Objective laboratory measurements also support the provocative hypothesis.
Past studies have suggested that several different infectious agents, including HHV-6, might be a trigger in the pathogenesis of Alzheimer’s disease (AD) and other dementias, although a role for HHV-6 remains controversial (Komaroff 2020). Moreover, some investigators doubt that any infectious agent is likely to be involved in the pathogenesis of AD.
The hypothesis that infection might play a role in the pathogenesis of neurodegeneration received support from a study in Nature Aging. The study evaluated not a clinical diagnosis of dementia—which was assessed in another study, but objective evidence of neurological damage following infections. The health of a large group of cognitively and neurologically normal adults was followed for many decades, with a subset receiving repeated MRI brain scans and cognitive testing, as well as blood tests evaluating markers of neurodegeneration (like amyloid-ß and tau), markers of inflammation and other variables. The authors found that influenza, viral, respiratory, and skin and subcutaneous infections were associated with increased long-term dementia risk, as well as with region-specific brain volume loss, most often in the temporal lobe.
The authors then examined several other large longitudinal databases including the UK Biobank data (n = 495,896) and a Finnish multicohort sample (n = 273,132) and found similar strong associations between a past history of infections and AD, vascular dementia and all-cause dementia.
The authors then conducted a proteomic study of 942 immunologically relevant plasma proteins. They found that—after multivariate statistical adjustment for cofactors that could influence the risk of dementia—260 of the proteins were differentially expressed in people with a past history of one of these infections. Of these 260 infection-related proteins, 35 predicted volumetric changes in brain regions vulnerable to infection-specific atrophy. In addition, several were related to cognitive decline and to plasma biomarkers of dementia such as amyloid-ß42/40 and pTau-181 as well as markers of neuronal injury, such as glial fibrillary acidic protein and neurofilament light chain. Genetic variants that influenced expression of these immunologically relevant infection-related proteins predicted loss of brain volume.
The results specific to a past history of human herpesvirus infection were:
- An increased risk of subsequent all-cause dementia: 1.53 HR (1.08-2.16, UK BioBank) and 1.70 (1.02-2.82, Finnish Multicohort)
- A significant loss in total white matter volume
- No gray or white matter volume loss specific to the temporal lobes—a relevant observation, given the tropism of HHV-6 for temporal lobes
Combined with the large clinical study finding a strong correlation between a clinical history of infection and the subsequent development of Alzheimer’s disease and other dementias, this study supports the hypothesis that chronic herpesvirus infections may be one trigger of dementia.
Read the full article: Duggan 2024