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Summary: This study investigates stress’s impact on Alzheimer’s disease (AD) using male APP/PS1 transgenic mice. Negative stressors (chronic social defeat, restraint) and positive hedonia (environmental enrichment, EE) were applied. Stress worsens AD pathology, while EE slows progression. Brain RNA sequencing reveals interleukin-6 (IL-6) and IL-10 as key stress-related AD regulators. Flow cytometry shows that the CD8+/CD4+ T cell ratio shifts in response to stress exposure and EE. Stress exposure increases CD8+/CD4+ ratio, opposite to EE. Depletion and enrichment of CD8+ T cells both accelerate AD, indicating immune intervention’s negative impact. Stress management and balanced immunity may aid AD therapy, highlighting novel potential treatment.