The liver, responsible for regulating the metabolism of the body; the kidney, the most important organ for waste elimination, and the spleen, in charge of filtering the blood and producing lymphocytes, are now considered to have clearance functions in Alzheimer’s disease (AD) eliminating Aβ from the brain. In the present work, we used different levels of study to examine the status and involvement of these three organs in 16-months-old male and female 3xTg-AD for AD and compared them to C57BL/6 counterparts with physiological aging, in two different social scenarios. All three organs presented morphological and structural changes due to acute amyloidosis focalised in the hepatic blood vessels parenchyma, the renal glomeruli, and the splenic red pulp, as well as oxidative stress observed by the reduction of antioxidant defences activity (GPx). All these changes correlated with the anxious-like phenotype of this mouse model manifested by the high neophobia presented when compared with their age- and sex-matched non-transgenic (NTg) counterparts. In addition, forced isolation, a cause of psychological stress, exerted a negative effect by intensifying genotype differences and causing differences to emerge also in NTg animals. All these results contribute to the expanding field of AD research to go beyond the brain to take a more systemic approach, as alterations in the peripheral organs could be related to the disease progression. The results highlight the relevance of a more integrative view of the complex interplay between systems in aging and AD, together with the impact of social conditions.