8 research outputs found
Interaction between APOE4 and herpes simplex virus type 1 in Alzheimer's disease
Introduction: Numerous results suggest the implication of infectious agents in the onset of Alzheimer's disease (AD).Methods: In the Bordeauxâ3C prospective cohort, we assessed the impact of herpes simplex virus type 1 (HSVâ1) infection on the incidence of AD according to apolipoprotein E (APOE) status, a genetic susceptibility factor. Cox models were performed to estimate the 10âyear risk of AD associated with antiâHSV antibodies in 1037 participants according to APOE4 status.Results: Among APOE4 carriers, subjects for whom the frequency of HSVâ1 reactivation is supposed to be high, that is, immunoglobulin M (IgM) positive or elevated levels of IgG, had an increased risk of AD with adjusted hazard ratios (HRs) of 3.68 (1.08â12.55) and 3.28 (1.19â9.03), respectively. No significant association was found in APOE4ânegative subjects.Discussion: These results, in accordance with a solid pathophysiological rationale, suggest a role for HSVâ1 in AD development among subjects with a genetic susceptibility factor, the APOE4 allele
Antiherpetic drugs: a potential way to prevent Alzheimer's disease?
BACKGROUND: Considering the growing body of evidence suggesting a potential implication of herpesviruses in the development of dementia, several authors have questioned a protective effect of antiherpetic drugs (AHDs) which may represent a new means of prevention, well tolerated and easily accessible. Subsequently, several epidemiological studies have shown a reduction in the risk of dementia in subjects treated with AHDs, but the biological plausibility of this association and the impact of potential methodological biases need to be discussed in more depth. METHODS: Using a French medico-administrative database, we assessed the association between the intake of systemic AHDs and the incidence of (i) dementia, (ii) Alzheimer's disease (AD), and (iii) vascular dementia in 68,291 subjects over 65 who were followed between 2009 and 2017. Regarding potential methodological biases, Cox models were adjusted for numerous potential confounding factors (including proxies of sociodemographic status, comorbidities, and use of healthcare) and sensitivity analyses were performed in an attempt to limit the risk of indication and reverse causality biases. RESULTS: 9.7% of subjects (n=6642) had at least one intake of systemic AHD, and 8883 incident cases of dementia were identified. Intake of at least one systemic AHD during follow-up was significantly associated with a decreased risk of AD (aHR 0.85 95% confidence interval [0.75-0.96], p=0.009) and, to a lesser extent with respect to p values, to both dementia from any cause and vascular dementia. The association with AD remained significant in sensitivity analyses. The number of subjects with a regular intake was low and prevented us from studying its association with dementia. CONCLUSIONS: Taking at least one systemic AHD during follow-up was significantly associated with a 15% reduced risk of developing AD, even after taking into account several potential methodological biases. Nevertheless, the low frequency of subjects with a regular intake questions the biological plausibility of this association and highlights the limits of epidemiological data to evaluate a potential protective effect of a regular treatment by systemic AHDs on the incidence of dementia
Herpes simplex virus, early neuroimaging markers and incidence of Alzheimer's disease
While previous studies suggest the implication of herpes simplex virus (HSV) in the onset of Alzheimer's disease (AD), no study has investigated its association with early neuroimaging markers of AD. In the Three-City and the AMI cohorts, the associations between HSV infection and (i) hippocampal volume (nâ=â349), (ii) white matter alterations in the parahippocampal cingulum and fornix using diffusion tensor imaging (nâ=â260), and (iii) incidence of AD (nâ=â1599) were assessed according to APOE4 status. Regardless of APOE4 status, infected subjects presented (i) significantly more microstructural alterations of the parahippocampal cingulum and fornix, (ii) lower hippocampal volumes only when their anti-HSV IgG level was in the highest tercile-reflecting possibly more frequent reactivations of the virus (pâ=â0.03 for subjects with a high anti-HSV IgG level while there was no association for all infected subjects, pâ=â0.19), and (iii) had no increased risk of developing AD. Nevertheless, among APOE4 carriers, infected subjects presented lower hippocampal volumes, although not significant (pâ=â0.09), and a two or three times higher risk of developing AD (adjusted Hazard ratio (aHR)â=â2.72 [1.07-6.91] pâ=â0.04 for infected subjects and aHRâ=â3.87 [1.45-10.28] pâ=â0.007 for infected subjects with an anti-HSV IgG level in the highest tercile) while no association was found among APOE4 noncarriers. Our findings support an association between HSV infection and AD and a potential interaction between HSV status and APOE4. This reinforces the need to further investigate the infectious hypothesis of AD, especially the associated susceptibility factors and the possibility of preventive treatments
Virus HerpĂšs Simplex de type 1 : une cible potentielle pour la prĂ©vention de la maladie dâAlzheimer ?
Despite many advances in the understanding of the mechanisms involved in Alzheimer's disease (AD), its precise etiology remains unknown. However, an increasing number of articles suggest that an involvement of the Herpes Simplex virus type 1 (HSV-1) could explain both the topographic and temporal sequences as well as the type of damage found in AD. Indeed, HSV-1 is a neurotropic virus found in the brains of elderly people and it has a particular tropism for the areas involved in AD. It is also able to spread from cell to cell. During life, HSV-1 remains latent in the body and is able to reactivate periodically. With advancing age, the decline of the immune system could allow more frequent and/or intense reactivations of the virus, potentially explaining the late and progressive onset of AD. In addition, the main pathological markers of AD (amyloid and tau pathologies, neuroinflammation) can be induced in vitro and in animal models by inoculation of the HSV-1 virus and the accumulation of the aÎČ peptide could be due to its involvement in antimicrobial defense. In this thesis, in order to test this hypothesis, we first evaluated the association between anti-HSV serologies and different markers of AD according to the presence of the APOE4 allele, a genetic risk factor for MA which may modulate the effect of the virus on the brain. Indeed, the presence of susceptibility factors, genetic or not, would explain why, despite a seroprevalence of approximately 80%, some infected subjects remain "healthy carriers" while others develop the disease. In the Trois CitĂ©s Bordeaux and the AMI (Aging Multidisciplinary Investigation) cohorts, we demonstrated that, among the APOE4 carriers, the infected subjects had 2 times the risk of developing AD than the non-infected and three times if they had a high level of anti-HSV IgG (possible reflection of more frequent viral reactivations over time); conversely, no association was found in APOE4 non-carriers. Infected subjects also had more alterations of the white matter microstructure in the parahippocampal cingulum and fornix than uninfected subjects, and if they had an elevated IgG levels, they also presented lower hippocampal volumes. Paradoxically, in the MAPT trial (Multidomain Alzheimer Preventive Trial), we demonstrated that, among APOE4 carriers, infected subjects (and particularly those with high IgG levels) had significantly less amyloid deposits than uninfected individuals while no association was found in APOE4 non carriers. This result, although going in the opposite direction to that expected, could potentially be explained by a selection bias of the subjects included in the trial. Then, using medico-administrative data from 68,291 elderly subjects monitored between 2009 and 2017, we demonstrated that taking at least one systemic anti-herpetic drug was associated with a 15% decrease in the risk of developing AD. Despite a low percentage of participants with regular intake during follow-up, this association could potentially reflect a protective effect of the treatment, in particular considering the possibility of more regular treatment during the period of life before inclusion. Overall, while our results seem in favor of the involvement of HSV-1 in AD, many questions still remain to confirm this hypothesis and its potential in terms of prevention.MalgrĂ© de nombreuses avancĂ©es concernant la comprĂ©hension des mĂ©canismes impliquĂ©s dans la maladie dâAlzheimer (MA), son Ă©tiologie prĂ©cise reste inconnue aujourdâhui. Cependant, un nombre croissant dâarticles suggĂšrent que lâimplication du virus HerpĂšs Simplex de type 1 (HSV-1) pourrait expliquer Ă la fois les sĂ©quences topographique et temporelle ainsi que le type dâatteintes retrouvĂ©es dans la MA. En effet, HSV-1 est un virus neurotrope retrouvĂ© dans le cerveau de personnes ĂągĂ©es et prĂ©sentant un tropisme particulier pour les zones impliquĂ©es dans la MA. Il est Ă©galement capable de se propager de cellules en cellules. Durant la vie, HSV-1 reste Ă lâĂ©tat latent dans le corps et est capable de se rĂ©activer pĂ©riodiquement. Avec lâavancĂ©e en Ăąge, le dĂ©clin du systĂšme immunitaire pourrait permettre la survenue de rĂ©activations plus frĂ©quentes et/ou plus intenses du virus, expliquant ainsi potentiellement la survenue tardive et progressive de la MA. De plus, les principaux marqueurs anatomopathologiques de la MA (lĂ©sions amyloĂŻde, tau, neuroinflammation) peuvent ĂȘtre induits in vitro et chez lâanimal par lâinoculation du virus HSV-1 et lâaccumulation du peptide aÎČ pourrait ĂȘtre due Ă son implication dans la dĂ©fense antimicrobienne. Dans cette thĂšse, afin de tester cette hypothĂšse, nous avons dans un premier temps Ă©valuĂ© lâassociation entre les donnĂ©es de sĂ©rologies anti-HSV et diffĂ©rents marqueurs de la MA en fonction de la prĂ©sence de lâallĂšle APOE4, facteur de risque gĂ©nĂ©tique de MA semblant moduler lâeffet du virus sur le cerveau. En effet, la prĂ©sence de facteurs de susceptibilitĂ©, notamment gĂ©nĂ©tiques, permettrait dâexpliquer pourquoi, malgrĂ© une sĂ©roprĂ©valence dâapproximativement 80%, certains sujets infectĂ©s restent « porteurs sains » tandis que dâautres dĂ©veloppent la maladie. Dans les cohortes Trois CitĂ©s Bordeaux et AMI (Aging Multidisciplinary Investigation), nous avons ainsi mis en Ă©vidence que, parmi les sujets porteurs de lâallĂšle APOE4, les sujets infectĂ©s avaient 2 fois plus de risque de dĂ©velopper une MA par rapport aux non-infectĂ©s et 3 fois plus sâils prĂ©sentaient un taux dâIgG anti-HSV Ă©levĂ© (reflet possible de rĂ©activations virales plus frĂ©quentes au cours du temps) ; Ă lâinverse, aucune association nâĂ©tait retrouvĂ©e chez les non-porteurs dâAPOE4. Les sujets infectĂ©s avaient Ă©galement plus dâaltĂ©rations de la microstructure de la substance blanche au niveau du cingulum et du fornix para-hippocampiques que les sujets non infectĂ©s et, pour ceux ayant un taux dâIgG Ă©levĂ©, ils prĂ©sentaient Ă©galement un volume hippocampique plus faible. Paradoxalement, au sein de lâessai MAPT (Multidomain Alzheimer Preventive Trial), nous avons mis en Ă©vidence que, parmi les porteurs de lâallĂšle APOE4, les sujets infectĂ©s (et particuliĂšrement ceux ayant un taux Ă©levĂ© dâIgG) avaient significativement moins de dĂ©pĂŽts amyloĂŻdes que les non-infectĂ©s tandis quâaucune association nâĂ©tait retrouvĂ©e chez les sujets non-porteurs dâAPOE4. Ce rĂ©sultat, bien quâallant dans le sens inverse de celui attendu, pourrait potentiellement ĂȘtre expliquĂ© par un biais de sĂ©lection des sujets inclus dans lâessai. Enfin, grĂące aux donnĂ©es de 68 291 sujets ĂągĂ©s issus de lâEchantillon GĂ©nĂ©raliste des BĂ©nĂ©ficiaires suivis entre 2009 et 2017, nous avons mis en Ă©vidence que la prise dâau moins un anti-herpĂ©tique Ă action systĂ©mique Ă©tait associĂ©e Ă une diminution de 15% du risque de dĂ©velopper une MA. MalgrĂ© un nombre faible de participants avec une prise rĂ©guliĂšre durant le suivi, cette association pourrait reflĂ©ter un effet protecteur du traitement, en particulier si lâon considĂšre la possibilitĂ© dâun traitement plus rĂ©gulier durant la pĂ©riode de vie prĂ©cĂ©dant lâinclusion. Au total, si nos rĂ©sultats semblent en faveur de lâimplication du virus HSV-1 dans la MA, de nombreuses questions restent encore en suspens pour confirmer cette hypothĂšse et son potentiel en termes de prĂ©vention
Herpes Simplex Virus type 1 : a potential target for the prevention of Alzheimer's disease?
MalgrĂ© de nombreuses avancĂ©es concernant la comprĂ©hension des mĂ©canismes impliquĂ©s dans la maladie dâAlzheimer (MA), son Ă©tiologie prĂ©cise reste inconnue aujourdâhui. Cependant, un nombre croissant dâarticles suggĂšrent que lâimplication du virus HerpĂšs Simplex de type 1 (HSV-1) pourrait expliquer Ă la fois les sĂ©quences topographique et temporelle ainsi que le type dâatteintes retrouvĂ©es dans la MA. En effet, HSV-1 est un virus neurotrope retrouvĂ© dans le cerveau de personnes ĂągĂ©es et prĂ©sentant un tropisme particulier pour les zones impliquĂ©es dans la MA. Il est Ă©galement capable de se propager de cellules en cellules. Durant la vie, HSV-1 reste Ă lâĂ©tat latent dans le corps et est capable de se rĂ©activer pĂ©riodiquement. Avec lâavancĂ©e en Ăąge, le dĂ©clin du systĂšme immunitaire pourrait permettre la survenue de rĂ©activations plus frĂ©quentes et/ou plus intenses du virus, expliquant ainsi potentiellement la survenue tardive et progressive de la MA. De plus, les principaux marqueurs anatomopathologiques de la MA (lĂ©sions amyloĂŻde, tau, neuroinflammation) peuvent ĂȘtre induits in vitro et chez lâanimal par lâinoculation du virus HSV-1 et lâaccumulation du peptide aÎČ pourrait ĂȘtre due Ă son implication dans la dĂ©fense antimicrobienne. Dans cette thĂšse, afin de tester cette hypothĂšse, nous avons dans un premier temps Ă©valuĂ© lâassociation entre les donnĂ©es de sĂ©rologies anti-HSV et diffĂ©rents marqueurs de la MA en fonction de la prĂ©sence de lâallĂšle APOE4, facteur de risque gĂ©nĂ©tique de MA semblant moduler lâeffet du virus sur le cerveau. En effet, la prĂ©sence de facteurs de susceptibilitĂ©, notamment gĂ©nĂ©tiques, permettrait dâexpliquer pourquoi, malgrĂ© une sĂ©roprĂ©valence dâapproximativement 80%, certains sujets infectĂ©s restent « porteurs sains » tandis que dâautres dĂ©veloppent la maladie. Dans les cohortes Trois CitĂ©s Bordeaux et AMI (Aging Multidisciplinary Investigation), nous avons ainsi mis en Ă©vidence que, parmi les sujets porteurs de lâallĂšle APOE4, les sujets infectĂ©s avaient 2 fois plus de risque de dĂ©velopper une MA par rapport aux non-infectĂ©s et 3 fois plus sâils prĂ©sentaient un taux dâIgG anti-HSV Ă©levĂ© (reflet possible de rĂ©activations virales plus frĂ©quentes au cours du temps) ; Ă lâinverse, aucune association nâĂ©tait retrouvĂ©e chez les non-porteurs dâAPOE4. Les sujets infectĂ©s avaient Ă©galement plus dâaltĂ©rations de la microstructure de la substance blanche au niveau du cingulum et du fornix para-hippocampiques que les sujets non infectĂ©s et, pour ceux ayant un taux dâIgG Ă©levĂ©, ils prĂ©sentaient Ă©galement un volume hippocampique plus faible. Paradoxalement, au sein de lâessai MAPT (Multidomain Alzheimer Preventive Trial), nous avons mis en Ă©vidence que, parmi les porteurs de lâallĂšle APOE4, les sujets infectĂ©s (et particuliĂšrement ceux ayant un taux Ă©levĂ© dâIgG) avaient significativement moins de dĂ©pĂŽts amyloĂŻdes que les non-infectĂ©s tandis quâaucune association nâĂ©tait retrouvĂ©e chez les sujets non-porteurs dâAPOE4. Ce rĂ©sultat, bien quâallant dans le sens inverse de celui attendu, pourrait potentiellement ĂȘtre expliquĂ© par un biais de sĂ©lection des sujets inclus dans lâessai. Enfin, grĂące aux donnĂ©es de 68 291 sujets ĂągĂ©s issus de lâEchantillon GĂ©nĂ©raliste des BĂ©nĂ©ficiaires suivis entre 2009 et 2017, nous avons mis en Ă©vidence que la prise dâau moins un anti-herpĂ©tique Ă action systĂ©mique Ă©tait associĂ©e Ă une diminution de 15% du risque de dĂ©velopper une MA. MalgrĂ© un nombre faible de participants avec une prise rĂ©guliĂšre durant le suivi, cette association pourrait reflĂ©ter un effet protecteur du traitement, en particulier si lâon considĂšre la possibilitĂ© dâun traitement plus rĂ©gulier durant la pĂ©riode de vie prĂ©cĂ©dant lâinclusion. Au total, si nos rĂ©sultats semblent en faveur de lâimplication du virus HSV-1 dans la MA, de nombreuses questions restent encore en suspens pour confirmer cette hypothĂšse et son potentiel en termes de prĂ©vention.Despite many advances in the understanding of the mechanisms involved in Alzheimer's disease (AD), its precise etiology remains unknown. However, an increasing number of articles suggest that an involvement of the Herpes Simplex virus type 1 (HSV-1) could explain both the topographic and temporal sequences as well as the type of damage found in AD. Indeed, HSV-1 is a neurotropic virus found in the brains of elderly people and it has a particular tropism for the areas involved in AD. It is also able to spread from cell to cell. During life, HSV-1 remains latent in the body and is able to reactivate periodically. With advancing age, the decline of the immune system could allow more frequent and/or intense reactivations of the virus, potentially explaining the late and progressive onset of AD. In addition, the main pathological markers of AD (amyloid and tau pathologies, neuroinflammation) can be induced in vitro and in animal models by inoculation of the HSV-1 virus and the accumulation of the aÎČ peptide could be due to its involvement in antimicrobial defense. In this thesis, in order to test this hypothesis, we first evaluated the association between anti-HSV serologies and different markers of AD according to the presence of the APOE4 allele, a genetic risk factor for MA which may modulate the effect of the virus on the brain. Indeed, the presence of susceptibility factors, genetic or not, would explain why, despite a seroprevalence of approximately 80%, some infected subjects remain "healthy carriers" while others develop the disease. In the Trois CitĂ©s Bordeaux and the AMI (Aging Multidisciplinary Investigation) cohorts, we demonstrated that, among the APOE4 carriers, the infected subjects had 2 times the risk of developing AD than the non-infected and three times if they had a high level of anti-HSV IgG (possible reflection of more frequent viral reactivations over time); conversely, no association was found in APOE4 non-carriers. Infected subjects also had more alterations of the white matter microstructure in the parahippocampal cingulum and fornix than uninfected subjects, and if they had an elevated IgG levels, they also presented lower hippocampal volumes. Paradoxically, in the MAPT trial (Multidomain Alzheimer Preventive Trial), we demonstrated that, among APOE4 carriers, infected subjects (and particularly those with high IgG levels) had significantly less amyloid deposits than uninfected individuals while no association was found in APOE4 non carriers. This result, although going in the opposite direction to that expected, could potentially be explained by a selection bias of the subjects included in the trial. Then, using medico-administrative data from 68,291 elderly subjects monitored between 2009 and 2017, we demonstrated that taking at least one systemic anti-herpetic drug was associated with a 15% decrease in the risk of developing AD. Despite a low percentage of participants with regular intake during follow-up, this association could potentially reflect a protective effect of the treatment, in particular considering the possibility of more regular treatment during the period of life before inclusion. Overall, while our results seem in favor of the involvement of HSV-1 in AD, many questions still remain to confirm this hypothesis and its potential in terms of prevention
Herpes Simplex Virus type 1 : a potential target for the prevention of Alzheimer's disease?
MalgrĂ© de nombreuses avancĂ©es concernant la comprĂ©hension des mĂ©canismes impliquĂ©s dans la maladie dâAlzheimer (MA), son Ă©tiologie prĂ©cise reste inconnue aujourdâhui. Cependant, un nombre croissant dâarticles suggĂšrent que lâimplication du virus HerpĂšs Simplex de type 1 (HSV-1) pourrait expliquer Ă la fois les sĂ©quences topographique et temporelle ainsi que le type dâatteintes retrouvĂ©es dans la MA. En effet, HSV-1 est un virus neurotrope retrouvĂ© dans le cerveau de personnes ĂągĂ©es et prĂ©sentant un tropisme particulier pour les zones impliquĂ©es dans la MA. Il est Ă©galement capable de se propager de cellules en cellules. Durant la vie, HSV-1 reste Ă lâĂ©tat latent dans le corps et est capable de se rĂ©activer pĂ©riodiquement. Avec lâavancĂ©e en Ăąge, le dĂ©clin du systĂšme immunitaire pourrait permettre la survenue de rĂ©activations plus frĂ©quentes et/ou plus intenses du virus, expliquant ainsi potentiellement la survenue tardive et progressive de la MA. De plus, les principaux marqueurs anatomopathologiques de la MA (lĂ©sions amyloĂŻde, tau, neuroinflammation) peuvent ĂȘtre induits in vitro et chez lâanimal par lâinoculation du virus HSV-1 et lâaccumulation du peptide aÎČ pourrait ĂȘtre due Ă son implication dans la dĂ©fense antimicrobienne. Dans cette thĂšse, afin de tester cette hypothĂšse, nous avons dans un premier temps Ă©valuĂ© lâassociation entre les donnĂ©es de sĂ©rologies anti-HSV et diffĂ©rents marqueurs de la MA en fonction de la prĂ©sence de lâallĂšle APOE4, facteur de risque gĂ©nĂ©tique de MA semblant moduler lâeffet du virus sur le cerveau. En effet, la prĂ©sence de facteurs de susceptibilitĂ©, notamment gĂ©nĂ©tiques, permettrait dâexpliquer pourquoi, malgrĂ© une sĂ©roprĂ©valence dâapproximativement 80%, certains sujets infectĂ©s restent « porteurs sains » tandis que dâautres dĂ©veloppent la maladie. Dans les cohortes Trois CitĂ©s Bordeaux et AMI (Aging Multidisciplinary Investigation), nous avons ainsi mis en Ă©vidence que, parmi les sujets porteurs de lâallĂšle APOE4, les sujets infectĂ©s avaient 2 fois plus de risque de dĂ©velopper une MA par rapport aux non-infectĂ©s et 3 fois plus sâils prĂ©sentaient un taux dâIgG anti-HSV Ă©levĂ© (reflet possible de rĂ©activations virales plus frĂ©quentes au cours du temps) ; Ă lâinverse, aucune association nâĂ©tait retrouvĂ©e chez les non-porteurs dâAPOE4. Les sujets infectĂ©s avaient Ă©galement plus dâaltĂ©rations de la microstructure de la substance blanche au niveau du cingulum et du fornix para-hippocampiques que les sujets non infectĂ©s et, pour ceux ayant un taux dâIgG Ă©levĂ©, ils prĂ©sentaient Ă©galement un volume hippocampique plus faible. Paradoxalement, au sein de lâessai MAPT (Multidomain Alzheimer Preventive Trial), nous avons mis en Ă©vidence que, parmi les porteurs de lâallĂšle APOE4, les sujets infectĂ©s (et particuliĂšrement ceux ayant un taux Ă©levĂ© dâIgG) avaient significativement moins de dĂ©pĂŽts amyloĂŻdes que les non-infectĂ©s tandis quâaucune association nâĂ©tait retrouvĂ©e chez les sujets non-porteurs dâAPOE4. Ce rĂ©sultat, bien quâallant dans le sens inverse de celui attendu, pourrait potentiellement ĂȘtre expliquĂ© par un biais de sĂ©lection des sujets inclus dans lâessai. Enfin, grĂące aux donnĂ©es de 68 291 sujets ĂągĂ©s issus de lâEchantillon GĂ©nĂ©raliste des BĂ©nĂ©ficiaires suivis entre 2009 et 2017, nous avons mis en Ă©vidence que la prise dâau moins un anti-herpĂ©tique Ă action systĂ©mique Ă©tait associĂ©e Ă une diminution de 15% du risque de dĂ©velopper une MA. MalgrĂ© un nombre faible de participants avec une prise rĂ©guliĂšre durant le suivi, cette association pourrait reflĂ©ter un effet protecteur du traitement, en particulier si lâon considĂšre la possibilitĂ© dâun traitement plus rĂ©gulier durant la pĂ©riode de vie prĂ©cĂ©dant lâinclusion. Au total, si nos rĂ©sultats semblent en faveur de lâimplication du virus HSV-1 dans la MA, de nombreuses questions restent encore en suspens pour confirmer cette hypothĂšse et son potentiel en termes de prĂ©vention.Despite many advances in the understanding of the mechanisms involved in Alzheimer's disease (AD), its precise etiology remains unknown. However, an increasing number of articles suggest that an involvement of the Herpes Simplex virus type 1 (HSV-1) could explain both the topographic and temporal sequences as well as the type of damage found in AD. Indeed, HSV-1 is a neurotropic virus found in the brains of elderly people and it has a particular tropism for the areas involved in AD. It is also able to spread from cell to cell. During life, HSV-1 remains latent in the body and is able to reactivate periodically. With advancing age, the decline of the immune system could allow more frequent and/or intense reactivations of the virus, potentially explaining the late and progressive onset of AD. In addition, the main pathological markers of AD (amyloid and tau pathologies, neuroinflammation) can be induced in vitro and in animal models by inoculation of the HSV-1 virus and the accumulation of the aÎČ peptide could be due to its involvement in antimicrobial defense. In this thesis, in order to test this hypothesis, we first evaluated the association between anti-HSV serologies and different markers of AD according to the presence of the APOE4 allele, a genetic risk factor for MA which may modulate the effect of the virus on the brain. Indeed, the presence of susceptibility factors, genetic or not, would explain why, despite a seroprevalence of approximately 80%, some infected subjects remain "healthy carriers" while others develop the disease. In the Trois CitĂ©s Bordeaux and the AMI (Aging Multidisciplinary Investigation) cohorts, we demonstrated that, among the APOE4 carriers, the infected subjects had 2 times the risk of developing AD than the non-infected and three times if they had a high level of anti-HSV IgG (possible reflection of more frequent viral reactivations over time); conversely, no association was found in APOE4 non-carriers. Infected subjects also had more alterations of the white matter microstructure in the parahippocampal cingulum and fornix than uninfected subjects, and if they had an elevated IgG levels, they also presented lower hippocampal volumes. Paradoxically, in the MAPT trial (Multidomain Alzheimer Preventive Trial), we demonstrated that, among APOE4 carriers, infected subjects (and particularly those with high IgG levels) had significantly less amyloid deposits than uninfected individuals while no association was found in APOE4 non carriers. This result, although going in the opposite direction to that expected, could potentially be explained by a selection bias of the subjects included in the trial. Then, using medico-administrative data from 68,291 elderly subjects monitored between 2009 and 2017, we demonstrated that taking at least one systemic anti-herpetic drug was associated with a 15% decrease in the risk of developing AD. Despite a low percentage of participants with regular intake during follow-up, this association could potentially reflect a protective effect of the treatment, in particular considering the possibility of more regular treatment during the period of life before inclusion. Overall, while our results seem in favor of the involvement of HSV-1 in AD, many questions still remain to confirm this hypothesis and its potential in terms of prevention
Infectious Agents as Potential Drivers of α-Synucleinopathies.
International audienceα-synucleinopathies, encompassing Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are devastating neurodegenerative diseases for which available therapeutic options are scarce, mostly because of our limited understanding of their pathophysiology. Although these pathologies are attributed to an intracellular accumulation of the α-synuclein protein in the nervous system with subsequent neuronal loss, the trigger(s) of this accumulation is/are not clearly identified. Among the existing hypotheses, interest in the hypothesis advocating the involvement of infectious agents in the onset of these diseases is renewed. In this article, we aimed to review the ongoing relevant factors favoring and opposing this hypothesis, focusing on (1) the potential antimicrobial role of α-synuclein, (2) potential entry points of pathogens in regard to early symptoms of diverse α-synucleinopathies, (3) pre-existing literature reviews assessing potential associations between infectious agents and Parkinson's disease, (4) original studies assessing these associations for dementia with Lewy bodies and multiple system atrophy (identified through a systematic literature review), and finally (5) potential susceptibility factors modulating the effects of infectious agents on the nervous system. © 2022 International Parkinson and Movement Disorder Society