Most people carry herpes simplex virus-1 and never develop Alzheimer’s disease — and that may be part of the problem with how negative data have been interpreted.

In a perspective published in Alzheimer's & Dementia, Chatila and colleagues argue that studies often cited to dismiss a link between infections and Alzheimer’s disease may not always be well-matched to the question they aim to answer.

Serum antibody titers, for example, may not reflect what is happening in the central nervous system. Electronic health record–based studies tend to capture infections severe enough to require clinical attention, potentially missing milder or latent infections. And when exposure to a pathogen like herpes simplex virus-1 (HSV-1) is widespread, comparing exposure rates between cases and controls may obscure meaningful differences.

Rather than definitively ruling out an infectious contribution, the authors suggest that many null findings may reflect limitations in study design or exposure measurement.

The perspective also raises a broader possibility: that the infectious hypothesis has often been framed too generally to test cleanly. The authors point to evidence that risk may depend on interactions between specific pathogens and host genetics — for example, associations involving APOE ε4 and HSV-1 in brain tissue, or variants such as PILRA and OAS1 that may influence viral entry or immune response. In this view, studies that do not account for genetic context may be less likely to detect meaningful associations.

At the same time, important gaps remain. There is still no unifying mechanistic explanation for why a wide range of pathogens — including viruses, bacteria, parasites, and fungi — have been linked to Alzheimer’s-related pathology. The authors highlight dysregulated host immunity as a possible connecting framework, but note that this remains an area of ongoing investigation.

The clinical implications are limited for now. The perspective does not suggest treating Alzheimer’s disease as an active infection. Instead, it emphasizes caution in interpreting negative findings and calls for more precise study designs that consider factors such as genetic susceptibility, central versus peripheral infection, and the role of viral reactivation.

The authors declared having no competing interests.

Source: Alzheimer's & Dementia