Alzheimer’s disease (AD) is a highly prevalent age-related neurological disorder, characterized by progressive cognitive decline and accumulation of neuropathological hallmarks in various brain regions. Emerging research highlights early-life stress (ELS) as a significant risk factor in its pathogenesis. We and others have demonstrated in preclinical models that ELS exacerbates both pathology of AD and glial response to amyloid-overexpression. Recently, we demonstrated possible convergence of ELS, AD and mitochondrial dysfunctions, utilizing proteomic analysis of synaptosomes​. Seeking to understand if and how ELS impacts microglial mitochondria, given their pivotal role in neuroinflammation, we exposed mice to limited nesting and bedding material from P2-P9, along with a high-fat high-sugar (HFHS) diet. Examining microglial mitochondria at the ultrastructural level across different ages, we found no impact of ELS on hypothalamic microglial mitochondrial density and structure at P9. However, at 8-9 weeks, exposure to the HFHS diet increased microglial cell density and altered mitochondrial circularity and coverage, depending on prior ELS exposure.To further explore the interplay between ELS- induced mitochondrial dysfunction in AD, our next steps involve assessing the impact of ELS on mitochondrial biology in various cell types in both WT and AD transgenic mice during different (pre-)pathological stages. Subsequently, we aim to elucidate whether targeting mitochondria can protect against these AD-related deficits. Finally, we will evaluate the enduring effects of ELS on mitochondrial measures in human blood monocytes, employing the unique longitudinal Dutch Famine Birth cohort. This comprehensive approach holds promise for identifying new targets for early intervention and potential AD biomarkers.