Seropositivity to Herpes Simplex Virus Antibodies and
Risk of Alzheimer’s Disease: A Population-Based Cohort
Luc Letenneur1,2*, Karine Pe ´re `s1,2, Herve ´ Fleury2,3, Isabelle Garrigue2,3, Pascale Barberger-Gateau1,2,
Catherine Helmer1,2, Jean-Marc Orgogozo1,2, Serge Gauthier4, Jean-Franc ¸ois Dartigues1,2
1INSERM, U897, Bordeaux, France, 2Universite Victor Segalen Bordeaux 2, Bordeaux, France, 3Universite Victor Segalen Bordeaux 2, Laboratoire de Virologie, Bordeaux,
France, 4McGill University, Centre for Studies in Aging, Montreal, Quebec, Canada
Background: Herpes Simplex Virus (HSV) infection has been proposed as a possible risk factor of Alzheimer’s Disease (AD)
notably because it is neurotropic, ubiquitous in the general population and able to establish lifelong latency in the host. The
fact that HSV was present in elderly subjects with AD suggests that the virus could be a co-factor of the disease. We
investigated the risk of developing AD in anti-HSV immunoglobulin G (IgG) positive subjects (indicator of a lifelong infection
to HSV) and IgM-positive subjects (indicator of primary infection or reactivation of the virus) in a longitudinal population-
based cohort of elderly subjects living in the community.
Methods: Cox proportional hazard models were used to study the risk of developing AD according to the presence or not of
anti-HSV IgG and IgM antibodies, assessed in the sera of 512 elderly initially free of dementia followed for 14 years.
Results: During the follow-up, 77 incident AD cases were diagnosed. Controlled for age, gender, educational level and
Apolipoprotein E4 (APOE4) status, IgM-positive subjects showed a significant higher risk of developing AD (HR=2.55; 95%
CI [1.38–4.72]), although no significant increased risk was observed in IgG-positive subjects (HR=1.67; 95%CI [0.75–3.73]).
No modification effect with APOE4 status was found.
Conclusion: Reactivation of HSV seropositivity is highly correlated with incident AD. HSV chronic infection may therefore be
contributive to the progressive brain damage characteristic of AD.
Citation: Letenneur L, Pe ´re `s K, Fleury H, Garrigue I, Barberger-Gateau P, et al. (2008) Seropositivity to Herpes Simplex Virus Antibodies and Risk of Alzheimer’s
Disease: A Population-Based Cohort Study. PLoS ONE 3(11): e3637. doi:10.1371/journal.pone.0003637
Editor: Richard Hornung, Cincinnati Childrens Hospital, United States of America
Received June 25, 2008; Accepted October 13, 2008; Published November 4, 2008
Copyright: ? 2008 Letenneur et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The PAQUID study was supported by grants from Fondation de France, Novartis Laboratories, IPSEN laboratories, Conseil Ge ´ne ´ral de la Gironde, Conseil
Re ´gional d’Aquitaine, SCOR Insurance (France). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: email@example.com
In the general population, Herpes Simplex Virus (HSV) is
highly prevalent (more than 70% after age 50) [1–3]. This virus
persists latently in the peripheral nervous system, and periodically
reactivates with production of active virus. Herpes Simplex
Encephalopathy (HSE) is a rare but very severe acute infection
of the central nervous system . Although it has a very different
course from Alzheimer’s disease (AD), it leads to the occurrence of
bilateral hippocampal-inner temporal lesions resulting in profound
verbal memory loss, characteristic of AD. On the basis of this
hippocampal and temporal tropism of the virus, HSV was
proposed as a candidate environmental risk factor for AD .
Some studies found that HSV has been detected in the brain of
many AD patients, both by direct detection of virus DNA by
polymerase chain reaction (PCR)  and by the detection of
intrathecal antibodies . However, as the virus was also
frequently detected in normal brains of aged individuals, it is
unlikely that HSV infection is the only cause of the disease, but it
may participate in the pathogenic process.
The fact that the frequency of HSV DNA-positive subjects was
not different between AD and control subjects  and that
intrathecal IgG antibodies were detected in a similar proportion of
patients with AD and elderly controls  indicates that chronic
HSV infection alone is not univocally associated with AD. It has
been suggested, however, that the risk of developing AD in
subjects positive for HSV DNA presence in the brain who carried
apolipoprotein E e4 allele (APOE-e4) was several fold that of
individuals possessing only one or neither of these factors .
However, this finding remains controversial as it has not been
confirmed by another study .
Few studies have investigated the seroprevalence of anti-HSV
antibodies in AD. Renvoize et al  found no statistically
significant difference in serum antibody titres to HSV in a sample
of 33 AD patients and 28 controls. Ounanian et al  in a sample
of 19 AD patients and 21 controls, showed increased titres of
PLoS ONE | www.plosone.org1 November 2008 | Volume 3 | Issue 11 | e3637
antibodies to HSV in the control group but the proportion of
HSV-positive subjects was not different between AD and control
groups. These studies were performed on small samples of
individuals and with IgG antibodies only, which characterise past
infections. IgM antibodies, which characterise primary infections
or reactivations, have not been investigated. Our objective is to
assess the risk of developing AD according to the baseline anti-
HSV-1 or HSV-2 immunoglobulin status (IgG and IgM) over a
14-year period of follow-up in a large prospective population-
based study of elderly subjects.
This study was part of the PAQUID (Personnes Agees QUID)
research programme, a prospective cohort study of normal and
pathological cerebral aging, composed of a randomly selected
sample of non-institutionalised individuals aged 65 years and over
living in the south west of France. The methodology of this study
has already been extensively described . The survey started in
1988, following 3777 subjects who were interviewed at home by
trained psychologists one, three, five, eight, 10, 13 and 15 years
after the baseline visit. Subjects who agreed to participate in the
study gave their written informed consent; the study was approved
by the Ethics Committee of the University Hospital of Bordeaux.
At each visit, cognitive performances were evaluated using a
comprehensive battery of neuropsychological tests including the
Mini Mental State Examination (MMSE) . After the
psychometric evaluation, the psychologists systematically complet-
ed an evaluation of the DSMIII-R criteria for dementia  and
subjects who met these criteria were subsequently seen by a senior
neurologist who confirmed the diagnosis of dementia. Alzheimer’s
disease was diagnosed according to the National Institute of
Neurological and Communicative Disorders and Stroke/the
(NINCDS/ADRDA) criteria .
At the first year visit in 1989, a subsample of 591 volunteers
agreed to have a blood sample. Serum samples were frozen and
stored in liquid nitrogen for subsequent analysis. The samples were
analysed in 2007 to assess seropositivity to HSV. The detection of
IgM and IgG antibodies to HSV was performed following the
manufacturer’s recommendations (Enzygnost Anti HSV/IgM and
IgG, Dade Behring, Marburg, Germany) from 10 ml of serum for
each parameter. The Enzygnost Anti-HSV/IgG (and Anti-HSV/
IgM) is an ELISA for the quantitative determination of human
IgG (respectively IgM) antibodies to HSV in serum. Subjects were
considered positive for an optical density greater or equal to 0.1.
IgG titres were expressed in international units per millilitre (IU/
ml). Twenty eight subjects already demented at the time of blood
collection were not included in the present analysis; in addition, 51
subjects who died or refused to participate to the follow-up after
the blood sampling were also excluded. A total of 512 were then
included in the present study. Subjects had only one blood
sampling and no lumbar puncture was performed during the
Statistical analysis: Cumulative incidence rates of AD were
estimated. The cumulative incidence rates which measure the
proportion of individuals who develop the disease during a
specified period of time were obtained by the Kaplan-Meier
method. The hazard ratios (HR) of AD and 95% confidence
intervals (95% CI) were estimated using a Cox proportional
hazard model. The association between IgG and IgM status and
the onset of AD was controlled for age at inclusion, gender,
educational level (primary school with diploma vs no schooling or
primary school without diploma) and APOE-e4 allele. To further
investigate the evolution of the cognitive performance over time,
the annual rate of change in MMSE score was modelled by a
linear mixed model . The adjusted model included terms for
IgG or IgM status, age at baseline, gender, education level, APOE-
e4, time (time in years since the baseline visit, i.e. the blood
sampling) and interaction terms between time and each covariate.
The parameters for time interactions represent the estimated effect
of the covariate on the annual rate of change since baseline. As the
distribution of MMSE scores was not normal, we analyzed the
square root of the number of errors, as proposed by Jacqmin-
Gadda et al . Indeed, these authors stated that, after
transformation, graphical examination of residuals indicated that
the hypotheses of normality and homoscedasticity were accept-
able. Therefore, we chose to apply the same transformation to our
data. All statistical analyses were done using SAS, version 9.1 (SAS
institute, Inc., Cary, North Carolina).
Among the 512 non-demented subjects at inclusion, 99
developed a dementia (including 77 AD) over 8.2 years
(SD=4.4) of follow-up on average. The main characteristics of
the subjects are given in table 1. As expected, subjects with
incident dementia were older at inclusion. Incident AD cases were
more frequently women and APOE-e4 bearers. At baseline, 424
subjects (82.8%) were IgG-positive and 43 (8.4%) were IgM-
positive. Only 86 (16.8%) subjects were negative for both IgG and
IgM. Among the 43 IgM-positive subjects, only 2 were IgG-
negative. Therefore, it is likely that most of the IgM-positive
subjects showed recent reactivation of the virus. Unfortunately, no
Table 1. Main characteristics of the sample according to dementia status.
Non dementedIncident Alzheimer’s disease Other incident dementia
Number of subjects 41377 22
Age at inclusion. mean (sd)72.8 (5.8) 75.8 (6.0) 74.4 (5.7)
Age at diagnosis or censorship. mean (sd) 82.8 (5.7) 85.8 (6.0) 85.4 (6.0)
Female gender (%)52.571.459.1
High educational level (%)76.561.077.3
APOE e4 allele (%) 20.729.331.8
Anti-HSV IgG positive (%)81.189.690.9
Anti-HSV IgM positive (%)7.0 16.94.5
PAQUID study, n=512.
Herpes Virus and Alzheimer
PLoS ONE | www.plosone.org 2November 2008 | Volume 3 | Issue 11 | e3637
information was available about clinical manifestations of the
infection to confirm this hypothesis.
During the follow-up, 69 (16.3%) of the 424 IgG-positive
subjects, and 8 (9.1%) of the 88 IgG negative subjects developed
AD. Among IgG-positive subjects, mean IgG titres were not
significantly different between non-demented and demented
subjects (mean (sd) :141 (57.3) and 151 (58.0), respectively,
p=0.13 ; median : 143 and 151 IU/ml, respectively). Thirteen
Figure 1. Cumulative Alzheimer’s disease rate according to anti-HSV IgG (top) or anti-HSV IgM (bottom) status. Kaplan-Meier
estimates, PAQUID study, n=512.
Herpes Virus and Alzheimer
PLoS ONE | www.plosone.org3November 2008 | Volume 3 | Issue 11 | e3637
(30.2%) of the 43 IgM-positive and 64 (13.7%) of the 469 IgM-
negative subjects developed AD. The cumulative AD rate curves
according to IgG and IgM status are displayed in figure 1. HSV-
positive subjects showed a greater cumulative probability of
developing AD than HSV-negative ones for both IgG and IgM.
Cumulative AD rates were about 25% (95% CI: 0.08–0.39) in
IgM positive subjects after 10 years of follow-up and reached a
frequency of more than 50% (95% CI: 0.33–0.76) after 14 years.
After controlling for age, gender, educational level, APOE-e4
and baseline MMSE, the hazard ratio of developing AD was not
significantly greater in IgG-positive subjects (Table 2). In contrast,
IgM-positive status at baseline was strongly associated with an
increased risk of developing AD (Table 3). No modification effect
was found between APOE and Ig status: p=0.49 for IgM and
p=0.94 for IgG.
No significant association was found when other types of
dementia (n=22) were compared to non-demented subjects
(n=413): for IgG-positive subjects, HR=2.16, (95% CI : [0.48 ;
9.69] p=0.31) and HR=0.61, (95% CI : [0.08 ; 4.68], p=0.63)
for IgM-positive subjects.
A linear mixed model was fitted to analyze the evolution of the
square root of the number of errors to the MMSE over a 14-year
period. After adjustment for age, sex, education level and APOE-
e4, IgG status was marginally associated with the baseline score
(b=0.14, p=0.056). The parameter was greater than 0 and this
indicated that the number of errors at baseline tended to be higher
for IgG positive subjects. The time parameter (b=0.017, p=0.17)
showed a negligible and non significant increase of the number of
errors over time. At baseline, IgM positive subjects tended to make
fewer errors (b=20.069, p=0.50) than IgM negative ones, but
the number of errors increased significantly over time (b=0.035,
The present cohort is the first to show the increased risk of AD
in elderly subjects with a positive detection of anti-HSV IgM
antibodies in a large population-based prospective study, after
adjustment for known risk factors of AD, i.e. age, education and
APOE status. This higher risk of dementia seems specific of AD,
since the HR for other dementias was not significant, but the
corresponding sample was small. In contrast, subjects with positive
detection of anti-HSV IgG antibodies in the sera were not at
higher risk of AD than IgG-negative subjects. This last result is in
accordance with previous case-control clinical series [10,11].
These results were confirmed when analysing the evolution of
cognitive performance measured by the MMSE. This analysis did
not rely only on a small sample of demented subjects and
confirmed the greater cognitive decline of IgM positive subjects.
Strandberg et al  analysed cognitive decline in 383 elderly
cardiovascular subjects according to viral burden (3 herpesviradae
: HSV1, HSV2, Cytomegalovirus (CMV)) and bacterial burden (C
pneumoniae, M Pneumoniae) and showed a greater cognitive decline
with viral burden in a stepwise manner. The HR of developing
cognitive decline was 1.8 in subjects with 2 seropositivities and 2.3
in subjects with 3 seropositivities compared to subjects with 0 or 1
seropositivity. Aiello et al  showed a higher rate of cognitive
decline over a 4 year period in subjects with the highest CMV
antibody levels and no association between cognitive decline and
HSV antibody levels. In this study, HSV-1 IgG antibodies were
assessed and, as in the other studies examining IgG antibodies, it is
likely that the titre remained unaltered between and during
periods of recrudescence.
In this study, the sub-type of HSV virus (HSV-1 or HSV-2) was
not determined. Since HSV-1 is more prevalent than HSV-2 ,
it is most likely that subjects were infected with HSV-1 virus. In
addition, HSE caused by HSV-2 is very rare in adults. Further
research is needed to analyse the impact of each virus type on the
risk of AD.
Contrary to the findings of Itzhaki et al  in the comparison of
brains of AD patients and controls, we did not find any interaction
between APOE status and IgM-positive status on risk of AD.
These negative results could be related to a lack of statistical power
of our study since only 12 subjects were APOE4 bearers and IgM-
positive. In our sample, we did not diagnose any case of herpes
encephalitis that involves acute infection of the brain  whereas
AD shows a progressive cognitive evolution.
Since IgM antibodies are present in the blood for a limited time
period (the IgM response tends to decline within about one to two
months , but in HSE, IgM persisted at a range from 56 days to
328 days ), IgM positive status indicated that HSV
reactivation was recent. In addition, a high prevalence of positive
IgM results among patients with established HSV infection 
has been observed. As antibodies detection was performed only
once in our study, we do not have any information of possible later
reactivation of the virus. However, we may hypothesise that we
had identified subjects involved in a chronic infection to regularly
reactivating HSV, as that was well known for other HSV
manifestations like cold sores. As no clinical information was
collected about the occurrence of cold sores, we do not have any
data to support this hypothesis.
Several interpretations could explain these findings. HSV1,
which causes the rare and very severe herpes encephalitis, could
possibly also produce a milder and chronic brain disease which
selectively damages the very same brain areas that are affected in
AD . Thus, multiple HSV reactivations would lead to a
Table 2. Hazard ratio of developing AD according to Anti-
HSV IgG status.
HR 95% CIp-value
Anti-HSV IgG status1.67 0.75–3.73 0.21
Female gender 1.510.88–2.60 0.13
High educational level0.920.53–1.600.77
APOE-e4 allele 2.321.35–3.990.002
MMS score0.83 0.75–0.920.0003
Cox Model, PAQUID study, n=512.
Table 3. Hazard ratio of developing AD according to Anti-
HSV IgM status.
HR95% CI p-value
Anti-HSV IgM status2.55 1.38–4.72 0.003
Age1.12 1.07–1.17 0.0001
Female gender 1.480.86–2.56 0.16
High educational level0.87 0.49–1.52 0.62
APOE-e4 allele 2.001.18–3.410.011
MMS score 0.820.74–0.91 0.0002
Cox Model, PAQUID study, n=512.
Herpes Virus and Alzheimer
PLoS ONE | www.plosone.org4November 2008 | Volume 3 | Issue 11 | e3637
progressive injury in parts of the brain that may favour the clinical
expression of AD. The dynamics of the incidence of AD according
to IgM status (figure 1) showed an increase more than 7 years after
blood sampling. These reactivations do not seem to lead to
instantaneous cognitive impairment, but rather may weaken
cerebral tissue, leading several years later to AD. This might also
explain the absence of association in IgG positive subjects since
they were not involved in persistent infection. Other authors have
proposed that HSV reactivations could enhance the aggregation of
the beta-amyloid protein . Another possibility is a cross-
reaction between HSV antibodies and beta-amyloid peptide.
Indeed, a significant region of homology between the beta-amyloid
protein found in AD and HSV-1 glycoprotein B (gB) has been
described . Specifically, gB residues 22–44 (gB22–44) share high
similarity to the beta-amyloid carboxyl putative neurotoxic,
nucleation and assembly domains. To be IgM positive would
then be a marker of the ongoing process of AD pathology.
Another hypothesis is the influence of inflammation due to HSV
infection on Alzheimer’s disease. In several models of chronic
neurodegenerative conditions, a pro-inflammatory response is
observed  but it is kept under tight control, probably by
appropriate anti-inflammatory mediators. The disruption of this
anti-inflammatory microglial state has deleterious consequences
for the progression of the disease [26,27]. In a triple-transgenic
mouse model of Alzheimer’s disease, repeated challenges with
lipopolysaccharide were shown to exacerbate central nervous
system inflammation and to cause increased tau phosphorylation
. As AD pathology begins many years before the dementia
stage, recurrent reactivation of HSV might act as a potent stimulus
to the brain microglia, increasing the level of cytokines and
initiating a positive feedback cycle that gives rise to an increasing
accumulation of pathological changes.
If one of both interpretations were true, the prevention of AD
by treating or preventing HSV reactivations could be actions to be
An important consequence of our results lies in the fact that
subjects with reactivation of HSV are easily detectable through a
simple serum analysis which, if repeated over time, could be the
basis of primary or secondary prevention strategies towards AD.
Conceived and designed the experiments: LL KP PBG HC DJF.
Performed the experiments: LL IG HC. Analyzed the data: LL DJF.
Contributed reagents/materials/analysis tools: KP HF IG. Wrote the
paper: LL HF PBG JMO SG DJF.
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