ABCA7-dependent Neuropeptide-Y signalling is a resilience mechanism required for synaptic integrity in Alzheimer's disease.

Alzheimer's disease (AD) remains a complex challenge characterized by cognitive decline and memory loss. Genetic variations have emerged as crucial players in the etiology of AD, enabling hope for a better understanding of the disease mechanisms; yet the specific mechanism of action for those genetic variants remain uncertain. Animal models with reminiscent disease pathology could uncover previously uncharacterized roles of these genes. Using CRISPR/Cas9 gene editing, we generated a knockout model for orthologous to human an established AD-risk gene. The zebrafish showed reduced astroglial proliferation, synaptic density, and microglial abundance in response to amyloid beta 42 (Aβ42). Single-cell transcriptomics revealed -dependent neuronal and glial cellular crosstalk through neuropeptide Y (NPY) signaling. The knockout reduced the expression of and , which are required for synaptic integrity and astroglial proliferation. With clinical data in humans, we showed reduced in AD correlates with elevated Braak stage, predicted regulatory interaction between and , identified genetic variants in associated with AD, found segregation of variants in and in AD families, and discovered epigenetic changes in the promoter regions of and in humans with specific single nucleotide polymorphisms in . These results suggest that ABCA7-dependent NPY signaling is required for synaptic integrity, the impairment of which generates a risk factor for AD through compromised brain resilience.