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