitivity analysis was used to determine the influence of individual studies on the pooled results. As part of the sensitivity analyses, we excluded studies in which fewer than 10% of individuals diagnosed with herpesvirus infection received anti-herpetic treatment. This exclusion was performed to assess the potential influence of low treatment rates, which may not reflect typical clinical practice, on the overall pooled estimates.

Results

Study selection

Selection process of study was guided by the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines, as shown in Figure 1.

Figure 1.

PRISMA flowchart of study selection.

Initially, 684 articles were retrieved from 7 databases, along with 2 through citation searching. After removing duplicate entries and screening the titles and abstracts, 22 studies remained for further assessment. Upon evaluating the full-text articles, 11 retrospective cohort studies,^13,15,16,^20–26 one prospective cohort study,²⁷ and one nested case-control study²⁸ were found to meet the criteria for inclusion in our systematic review and meta-analysis. Schnier et al.¹⁶ included four different cohorts, thus we analyzed them separately and treated them as four distinct studies. This approach was taken to account for potential differences in population characteristics, healthcare systems, and antiviral prescribing practices across the countries. Analyzing each cohort individually allowed for a more accurate assessment of heterogeneity and prevented aggregation of potentially heterogeneous data into a single estimate. A highly relevant Swedish study,²⁸ despite being a nested case-control design, was included in our review, but due to its study design, our meta-analysis only incorporated 14 distinct cohort studies,^13,15,16,^20–27 with the nested case-control study solely included in the review.

Study characteristics

The detailed characteristics of the studies included in our systematic review and meta-analysis were detailed in Table 1.

Table 1.

Main characteristics of the included studies in our systematic review and meta-analysis.

Author, year	Study design	Country/Study period	Age (y/o)	Mean or median follow-up times (years)*	Sample size (n)	Exposure	Outcome
Linard et al., 2022²²	Retrospective cohort study	France (2009–2017)	≥65	8 (±NP)	6642 (treated) / 61649 (untreated)	AHDs identified by ATC codes (J05AB01-15, S01AD01-03, S01AD07, S01AD09, D06BB02-03, D06BB08, D06BB11)	Dementia (AD/VaD)
Warren-Gash et al., 2022¹⁵	Retrospective cohort study	UK (2000–2017)	≥40	4.6 [2.0–8.1]	110,997 (treated HZ) / Matched controls (NP)	Antiviral treatment within 7 days of HZ index date	All cause dementia
Lopatko Lindman et al., 2021²³	Retrospective cohort study	Sweden (2005–2017)	≥50	D + T-: 3.8 [0–12]	255,239 (treated) / 255,239 (controls); 29,593 (treated HZ) / 29,593 (controls)	AHDs: acyclovir, cidofovir, famciclovir, ganciclovir, valacyclovir, or valganciclovir	All cause dementia
				D + T+: 4.8 [0–12]
				T+: 5.0 [0–12]
Yinong et al., 2021²⁴	Retrospective cohort study	US (2001–2019)	≥50	HSV cohorts: 8.9 [6–12.2]	61,776 (treated HSV) / 217,895 (controls)	AHDs: acyclovir, famiciclovir, ganciclovir, valacyclovir, or valganciclovir	All cause dementia
Yinong et al., 2021²⁴	Retrospective cohort study	US (2001–2019)	≥50	Matched controls: 8.0 [5.2–11.3]	61,776 (treated HSV) / 217,895 (controls)		All cause dementia
Schnier et al., 2021a¹⁶	Retrospective cohort study	Scotland (2004–2020)	≥60	2.7 [1.4–4.2]	8625 (treated) / 334,012 (controls)	AHDs: acyclovir, valaciclovir, or famciclovir	All cause dementia
Schnier et al., 2021b¹⁶	Retrospective cohort study	Danish (2000–2015)	≥50	7.4 [3.8–12.2]	169,989 (treated) / 1,542,111 (controls)	AHDs: acyclovir, valaciclovir, or famciclovir	All cause dementia
Schnier et al., 2021c¹⁶	Retrospective cohort study	Wales (1995–2018)	≥60	6.7 [3.3–11.3]	39,997 (treated HSV or HZ) / 394,692 (controls)	AHDs: acyclovir, valaciclovir, or famciclovir	Dementia (AD/VaD)
Schnier et al., 2021d¹⁶	Retrospective cohort study	Germany (1992–2017)	≥60	8.8 [4.5–14.5]	10,352 (treated HSV or HZ) / 43,277 (controls)	AHDs: acyclovir, valaciclovir, or brivudine	Dementia (AD/VaD)
Bae et al., 2021¹²	Retrospective cohort study	Korea (2002–2013)	≥50	Unclear (Max11)	34,505 (HZ) with 5618 (treated) /5618 (controls)	AHDs: acyclovir, famciclovir, or valaciclovir within 1-month post-HZ	All cause dementia
Tzeng et al., 2018¹⁴	Retrospective cohort study	Taiwan (2000–2010)	≥50	Unclear (Over a 10-year periods)	8362 (symptomatic HSV) with 7215 (treated) / 25,068 (controls)	AHDs: acyclovir, famciclovir, ganciclovir, idoxuridine, penciclovir, tromantadine, valaciclovir, or valganciclovir	All cause dementia
Chen et al., 2018¹³	Retrospective cohort study	Taiwan (2000–2013)	≥50	HZ cohort: 6.08 (±4.05) Matched controls: 6.35 (±4.04)	39,205 (HZ) with 2131 (treated) and37,074 (not treated)	AHDs: acyclovir, tromantadine, famciclovir, or valacyclovir	All cause dementia
Helmer et al., 2015²¹	Retrospective cohort study	France (NP)	NP	Max 12	NP^†	AHDs	All cause dementia
Vestin et al., 2024²⁷	Prospective cohort study	Sweden (NP)	≥70	15.0 [13.5–15.0]	1002 (total) / 36 (AD) / 71 (Dementia)	AHDs identified by ATC codes (J05AB01-J05AB20, J05AP01, and J05AD01)	Dementia/AD
Tan et al., 2024²⁵	Cross-sectional, time-series and retrospective cohorts	Australia (2013–2022)	≥60	Unclear (Over a 9-year periods)	723,151 (total) / 6868 (AD)	AHDs identified by ATC codes (J05AB)	AD
Hemmingsson et al., 2021²⁸	Nested case-control study	Sweden (1998–2013)	NP	Case: 9.3 ± 6.1	262 (AD) / 224 (controls)	AHDs identified by ATC codes (J05AB)	AD
Hemmingsson et al., 2021²⁸	Nested case-control study	Sweden (1998–2013)	NP	Control: 13.5 ± 6.9	262 (AD) / 224 (controls)	AHDs identified by ATC codes (J05AB)	AD
Weinmann et al., 2024²⁶	Retrospective cohort study	US (2000–2019)	≥50	6.2 ± 5.0	101,328 (total) / 25,332 (HZ) / 4490 (HZ without AHDs) / 75,996 (controls)	AHDs: acyclovir, famciclovir, ganciclovir, or valganciclovir	All cause dementia

*Mean (±SD) or Median [IQR]

^†Only mentioned 3789 subjects with available claim data, 11.7% had at least one reimbursement for anti-herpetic medication.

y/o: years old; NP: not provided; ICD: International Classification of Diseases; VHA: Veterans Health Administration; NHIRD: Taiwan National Health Insurance Research Database; HZ: herpes zoster; HSV: herpes simplex virus; AHDs: anti-herpetic drugs; AD: Alzheimer's disease; VaD: vascular dementia; ICD: International Classification of Diseases; ATC: Anatomical Therapeutic Chemical Classification System; D+: diagnosis of human herpes virus infection; D-: no diagnosis of human herpes virus infection; T+: anti-herpetic treatment; T-: no anti-herpetic treatment; US: United States; UK: United Kingdom; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; NHI: National Health Insurance; IQR: interquartile range; SD: standard deviation.

A total of 10,361,846 older adults from 14 distinct cohort studies,^13,15,16,^20–27 with mean/median ages ranging from 61.7 to 76 years, were included in our meta-analysis to assess the association between anti-herpetic medications and the dementia risk in non-demented older adults. The mean/median follow-up times varied between 1.4 to 15 years, with the longest follow-up extending to 15 years. Among these studies, seven compared treated subjects (irrespective of whether they had a diagnosed infection) to untreated subjects (T + versus T-), five compared subjects diagnosed with and treated for an infection to those diagnosed but untreated (D + T + versus D + T-), and six compared subjects diagnosed with and treated for an infection to those no diagnosis and no treatment (D + T + versus D-T-).

Notably, studies that mentioned the specific herpesvirus type all focused only on alpha herpesvirus infections.^13–16^,23,24,26,29 Anti-herpetic medications were identified using a code-based approach in medico-administrative databases and generally included drugs such as acyclovir, famciclovir, ganciclovir, and valacyclovir. Among these medications, acyclovir and valacyclovir were the most prescribed in eleven studies^13,14,16,20,^22–27 except for two studies’^15,21 prescriptions were unclear. Anti-herpetic medications were prescribed only once during follow-up in most studies. Five studies^14,24,26,30 also included measurements of the duration and/or frequency of treatment to explore the relationship between anti-herpetic medication usage duration and dementia risk.

Furthermore, the prevalence of anti-herpetic treatments among study participants with alpha herpesvirus infection of each study was detailed in Supplemental Table 2. Notably, in a study from Taiwan,¹³ the prevalence of treatment in the infected population was significantly lower compared to other retrospective cohort studies, with only 5.44% of participants infected with HHV having received anti-herpetic medications. Also, a serology based prospective cohort study from Sweden²⁷ had much lower prescription proportion (6.2%) compared to other registry-based retrospective cohort studies included in our meta-analysis.

Lastly, all studies included assessment of all cause dementia,^13,15,16,^20–27 with four studies also investigating the association between dementia subtypes such as AD or VaD and anti-herpetic medications.^16,22,27 The corresponding aHR for conducting the meta-analysis were shown in Supplemental Table 3.

Quality assessment

Studies included for meta-analysis were of moderate to high quality, as indicated by NOS (Newcastle-Ottawa Scale) scores ranging from 6 to 9 (Table 2 and Supplemental Table 4). However, one study²¹ scored only 5.5, indicating a higher risk of bias due to inadequate information provided about the selection process of the study population.

Table 2.

Risk of bias judgements based on Newcastle-Ottawa Quality Assessment Scale (NOS).

Author, year	Representativeness of exposed cohort	Selection of non-exposed cohort	Ascertainment of exposure	Outcome does not present before study	Comparability	Assessment of outcome	Follow-up long enough*	Adequacy of follow up of cohorts	Quality score
Linard et al., 2022²²	★	★	★	★	★	★	★	★	8
Warren-Gash et al., 2022¹⁵	★	★	★	★	★	★	★	★	8
Lopatko Lindman et al., 2021²³	★	★	★	★	★★	★	★	★	9
Yinong et al., 2021²⁴	✬	★	★	★	★	★	★	★	7.5
Schnier et al., 2021a¹⁶	★	★	★	★	★	⋆	⋆	★	6
Schnier et al., 2021b¹⁶	★	★	★	★	★	⋆	★	★	7
Schnier et al., 2021c¹⁶	★	★	★	★	★	★	★	★	8
Schnier et al., 2021d¹⁶	★	★	★	★	★	★	★	★	8
Bae et al., 2021¹²	★	★	★	★	★	★	✬	★	7.5
Tzeng et al., 2018¹⁴	★	★	★	★	★	★	✬	★	7.5
Chen et al., 2018¹³	★	★	★	★	★	★	★	★	8
Helmer et al., 2015²¹	⋆	⋆	★	★	★	★	✬	★	5.5
Vestin et al., 2024²⁷	★	★	★	★	★★	★	★	★	9
Tan et al., 2024²⁵	★	★	★	★	★	⋆	✬	★	6.5
Weinmann et al., 2024²⁶	★	★	★	★	★	★	★	★	8

*Median follow-up of more than 3 years or maximum follow-up of more than 5 years was considered enough.

Additionally, the quality of the pooled evidence on the impact of anti-herpetic medications on dementia was rated as “very low” to “low” based on GRADE criteria, primarily as notable inconsistency (refer to Supplemental Table 5).

Association between anti-herpetic medications and dementia

To account for the intrinsic heterogeneity across studies, the random-effects model was used in all comparison groups, allowing the true effect size to differ between studies.³¹ Significant effects of anti-herpetic medications on reducing the risk of dementia were observed in all comparison groups: the pooled aHR were 0.90 (95% CI: 0.85–0.94, p _{overall effect} < 0.0001, I² = 67%; p _{heterogeneity} = 0.006) in T + versus T- and 0.77 (95% CI: 0.67–0.89, p _{overall effect} = 0.0004, I² = 64%; p _{heterogeneity} = 0.02) in D + T + versus D + T-, and 0.87 (95% CI: 0.78–0.97, p _{overall effect} = 0.01, I²= 97%; p_{heterogeneity} < 0.00001) in D + T + versus D-T-. Suggesting that anti-herpetic medications overall significantly reduced the risk of dementia by 10%, 26%, and 13% in each comparison groups (Figure 2).

Figure 2.

Forest plots of the effects of anti-herpetic medications on dementia risk among older adults in each comparison group.

Leave-one-out sensitivity analysis and other sensitivity analysis

Due to the high heterogeneity among included studies, leave-one-out and low treatment rate (<10%) sensitivity analyses were performed to assess the influence of individual studies on the meta-analysis results (see Supplemental Figure 1).

In studies that compared subjects diagnosed with and treated for infection versus diagnosed but untreated (D + T + versus D + T-), the 95% confidence interval and p-value of pooled aHR were influenced by study of Chen et al.,¹³ which reported a significantly lower treatment prevalence. The studies’ exclusion also revealed a notable decrease in heterogeneity, as shown in Supplemental Figure 1A and 1B. To enhance reliability, it was therefore excluded from the subgroup analysis.

After excluding two studies with low treatment rates (<10%), one from Taiwan¹³ and one from Sweden,²⁷ the pooled aHR remained quite similar, changing slightly from 0.77 (95% CI: 0.67–0.89) to 0.79 (95% CI: 0.72–0.88). Heterogeneity decreased from 64% to 46%, indicating improved consistency across studies after exclusion (see Supplemental Figure 2).

Subgroup analysis and meta-regression

Because of small number of studies included in our meta-analysis, we could not conduct subgroup analysis according to different follow-up time (median or mean follow-up times ≥5 years or <5 years), baseline age (≥70 years old or < 70 years old), study setting (serology or registry-based study).

Subgroup analysis was conducted according to the severity of alpha herpesvirus infection, revealing a statistically significant impact of anti-herpetic medications on lowering dementia risk in two studies from Taiwan¹⁴ and the US.²⁴ These studies involved subjects with potentially more severe infections (pooled aHR = 0.74, 95% CI: 0.71–0.76, p _{overall effect} < 0.00001; I² = 36%, p _{heterogeneity} = 0.21, p-value of subgroup difference < 0.00001; see Supplemental Figure 3A). Heterogeneity was also decreased, suggesting that the severity of alpha herpesvirus infection may be a source of heterogeneity. A meta-regression confirmed that the severity of alpha herpesvirus infection significantly moderated the treatment effect (p < 0.0001), explaining 89.01% of heterogeneity.

Lastly, significant subgroup effect was not found when considering study quality (p = 0.05; see Supplemental Figure 3B).

Discussion

Summary of findings

This systematic review and meta-analysis of cohort studies comprehensively investigated the association between anti-herpetic medication use and the risk of dementia in non-demented older adults. Our results demonstrate that anti-herpetic medications were significantly associated with a reduced risk of dementia. Notably, the protective association was most pronounced in individuals diagnosed and treated for alpha herpesvirus infection (D + T + versus D + T− comparison), suggesting that timely antiviral intervention following herpesvirus reactivation may mitigate the risk of subsequent cognitive decline.

Findings in relation to previous studies

Our results align with prior observational studies suggesting that alpha herpesvirus infection may contribute to neurodegenerative processes leading to dementia. Although the exact mechanisms by which herpesvirus contributes to dementia remain unclear. The findings are consistent with in vitro studies showing that anti-herpetic agents (such as acyclovir, penciclovir, and foscarnet) significantly inhibit HSV-1 growth and decrease amyloid-β (Aβ) and phosphorylated tau accumulation, which are hallmark pathologies of AD.^7,32 Furthermore, our study extends the work of previous systematic reviews of anti-herpetic medications conducted by Warren-Gash et al.¹⁷ by incorporating a larger number of cohort studies and employing meta-analysis and refined analytical approaches to address heterogeneity. However, some discrepancies exist, particularly with studies that did not observe a significant association,^27,28 potentially due to differences in study populations, follow-up durations, or unmeasured confounders such as APOE ε4 status.

Anti-herpetic medications and dementia

Our study demonstrated that the effect of anti-herpetic medications on lowering the dementia risk was most significant in studies comparing individuals who were diagnosed and treated (D + T+) with those who were diagnosed but untreated (D + T-), reducing potential bias introduced by differences in baseline infection risk. This association provides compelling evidence that older adults with herpesvirus reactivation symptoms, such as herpes labialis caused by HSV-1, could potentially benefit from anti-herpetic treatment to prevent the subsequent development of cognitive decline. Sensitivity analyses excluding studies with treatment rates below 10% further confirmed the robustness of this finding. The pooled effect size remained quite similar (aHR changing from 0.77 to 0.79), while heterogeneity substantially decreased (I² from 64% to 46%), suggesting that studies with atypically low treatment uptake had only a minor influence on the variability observed in the overall analysis. These results further reinforced confidence in the robustness of the observed association between anti-herpetic medication use and reduced dementia risk. However, these findings must be interpreted in the context of the underlying methodological limitations.

Increased levels of heterogeneity were seen in the studies that compared subjects diagnosed and treated (D + T+) versus those without a diagnosis and treatment (D-T-). Subgroup analyses suggested that heterogeneity decreased when stratifying by alpha herpesvirus infection severity. The protective effect was most evident in individuals with symptomatic infections whereas a marginally significant effect was observed when considering alpha herpesvirus infection regardless of severity. Although HHV frequently reactivates in older adults, only 30% of them show symptoms such as cold sores or herpes zoster. Hence, classifying infection status based on symptoms could be subject to misclassification bias, potentially categorizing asymptomatic but seropositive individuals as uninfected. This misclassification could bias results toward a null effect, underestimating the potential protective association between anti-herpetic medications and dementia risk. Nevertheless, our meta-analysis consistently demonstrated a reduced dementia risk among individuals prescribed anti-herpetic medications, even with these limitations. Thus, while the true protective effect may be lower than estimated, the overall trend remains robust.

Possible mechanisms of anti-herpetic medications and dementia

The biological mechanism linking alpha herpesvirus infections and increased dementia risk remains unclear, but several hypotheses have been proposed. Alpha herpesvirus infections have been associated with Aβ deposition and neuroinflammation, mediated by infiltration of IFN-γ-secreting T cells and astrocyte activation.³³ In APOE ε4 carriers, frequent HSV-1 reactivation due to immunosuppression may cause cumulative neuronal damage,³⁴ leading to misfolded oligomers, amyloid plaques, and neurofibrillary tangles.^35–37

By inhibiting viral replication, anti-herpetic medications may indirectly attenuate these pathogenic cascades, potentially reducing the burden of neurodegeneration and dementia risk.^38,39 This may explain why, as demonstrated by two retrospective cohort studies included in our meta-analysis,^14,24 anti-herpetic medications provide a stronger protective effect for older adults with more severe infections. While our findings do not establish a direct causal relationship between antiviral treatment and dementia prevention, they suggest that reducing HHV burden may be a modifiable factor in lowering dementia risk. Future research should focus on longitudinal studies and biomarker analyses to better understand the role of HHV in neurodegeneration and evaluate whether sustained antiviral therapy could offer long-term cognitive benefits.

In recent years, shingle vaccines that directly protect against VZV infection have been linked to a reduced risk of dementia, as shown by previous meta-analyses⁴⁰ and pseudorandomized studies.⁴¹ Vaccinating could potentially prevent cases of encephalitis and lower the associated risk of AD and other forms of dementia. Our study was consistent with recent quasi-experimental evidence from UK,⁴² demonstrating a 20% reduction in dementia incidence following herpes zoster vaccination, supporting the role of herpesvirus-targeted interventions—whether through vaccination or antiviral treatment—in preventing viral reactivation and mitigating dementia risk among older adults. These findings further support the notion that alpha herpesvirus infection may be a contributing risk factor for dementia.

Current clinical practice⁴³ generally reserves anti-herpetic medication for HSV-1 cases involving severe, cosmetically sensitive areas (e.g., face, nasal tip, oropharynx) or frequent, disabling recurrences, while mild or infrequent episodes are often managed symptomatically. Similarly, for VZV, antiviral treatment is typically recommended for patients over 50, immunocompromised individuals, or those with moderate to severe symptoms or ocular complications.⁴⁴ However, our findings suggest that both recurrent infections and cases of any severity may benefit from anti-herpetic treatment in terms of long-term cognitive outcomes. This challenges the current treatment paradigm, which remains narrowly focused on acute symptom control. Antiviral therapy may warrant consideration in HHV-infected individuals to suppress viral reactivations and potentially mitigate future cognitive decline.

An additional consideration is the possibility that younger age at the time of treatment for herpesvirus infection may confer a lasting protective effect against dementia. Early therapeutic intervention might reduce cumulative viral reactivation episodes, systemic inflammation, or neuro-invasion over the lifespan, all of which are hypothesized contributors to neurodegeneration.⁴⁵ However, most included studies do not report the age at first treatment, making it difficult to directly assess this hypothesis. Future longitudinal studies with detailed temporal treatment data are needed to clarify whether early antiviral therapy modifies the trajectory of cognitive aging or dementia risk.

Strength and limitations

Our systematic review and meta-analysis comprehensively investigated the association between anti-herpetic medication and dementia risk using population-based cohort studies. The large sample size (over 10 million individuals) enhances statistical power and generalizability. Rigorous subgroup and sensitivity analyses enhanced the validity of our findings. All studies included in the meta-analysis that specified the type of herpesvirus infection focused exclusively on alpha herpesviruses, thereby minimizing potential confounding from other herpesvirus subfamilies. Furthermore, by separating country-level data for large datasets such as Schnier et al., we addressed potential geographic heterogeneity more precisely.

However, it is crucial to consider several limitations of this study. First, differences in study design, population characteristics, and definitions of HHV-infected individuals and medication use contributed to heterogeneity across studies. Specifically, healthier behaviors and better healthcare access among treatment-adherent individuals may partially account for the observed protective association. The observational study design, while informative, cannot establish causality, and residual confounding may still be present despite adjustments for known confounders. Second, the relationship between antiviral treatment and dementia risk could be significantly influenced by the duration and frequency of anti-herpetic medication use. However, most studies included in our analysis did not provide this information. Also, confounding by indication may be a significant problem in most observational studies in our meta-analysis. Third, the data available were insufficient for a meaningful subgroup analysis and publication bias assessment in our study. Lastly, it is important to note that most studies included in this meta-analysis investigated the treatment of HSV and few VZV infections, and thus the observed protective effects may not be generalizable to other herpesviruses such as CMV. Future research should aim to specifically evaluate the impact of anti-herpetic medications on dementia risk associated with other herpesvirus infections, particularly VZV, given its prevalence in older adults and its potential contribution to neurodegenerative processes.

Conclusions

This systematic review and meta-analysis of population-based cohort studies provide compelling evidence that anti-herpetic medications are associated with a reduced risk of dementia. Notably, our findings indicate that patients with recurrent or severe alpha herpesvirus infections exhibit the greatest protective effect from antiviral treatment, underscoring the importance of antiviral use in this population to effectively suppress viral reactivation and mitigate long-term cognitive risk. This challenges the current clinical paradigm, which largely reserves antiviral therapy for acute symptom control. It may be worth considering antiviral treatment in HHV-infected individuals to reduce viral reactivations and the subsequent risk of cognitive decline. Moving forward, future studies should focus on elucidating the underlying biological mechanisms by which antiviral therapy may influence neurodegenerative processes, such as Aβ accumulation, tau pathology, and chronic neuroinflammation. Furthermore, exploring how host factors—such as APOE ε4 status and immune function—modulate the impact of alpha herpesvirus infection on brain aging may help identify populations most likely to benefit from early intervention. If validated, these findings may inform future public health strategies for dementia prevention.

Supplemental Material

sj-docx-1-alz-10.1177_13872877251409323 - Supplemental material for Anti-herpetic treatment reduces dementia risk: A systematic review and meta-analysis

Supplemental material, sj-docx-1-alz-10.1177_13872877251409323 for Anti-herpetic treatment reduces dementia risk: A systematic review and meta-analysis by Syuan-Ting Chang, Hon-Yen Wu, Yen-Ling Chiu and Yi-Fang Chuang in Journal of Alzheimer's Disease

Footnotes

Acknowledgements

The authors have no acknowledgments to report.

ORCID iDs

Syuan-Ting Chang

Hon-Yen Wu

Yen-Ling Chiu

Yi-Fang Chuang

Ethical considerations

Not applicable

Consent to participate

Not applicable

Consent for publication

Not applicable

Author contribution(s)

Syuan-Ting Chang: Conceptualization; Data curation; Formal analysis; Methodology; Software; Visualization; Writing – original draft.

Hon-Yen Wu: Supervision; Validation; Writing – review & editing.

Yen-Ling Chiu: Supervision; Validation; Writing – review & editing.

Yi-Fang Chuang: Conceptualization; Investigation; Methodology; Project administration; Validation; Writing – review & editing.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Far Eastern Memorial Hospital-National Yang Ming University collaboration grant 110DN18.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

The data supporting the findings of this study are available within the article and its Supplemental Material.

Supplemental material

Supplemental material for this article is available online.

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