A few recent papers have, collectively, added evidence for persistent viral infection to be a significant contributing cause of Alzheimer's disease. A number of viruses in the herpesvirus family are prevalent in the population but cause few obvious symptoms, such as HSV-1 and cytomegalovirus (CMV). Some of these, particularly CMV, are already under suspicion as being the cause of long-term dysfunction in the immune system. Viral infection is an attractive way to explain why only some of the people who exhibit all of the known risk factors for Alzheimer's disease actually go on to develop the full clinical manifestation of the condition. The proportion of the population with latent infection is high, but not too high: other candidate differentiating factors are a lot less convincing because either the population size is too small, or near everyone has it.
How can viral infections contribute to the development of Alzheimer's disease? The amyloid cascade hypothesis tells us that, in the first early stages of Alzheimer's disease, amyloid-β accumulates in the brain, producing only comparatively minor symptoms of degeneration. In later life, this accumulation reaches a critical point that causes tau protein to alter and form solid neurofibrillary tangles in significant amounts. It is this tau aggregation that causes the lion's share of the damage in the later stages of the condition - though a high enough level of amyloid-β can still be harmful in and of itself. Infection is important because amyloid generation is an innate immune mechanism that evolved to respond to viral infection. Thus infection speeds up the production and aggregation of amyloid-β in the brain, pushing things ever closer to the tipping point into pathology.
Authors have recently reported that infection with a different herpes virus, herpes simplex virus type 1 (HSV1), leads to a similarly increased risk of later developing senile dementia (SD). Further, when the authors looked at patients treated aggressively with antiherpetic medications at the time, the relative risk of SD was reduced by a factor of 10. It should be stressed that no investigations were made on subjects already suffering from SD, and that those treated were the few rare cases severely affected by HSV. Nonetheless, antiherpetic medication prevented later SD development in 90% of their study group. These articles provide the first population evidence for a causal link between herpes virus infection and senile dementia.
Investigators have long suspected that pathogenic microbes might contribute to the onset and progression of Alzheimer's disease (AD) although definitive evidence has not been presented. Whether such findings represent a causal contribution, or reflect opportunistic passengers of neurodegeneration, is also difficult to resolve. We constructed multiscale networks of the late-onset AD-associated virome, integrating genomic, transcriptomic, proteomic, and histopathological data across four brain regions from human post-mortem tissue. We observed increased human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) from subjects with AD compared with controls. These results were replicated in two additional, independent and geographically dispersed cohorts. We observed regulatory relationships linking viral abundance and modulators of APP metabolism.
Amyloid-β peptide (Aβ) fibrilization and deposition as β-amyloid are hallmarks of Alzheimer's disease (AD) pathology. We recently reported Aβ is an innate immune protein that protects against fungal and bacterial infections. Fibrilization pathways mediate Aβ antimicrobial activities. Thus, infection can seed and dramatically accelerate β-amyloid deposition. Here, we show Aβ oligomers bind herpesvirus surface glycoproteins, accelerating β-amyloid deposition and leading to protective viral entrapment activity in mouse and human neural cell culture infection models against neurotropic herpes simplex virus 1 (HSV1) and human herpesvirus 6A and B. Herpesviridae are linked to AD, but it has been unclear how viruses may induce β-amyloidosis in brain. These data support the notion that Aβ might play a protective role in central nervous system innate immunity, and suggest an AD etiological mechanism in which herpesviridae infection may directly promote Aβ amyloidosis.