Herpes simplex-1 as an additive risk factor for cognitive decline in apolipoprotein E4 carriers




Eagan, Danielle Erin

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The identification of early, modifiable risk factors for cognitive decline presents the most promising opportunity for intervention. To date one of the most robustly replicated risk factors for the most common form of dementia, Alzheimer’s disease (AD), is the Apolipoprotein E4 (ApoE4) allele. Risk for sporadic and familial late onset AD increases nearly threefold for each E4 allele an individual carries. However some E4 carriers do not develop cognitive decline, and many non-E4 carriers do, highlighting the role of environmental variables in the progression to clinical symptoms. There is evidence that herpes simplex-1 (HSV-1), a common neurotropic viral infection with affinity for the same brain structures affected in AD, is an acquired risk factor that may compound the genetic risk associated with ApoE4. We examined the interaction between the ApoE4 allele and HSV-1 in cognitively normal middle-aged adults using neuropsychological testing and structural and functional neuroimaging. Neuropsychological assessments were used to determine cognitive differences between groups. Structural neuroimaging was used to measure group differences in bilateral hippocampal volumes, and cortical thickness in brain regions most likely to be affected by AD and HSV-1. Functional neuroimaging was used to examine differences in resting- state brain activity within the default mode network (DMN), a network known for alterations in functional connectivity during the progression from normal aging to AD. With regard to cognition we found that ApoE4 carriers performed significantly lower on tests of executive functioning when they were infected with HSV-1. HSV-1 infection alone also correlated with significantly lower full scale IQ (FSIQ). Within the structural domain we found that individuals with ApoE4 had significantly smaller bilateral hippocampal volumes compared to individuals without the virus, regardless of HSV-1 status. Within the functional domain we failed to find any group differences in functional connectivity within the DMN. Together these findings suggest that HSV-1 may contribute to cognitive changes linked to cognitive vulnerability, and that ApoE4 may contribute to structural brain vulnerability. Because these factors are identifiable prior to the onset of frank cognitive decline, antiviral intervention could be considered as a means of mitigating risk for cognitive decline.




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