Validation of a Cytomegalovirus-based biomarker for Alzheimer’s disease

Project Summary:

A project to validate a blood-based biomarker capable of reflecting the presence of activated microglia neuroimmune cells and Cytomegalovirus infection of the gut and vagus nerve in certain Alzheimer’s disease patients. Validation of the biomarker should allow specific Alzheimer’s patients to be more selectively recruited into clinical trials of affordable antivirals that might help ameliorate or slow the disease process.

Project Background:

The Alzheimer’s disease process is increasingly connected to chronic infection of the brain and nervous system. For example, one Harvard team found that the “plaque” that forms in the Alzheimer’s brain evolved as an antimicrobial peptide that forms in response to viruses, bacteria, or fungi in brain tissue. Another team found that a vaccine for shingles – which targets the herpesvirus varicella zoster virus – is associated with a lower risk of dementia. Yet other groups have shown that treatment with antivirals – including affordable generic herpesvirus therapeutics – is connected to a reduced risk of developing dementia.

The current project builds on this body of work to further delineate how herpesvirus activity may be at the heart of Alzheimer’s disease pathogenesis and progress in a subset of affected patients. More specifically, in a recent paper in the journal Nature Communications, the team identified an Alzheimer’s disease associated cortical CD83(+) microglia subtype in brain tissue collected from 20-40% of patients with the disease. Further sets of experiments and extended tissue analysis found that this microglia subtype is linked with elevated immunoglobulin IgG4 and the presence of the cytomegalovirus virus in colon (gut) tissue collected from Alzheimer’s patients. It is also associated with increased anti-Cytomegalovirus IgG4 antibodies in cerebrospinal fluid from the same participants, and the presence of both Cytomegalovirus and IgG4 in the vagus nerve and the brain.

Overall, this paints a picture of a chronic Cytomegalovirus infection in the gut as a precondition for transvagal passage of Cytomegalovirus to the brain in a subset of patients with Alzheimer’s disease. To reverse this pathogenesis, the project team seeks to run a clinical trial of the herpesrvirus antiviral valaciclovir (which is safe, available as a generic drug, has good anti-Cytomegalovirus activity, and is brain penetrant) in subjects with mild cognitive impairment who are Alzheimer’s disease biomarker positive (pTau-217), and Cytomegalovirus IgG4 biomarker positive. However, before they run this important clinical trial, they must further validate the the Cytomegalovirus IgG4 blood-based biomarker in samples collected from an independent population of subjects with Alzheimer’s. The current project will accomplish validation by analyzing blood, cerebrospinal fluid, gut tissue, and vagus nerve tissue from a new cohort of Alzheimer’s patients. If the team’s IgG4 blood-based biomarker continues to accurately reflect the presence of activated microglia and Cytomegalovirus in tissue, the team will have the data required to confidently run the valaciclovir clinical trial.