Gene expression changes likely mediate the impact of Alzheimer's disease (AD) neuropathology on cognition, but there are challenges to resolve the proximal causal pathways from postmortem brain transcriptome profiles which lack temporal resolution and are further confounded by mixed pathologies. Here, we functionally dissect 30 AD-associated human brain gene co-expression modules using fruit fly (Drosophila melanogaster) models. Integrating longitudinal RNA-sequencing and behavioral phenotyping, we interrogated the consequences of amyloid beta (Aβ) plaques, tau neurofibrillary tangles, and aging, highlighting hundreds of conserved, differentially expressed genes. To pinpoint causal modules and drivers, we manipulated 344 prioritized targets in vivo, identifying 141 modifiers of Aβ- or tau-induced neurodegeneration. We discovered an upregulated immune module enriched for AD risk variants that promotes neurodegeneration based on genetic manipulations in neurons. By contrast, a downregulated human brain synaptic regulatory network includes many loss-of-function suppressors of Aβ/tau and modulates glutamatergic hyperexcitation injury. Additional analyses support a biphasic model in which early AD pathology activates expression of a synaptic transcriptional signature that promotes neuronal injury, followed by a decrease that is compensatory. In sum, our cross-species strategy establishes a causal chain linking AD pathology, transcriptome perturbation, N-Methyl-D-Aspartate receptor excitotoxicity, and neurodegeneration.
© 2026. The Author(s).