Chronic social isolation-unpredictable stress induces early-onset cognitive deficits and exacerbates Aβ accumulation in the 5xFAD mouse model of Alzheimer's disease.

Aging and genetic predisposition are the primary risk factors for Alzheimer's disease (AD), while chronic stress represents a modifiable risk factor that can accelerate aging and drive AD progression. However, the complex interplay between aging, chronic stress and genetic underpinnings in AD pathogenesis remains poorly understood. Notably, cognitive phenotyping in AD mouse models has yielded inconsistent results. In this study, we characterized the age-dependent trajectory of phenotypes in 5xFAD mice on a congenic C57BL/6 J background. These mice harbor five familial AD (FAD)-related mutations in the amyloid precursor protein (APP) and presenilin 1 (PSEN1) genes. Aβ plaque deposition was detected in specific brain regions by 4 months of age, but cognitive performance remained intact at this stage. However, by 8-9 months, these mice developed impairments in spatial working memory, novel object recognition memory, and social recognition memory. By 11 months, they also showed metabolic alterations, including lower body weight, higher energy expenditure and increased locomotor activity. Furthermore, after 10 days of chronic social isolation-unpredictable stress, 4-month-old 5xFAD mice exhibited cognitive deficits, accompanied by increased Aβ accumulation in the medial prefrontal cortex, hippocampus, and entorhinal cortex. In contrast, age- and sex-matched wild-type littermate controls subjected to the same stress paradigm showed no significant cognitive changes. These observations suggest that Aβ deposition increases stress vulnerability in 5xFAD mice. We conclude that the phenotypic expression of AD-related gene mutations, including pathological changes and cognitive decline, progresses with age and can be induced by chronic psychological stress, underscoring the interactive effects of stress, aging, and genetic vulnerability on disease onset and severity.