Abstract
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 (n = 349), (ii) white matter alterations in the parahippocampal cingulum and fornix using diffusion tensor imaging (n = 260), and (iii) incidence of AD (n = 1599) 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 (p = 0.03 for subjects with a high anti-HSV IgG level while there was no association for all infected subjects, p = 0.19), and (iii) had no increased risk of developing AD. Nevertheless, among APOE4 carriers, infected subjects presented lower hippocampal volumes, although not significant (p = 0.09), and a two or three times higher risk of developing AD (adjusted Hazard ratio (aHR) = 2.72 [1.07–6.91] p = 0.04 for infected subjects and aHR = 3.87 [1.45–10.28] p = 0.007 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.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by visible changes within the brain several years before the clinical stage of dementia [1], including hippocampal atrophy and microstructural alterations of white matter (WM) [2,3,4,5]
We aimed to evaluate the association between herpes simplex virus (HSV) status and (i) hippocampal volume (HV), (ii) WM
Characteristics of participants The characteristics of participants are presented in Table 1 in the three studied samples: HV (n = 349), WM integrity (n = 259), and Translational Psychiatry (2021)11:414
Summary
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by visible changes within the brain several years before the clinical stage of dementia [1], including hippocampal atrophy and microstructural alterations of white matter (WM) [2,3,4,5]. The implication of HSV-1 could potentially explain the location, chronology and the type of damage described in AD. HSV-1 is a neurotropic virus with a particular tropism for the temporal cortex, as shown by the localization of lesions in HSV-1 encephalitis and postmortem studies highlighting the presence of HSV DNA in the brains of older adults (reviewed in [9]). HSV-1 could be linked to genetic risk factors of AD [19, 20], especially APOE4. The existence of such genetic susceptibility factors could explain why, despite a seroprevalence of ~80% in the elderly [21], some infected individuals remain “healthy carriers”, while others develop clinical consequences of the infection
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