Anesthesia and Surgery Rewire the Alzheimer’s Brain Differently, Mouse Study Suggests

Millions of older adults undergo anesthesia and surgery every year, and a troubling minority emerge with lasting problems in memory and thinking, a cluster of conditions known as perioperative neurocognitive disorders. For decades, researchers have suspected that brains already carrying Alzheimer-related pathology may be especially vulnerable to the double insult of general anesthesia and surgical trauma. What has remained stubbornly unclear is exactly how that vulnerability works at the molecular level. Does an Alzheimer-like brain simply mount a bigger version of the same inflammatory response that a healthy brain produces, or does it respond in a fundamentally different way, activating different genes and different biological programs altogether? A new exploratory study published in BMC Genomics by Shengjie Wang, Junyan Yao and colleagues at Shanghai East Hospital, Tongji University School of Medicine, tackles precisely this question, and its answer leans toward the more unsettling of the two possibilities.

The research team used 5xFAD mice, a widely studied transgenic model that carries five human Alzheimer’s disease mutations and progressively accumulates amyloid-beta plaques in the brain, as a proxy for an amyloid-associated brain state. Four-month-old female 5xFAD mice and age-matched wild-type controls were divided into two exposure groups: one received only routine handling, while the other underwent combined isoflurane anesthesia and abdominal surgery, a standard experimental paradigm for modeling the perioperative experience. Twenty-four hours later, a time point chosen to capture the acute molecular aftermath rather than the immediate chaos of the operation itself, the researchers dissected the hippocampus, the seahorse-shaped structure essential for memory formation that is also among the first brain regions damaged in Alzheimer’s disease, and performed bulk RNA sequencing to read out the activity of every gene in that tissue.

The experimental design followed a factorial structure, with three animals in each of the four genotype-by-exposure cells, and the team applied DESeq2, a widely used statistical framework for count-based gene expression data, to estimate three separate effects: the effect of genotype, the effect of anesthesia and surgery exposure, and, most importantly, the genotype-by-exposure interaction. This interaction term is the statistical heart of the study. It asks whether the transcriptional response to surgery differs between the two genotypes in direction, not merely in magnitude. When the researchers examined each genotype separately, the wild-type mice showed 20 genes significantly associated with exposure at a false discovery rate below 0.05, while the 5xFAD mice showed only 3. On its face, that might suggest the Alzheimer-model brain responds less to surgery. But the interaction analysis told a strikingly different story.

Testing the interaction directly, the team identified 53 genes whose response to anesthesia and surgery differed between genotypes at false discovery rate below 0.05, with 37 of those also showing an interaction effect size of at least one log2 unit, meaning the exposure effect was at least doubled in one genotype relative to the other. Remarkably, all 53 of these genes had opposite-signed exposure-effect estimates in wild-type versus 5xFAD mice: genes that went up after surgery in one genotype went down in the other, and vice versa. In other words, the Alzheimer-like brain did not simply mount a weaker or stronger version of the surgical response; it mounted a directionally inverted one. The authors are careful to note that separate within-genotype significance was not required for these genes, which is precisely why the interaction model, rather than the two separate contrasts, was the appropriate lens.

Because small exploratory cohorts are vulnerable to the influence of any single animal, the researchers subjected their findings to an unusually thorough battery of sensitivity analyses. They re-ran the model twelve times, each time leaving out one sample, and found that all 53 interaction genes retained their direction of effect in every leave-one-out fit. They repeated the analysis with edgeR quasi-likelihood modeling, a second independent statistical framework, and again all 53 genes kept their direction, although none reached genome-wide false discovery rate significance in edgeR, a candid acknowledgment that gene-level significance in this dataset is method-dependent. Cook’s-distance diagnostics, which flag individual data points with disproportionate influence on a regression, showed that no gene exceeded the cutoff. The directional finding, in short, was robust; the gene-by-gene statistical significance was not, and the authors say so plainly.

To move from individual genes to biological meaning, the team performed gene-set enrichment analysis using the Mouse Hallmark collection of curated pathway definitions, ranking genes by their interaction statistics rather than by any single genotype’s effect. This revealed 10 Hallmark pathways significantly enriched at false discovery rate below 0.05, and the pattern they formed was coherent and provocative. On the positive side of the interaction, meaning programs amplified in the 5xFAD response relative to wild type, sat inflammatory signaling pathways, including the TNF-alpha/NF-kappaB axis, a canonical pro-inflammatory cascade, and interferon programs, the antiviral-style immune signaling increasingly implicated in neurodegeneration. On the negative side, meaning programs blunted in the 5xFAD response, sat oxidative phosphorylation, the mitochondrial energy-generating machinery, and lipid and metabolic programs. All 10 pathways retained their direction and significance when the analysis was repeated with edgeR-ranked statistics.

That immune-up, energy-down signature is a pattern that will look familiar to anyone who follows Alzheimer’s research. Chronic neuroinflammation and mitochondrial dysfunction are two of the most consistently reported features of the diseased brain, and the study suggests that anesthesia and surgery may push an amyloid-burdened hippocampus further along both of these axes while a healthy hippocampus responds with a different, less inflammatory and less metabolically suppressed program. The authors also scored the expression of four marker-based cell-type signatures to ask whether the interaction effects could be explained by shifts in the relative abundance or activity of specific cell populations such as neurons, astrocytes, or microglia, but none of the four scores showed a significant interaction, leaving the cellular source of the reconfiguration an open question for future single-cell work.

The team also checked their findings against two public mouse transcriptomic datasets for external context, and here the results were sobering: none of the highlighted genes replicated at false discovery rate below 0.05 in those external datasets. This is not entirely surprising, since public datasets rarely match the precise combination of genotype, age, sex, exposure type, and post-exposure time point used here, but it underscores the exploratory nature of the work. The authors are equally explicit about the limits of interpretation in the other direction: the study does not establish a perioperative neurocognitive disorder phenotype, because no behavioral testing was performed; it cannot distinguish the effects of anesthesia from those of surgery, because the two were always combined; and it does not validate any biomarker. With three animals per group, the findings are hypothesis-generating by design, not definitive.

What the study does deliver is a well-guarded hypothesis with an unusually honest statistical presentation. By framing the question as an interaction rather than a pair of separate contrasts, the researchers were able to detect a phenomenon that the conventional approach would have missed entirely: a qualitative reorganization, rather than a quantitative amplification, of the hippocampal transcriptional response to the perioperative period in an Alzheimer-susceptible brain. The robustness of the pathway-level immune-metabolic pattern, which survived every sensitivity check the authors threw at it, contrasts instructively with the fragility of individual gene significance, a lesson in where the signal in small transcriptomic studies is most likely to live. The authors call for larger, longitudinal, behaviorally phenotyped and experimentally validated studies to determine whether this molecular reconfiguration translates into the cognitive vulnerability that clinicians observe in the operating room, and whether protecting the hippocampus from that inverted inflammatory-metabolic shift could one day shield vulnerable patients from postoperative cognitive decline.

Subject of Research: Genotype-dependent hippocampal transcriptional responses to anesthesia and surgery in 5xFAD Alzheimer-model mice

Article Title: Genotype-dependent reconfiguration of hippocampal transcriptional responses to anesthesia/surgery at 24 h in 5xFAD mice: an exploratory interaction-based analysis

Article References: Wang, S., Song, J., Sun, S., Xiao, R., Zhang, Z., Zhang, J., & Yao, J. (2026). Genotype-dependent reconfiguration of hippocampal transcriptional responses to anesthesia/surgery at 24 h in 5xFAD mice: an exploratory interaction-based analysis. BMC Genomics. https://doi.org/10.1186/s12864-026-13390-7

Image Credits: AI Generated

DOI: 10.1186/s12864-026-13390-7

Keywords: Alzheimer's disease, 5xFAD mice, anesthesia, surgery, perioperative neurocognitive disorders, hippocampus, RNA sequencing, gene expression, genotype-by-exposure interaction, gene-set enrichment analysis, neuroinflammation, oxidative phosphorylation