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Background:Numerous cross-sectional studies have related exposure to neurotropic infectious agents with cognitive dysfunction in older adults, however, the temporal sequence is uncertain.Methods:In a representative, well-characterized, population-based aging cohort, we determined whether the temporal trajectories of multiple cognitive domains are associated with exposure to cytomegalovirus (CMV), Herpes Simplex virus, type 1 (HSV-1), Herpes Simplex virus, type 2 (HSV-2), or Toxoplasma gondii (TOX). Complex attention, executive functions, memory, language, and visuospatial function were assessed annually for 5 years among consenting individuals. Study entry IgG antibody titers indexing exposure to each infectious agent were examined in relation to slopes of subsequent temporal cognitive decline using multiple linear regressions adjusted for potential confounders.Results:The IgG levels for HSV-2 were significantly associated with baseline cognitive domain scores (N=1022 participants). Further, the IgG levels for HSV-2, TOX, and CMV, but not HSV-1 were significantly associated with greater temporal cognitive decline that varied by type of infection.Conclusions:Exposure to CMV, HSV-2, or TOX is associated with cognitive deterioration in older individuals, independent of general age-related variables. An increased understanding of the role of infectious agents in cognitive decline may lead to new methods for its prevention and treatment.