Basic Science and Pathogenesis

Several viruses, including HSV-1, can establish latent infections in neurons and have been linked to Alzheimer disease (AD).

Whole genome sequence reads derived from brain (561 AD cases, 259 controls) and blood (5,033 AD cases, 4,907 controls) specimens obtained from European ancestry, African American, Native American Hispanic, Indian, and Caribbean Hispanic participants in the Alzheimer's Disease Sequencing Project that did not align to the human reference genome were aligned to viral reference genomes. We evaluated the association of HSV-1 DNA presence with harmonized measures of cognitive performance in four cognitive domains (memory, executive functioning, language, and visual-spatial perception) using regression models with covariates for AD diagnosis, APOE genotype, age, sex, tissue source, ancestry, and PCR amplification. One model evaluated the interaction between HSV-1 and age on cognitive decline using Generalized Estimating Equations to account for repeated measures. A second model considered only the most recent cognitive scores. Both models were performed separately within AD cases, mild cognitively impaired (MCI), and controls.

In the cross-sectional; model, HSV-1 was associated with lower memory performance in AD cases (b= -0.082, p = 0.002). HSV-1 was significantly associated with decline across multiple domains, including executive function (b = -0.032, p =  0.012), language (b = -0.028, p = 0.027), and memory (b = -0.033, p = 0.008). Among AD cases, HSV-1 was associated with reduced memory scores (b= -0.10, p =  4.35x10^-6). The HSV-1 × age interaction term was significant for executive function (b = -0.003, p = 0.02) and memory (b = -0.003, p = 0.02) domains. In individuals with MCI (b = 0.012, p = 0.046) and controls (b = 0.091, p = 0.016), HSV-1 was associated with higher visual-spatial scores.

These findings provide further evidence for the role of HSV-1 presence in AD pathogenesis and may exacerbate cognitive decline in individuals with AD.