Language
English
Publication Date
6-1-2026
Journal
Molecular Psychiatry
DOI
10.1038/s41380-026-03479-6
PMID
41691109
PMCID
PMC13190313
PubMedCentral® Posted Date
2-14-2026
PubMedCentral® Full Text Version
Post-print
Abstract
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.
Keywords
Animals, Alzheimer Disease, Humans, Brain, Amyloid beta-Peptides, tau Proteins, Disease Models, Animal, Drosophila melanogaster, Transcriptome, Gene Expression, Neurons, Neurofibrillary Tangles, Plaque, Amyloid, Gene Expression Profiling, Psychiatric disorders, Genetics, Neuroscience
Published Open-Access
yes
Recommended Citation
Zhao, Pinghan; El Fadel, Omar; Le, Anh; et al., "Systems Genetic Dissection of Brain Gene Expression Reveals Excitotoxic Mechanisms of Alzheimer’s Disease" (2026). Faculty, Staff and Students Publications. 7115.
https://digitalcommons.library.tmc.edu/baylor_docs/7115