INTRODUCTION: Loss-of-function variants of the ABCA7 gene are associated with an increased risk of Alzheimer's disease (AD). How neuronal ABCA7 contributes to AD pathogenesis is unknown. METHODS: Using neuron-specific Abca7 KO mice (nAbca7(-/-)) with or without 5×FAD amyloid model background and post mortem AD brains, we investigated AD-related phenotypes through comprehensive approaches including transcriptomics and lipidomics. RESULTS: Lipidomics analysis detected altered lipid profiles in the brains and synaptosomes of 5×FAD; nAbca7(-/-) mice compared to controls. Transcriptomics profiling revealed that neuronal ABCA7 deficiency altered the expression of genes and pathways related to mitochondrial homeostasis and apoptosis, particularly in excitatory neurons. Consistently, synaptosomes isolated from 5×FAD; nAbca7(-/-) mice showed diminished mitochondria respiration and reduced synaptic protein levels, which is further supported by results from human AD brains. DISCUSSION: Our findings reveal that neuronal ABCA7 plays a critical role in mitochondrial homeostasis important for neuronal function and survival in the presence of AD pathology. HIGHLIGHTS: Neuronal ABCA7 deficiency exacerbates Aβ pathology and neuronal damage in 5×FAD mice. Neuronal ABCA7 deficiency alters brain transcriptomes and lipidomes of 5×FAD mice. Neuronal ABCA7 deficiency disturbs mitochondria functions in synaptosomes from 5×FAD mice. Neuronal ABCA7 expression associates with genes and pathways related to mitochondrial homeostasis in AD brains.