Herpes simplex virus (HSV) has been suggested to play a role in Alzheimer’s disease (AD) development.
Objective:
The aim of the present study was to investigate the early AD-related symptom episodic memory decline in relation to HSV and carriage of allele 4 of the apolipoprotein E gene (APOEɛ4) in a large population-based cohort with a long follow-up time.
Methods:
The study included 3,413 persons, with longitudinal data available for 1,293 persons with a mean follow-up time of 11.6 years. The associations between HSV carriage, APOEɛ4 carriage, and episodic memory was investigated at baseline, as well as in longitudinal analyses where individuals with and without HSV antibodies (HSV1/2 non-specific) were matched and episodic memory decline compared.
Results:
Cross-sectional analyses revealed an age-dependent association of HSV carriage with lower episodic memory function, particularly among APOEɛ4 carriers (p = 0.008). Longitudinal analyses showed an increased risk of episodic memory decline in HSV carriers (≥65 years: p < 0.001, all ages: non-significant), and a significant interaction between HSV and APOEɛ4 for episodic memory decline (p < 0.001).
Conclusion:
In this large population-based cohort study, both cross-sectional and longitudinal results support an association between HSV carriage and declining episodic memory function, especially among APOEɛ4 carriers. The results strengthen the hypothesis that HSV is associated with AD development.
World Health Organization, Alzheimer’s Disease International (2012) Dementia: A public health priority,World Health Organization.
4.
OlssonJ, LovheimH, HonkalaE, KarhunenPJ, ElghF, KokEH (2016) HSV presence in brains of individuals without dementia: The TASTY brain series. Dis Model Mech9,1349–1355.
5.
OlssonJ, KokE, AdolfssonR, LovheimH, ElghF (2017) Herpes virus seroepidemiology in the adult Swedish population. Immun Ageing14,10.
6.
SteinerI, KennedyPG, PachnerAR (2007) The neurotropic herpes viruses: Herpes simplex and varicella-zoster. Lancet Neurol6,1015–1028.
7.
BearerEL (2012) HSV, axonal transport and Alzheimer’s disease: In vitro and in vivo evidence for causal relationships. Future Virol7,885–899.
8.
BallMJ (1982) Limbic predilection in Alzheimer dementia: Is reactivated herpesvirus involved?Can J Neurol Sci9,303–306.
9.
ItzhakiRF, LinWR, ShangD, WilcockGK, FaragherB, JamiesonGA (1997) Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet349,241–244.
10.
ReadheadB, Haure-MirandeJV, FunkCC, RichardsMA, ShannonP, HaroutunianV, SanoM, LiangWS, BeckmannND, PriceND, ReimanEM, SchadtEE, EhrlichME, GandyS, DudleyJT (2018) Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron99,64–82e67.
11.
WozniakMA, MeeAP, ItzhakiRF (2009) Herpes simplex virus type 1 DNA is located within Alzheimer’s disease amyloid plaques. J Pathol217,131–138.
12.
SantanaS, RecueroM, BullidoMJ, ValdiviesoF, AldudoJ (2012) Herpes simplex virus type I induces the accumulation of intracellular beta-amyloid in autophagic compartments and the inhibition of the non-amyloidogenic pathway in human neuroblastoma cells. Neurobiol Aging33,430e419–433.
13.
EimerWA, Vijaya KumarDK, Navalpur ShanmugamNK, RodriguezAS, MitchellT, WashicoskyKJ, GyorgyB, BreakefieldXO, TanziRE, MoirRD (2018) Alzheimer’s disease-associated beta-amyloid is rapidly seeded by her-pesviridae to protect against brain infection. Neuron99,56–63e53.
14.
AlvarezG, AldudoJ, AlonsoM, SantanaS, ValdiviesoF (2012) Herpes simplex virus type 1 induces nuclear accumulation of hyperphosphorylated tau in neuronal cells. J Neurosci Res90,1020–1029.
15.
BourgadeK, GarneauH, GirouxG, Le PageAY, BoctiC, DupuisG, FrostEH, FulopTJr (2015) Beta-Amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1. Biogerontology16,85–98.
16.
SosciaSJ, KirbyJE, WashicoskyKJ, TuckerSM, IngelssonM, HymanB, BurtonMA, GoldsteinLE, DuongS, TanziRE, MoirRD (2010) The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One5,e9505.
17.
KumarDK, ChoiSH, WashicoskyKJ, EimerWA, TuckerS, GhofraniJ, LefkowitzA, McCollG, GoldsteinLE, TanziRE, MoirRD (2016) Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci Transl Med8,340ra372.
18.
LittleCS, JoyceTA, HammondCJ, MattaH, CahnD, AppeltDM, BalinBJ (2014) Detection of bacterial antigens and Alzheimer’s disease-like pathology in the central nervous system of BALB/c mice following intranasal infection with a laboratory isolate of Chlamydia pneumoniae. Front Aging Neurosci6,304.
19.
TanakaS, NagashimaH (2018) Establishment of an Alzheimer’s disease model with latent herpesvirus infection using PS2 and Tg2576 double transgenic mice. Exp Anim67,185–192.
20.
LetenneurL, PeresK, FleuryH, GarrigueI, Barberger-GateauP, HelmerC, OrgogozoJM, GauthierS, DartiguesJF (2008) Seropositivity to herpes simplex virus antibodies and risk of Alzheimer’s disease: A population-based cohort study. PLoS One3,e3637.
21.
LovheimH, GilthorpeJ, AdolfssonR, NilssonLG, ElghF (2015) Reactivated herpes simplex infection increases the risk of Alzheimer’s disease. Alzheimers Dement11,593–599.
22.
LovheimH, GilthorpeJ, JohanssonA, ErikssonS, HallmansG, ElghF (2015) Herpes simplex infection and the risk of Alzheimer’s disease: A nested case-control study. Alzheimers Dement11,587–592.
23.
BurgosJS, RamirezC, SastreI, ValdiviesoF (2006) Effect of apolipoprotein E on the cerebral load of latent herpes simplex virus type 1 DNA. J Virol80,5383–5387.
24.
KoelleDM, MagaretA, WarrenT, SchellenbergGD, WaldA (2010) APOE genotype is associated with oral herpetic lesions but not genital or oral herpes simplex virus shedding. Sex Transm Infect86,202–206.
25.
SalmonDP, BondiMW (2009) Neuropsychological assessment of dementia. Annu Rev Psychol60,257–282.
26.
RonnlundM, SundstromA, AdolfssonR, NilssonLG (2015) Subjective memory impairment in older adults predicts future dementia independent of baseline memory performance: Evidence from the Betula prospective cohort study. Alzheimers Dement11,1385–1392.
27.
JosefssonM, de LunaX, PudasS, NilssonLG, NybergL (2012) Genetic and lifestyle predictors of 15-year longitudinal change in episodic memory. J Am Geriatr Soc60,2308–2312.
28.
RonnlundM, NybergL, BackmanL, NilssonLG (2005) Stability, growth, and decline in adult life span development of declarative memory: Cross-sectional and longitudinal data from a population-based study. Psychol Aging20,3–18.
29.
HaydenKM, ReedBR, ManlyJJ, TommetD, PietrzakRH, CheluneGJ, YangFM, RevellAJ, BennettDA, JonesRN (2011) Cognitive decline in the elderly: An analysis of population heterogeneity. Age Ageing40,684–689.
30.
DickersonF, StallingsC, SullensA, OrigoniA, LeisterF, KrivogorskyB, YolkenR (2008) Association between cognitive functioning, exposure to Herpes Simplex Virus type 1, and the COMT Val158Met genetic polymorphism in adults without a psychiatric disorder. Brain Behav Immun22,1103–1107.
31.
StrandbergTE, PitkalaK, EerolaJ, TilvisR, TienariPJ (2005) Interaction of herpesviridae, APOE gene, and education in cognitive impairment. Neurobiol Aging26,1001–1004.
32.
StrandbergTE, PitkalaKH, LinnavuoriKH, TilvisRS (2003) Impact of viral and bacterial burden on cognitive impairment in elderly persons with cardiovascular diseases. Stroke34, 2126–2131.
KatanM, MoonYP, PaikMC, SaccoRL, WrightCB, ElkindMS (2013) Infectious burden and cognitive function: The Northern Manhattan Study. Neurology80, 1209–1215.
35.
FruchterE, GoldbergS, FenchelD, GrottoI, GinatK, WeiserM (2015) The impact of Herpes simplex virus type 1 on cognitive impairments in young, healthy individuals - A historical prospective study. Schizophr Res168,292–296.
36.
TarterKD, SimanekAM, DowdJB, AielloAE (2014) Persistent viral pathogens and cognitive impairment across the life course in the third national health and nutrition examination survey. J Infect Dis209,837–844.
37.
BrownWD, BearerEL, DonahueJE (2010) Chronic active herpes simplex type 2 encephalitis in an asymptomatic immunocompetent child. J Child Neurol25,901–908.
38.
WrightCB, GardenerH, DongC, YoshitaM, DeCarliC, SaccoRL, SternY, ElkindMS (2015) Infectious burden and cognitive decline in the Northern Manhattan Study. J Am Geriatr Soc63,1540–1545.
39.
AielloAE, HaanM, BlytheL, MooreK, GonzalezJM, JagustW (2006) The influence of latent viral infection on rate of cognitive decline over 4 years. J Am Geriatr Soc54,1046–1054.
40.
NilssonLG, BackmanL, ErngrundK, NybergL, AdolfssonR, BuchtG, KarlssonS, WidingM, WinbladB (1997) The Betula prospective cohort study: Memory, health and aging. Aging Neuropsychol Cogn4, 1–32.
41.
SundstromA, MarklundP, NilssonLG, CrutsM, AdolfssonR, Van BroeckhovenC, NybergL (2004) APOE influences on neuropsychological function after mild head injury: Within-person comparisons. Neurology62, 1963–1966.
42.
PudasS, PerssonJ, JosefssonM, de LunaX, NilssonLG, NybergL (2013) Brain characteristics of individuals resisting age-related cognitive decline over two decades. J Neurosci33, 8668–8677.
43.
AbadieA, ImbensG (2006) Large sample properties of matching estimators for average treatment effects. Econometrica74,235–267.
44.
SekhonJ (2011) Multivariate and propensity score matching software with automated balance optimization: The matching package for R. J Stat Softw42,1–18.
45.
LovheimH, OlssonJ, WeidungB, JohanssonA, ErikssonS, HallmansG, ElghF (2018) Interaction between cytomegalovirus and herpes simplex virus type 1 associated with the risk of Alzheimer’s disease development. J Alzheimers Dis61,939–945.
