Zheng Liu

Perioperative delirium is an acute disturbance of attention and awareness that arises when surgical stress interacts with limited brain reserve. Synaptic dysfunction provides a plausible connection between genetic susceptibility, neuroimmune responses and fluctuating network activity, but the strength of evidence differs substantially across these levels. This narrative review examines human genetic and molecular studies alongside experimental investigations of synaptic plasticity, with emphasis on recent primary research. Large association studies now support an association between APOE ε4 and delirium susceptibility, whereas blood transcriptomics and brain tissue profiling implicate complement regulation, immune responses and glial cell states. Experimental studies identify mechanisms involving complement-dependent synaptic engulfment, astrocytic cholesterol and glucose support, glutamate handling, mitochondrial stress and epigenetic regulation of BDNF–ARC signaling. These findings suggest that reversible changes in synaptic efficacy and slower structural remodeling can coexist, without requiring synapse loss to explain every delirium episode. Human neurogranin, neurofilament and electrophysiological studies also reveal important negative or context-dependent findings. Translation therefore requires separation of preoperative vulnerability from acute disease activity, direct assessment of attention and arousal, and evidence that a molecular intervention improves clinically meaningful outcomes. The phase 2 trial of the APOE mimetic CN-105 illustrates the distinction between mechanistic plausibility and clinical efficacy, as its benefit for delirium prevention remains unproven. A cell-specific, temporally resolved approach is needed to determine which synaptic mechanisms are causal, reversible and therapeutically accessible in human perioperative delirium.

Genetic and molecular studies increasingly explain anesthetic and analgesic responses at the level of defined conductances, neuronal populations, and injury states. Their clinical implications depend on distinguishing target engagement from changes in firing and, ultimately, from a measurable therapeutic effect. This review examines recent evidence linking sodium, potassium, calcium, and sensory transduction channels to pain and inhibitory receptor composition, chloride regulation, and arousal circuits to anesthesia. Selective NaV1.8 inhibition provides an unusually complete translational example, spanning channel pharmacology, recordings from human sensory neurons, and randomized postoperative trials. Nevertheless, residual firing during substantial NaV1.8 inhibition and divergent explanations of NaV1.7-null analgesia show why the effects of a drug cannot be inferred directly from a genetic phenotype. Structural studies now resolve anesthetic binding and gating mechanisms in GABAA, NMDA, and HCN1 channels, while circuit experiments distinguish emergence, immobility, and antinociception. Neuroimmune signaling extends beyond cytokine-driven excitation to include inhibitory synapse removal, sex-dependent cellular pathways, and active pain resolution. Chromatin regulation, RNA modification, and neuronal senescence can stabilize altered excitability after injury. Human ganglion and spinal cord atlases, Patch-seq, and sensory assembloids provide more relevant models for connecting these mechanisms across scales, although none substitute for clinical validation. We emphasize research published from 2021 onward, retaining foundational studies where they establish a causal mechanism. The resulting evidence supports cell- and state-specific intervention rather than a single molecular explanation of anesthesia or chronic pain and identifies practical requirements for translating genetic discovery into perioperative treatment.

Perioperative neurocognitive disorders (PND) include postoperative delirium within 7 days after surgery, delayed neurocognitive recovery up to 30 days, and postoperative neurocognitive disorder up to 12 months. These outcomes are related, but they are not the same. They arise from the interaction of baseline brain vulnerability and perioperative stress, including inflammation, vascular instability, blood–brain barrier injury, metabolic strain, and reduced neural reserve. Preoperative genetic profiling is useful because it can estimate latent susceptibility before surgery. Among current signals, APOE is the strongest and most biologically relevant locus. At the same time, Alzheimer’s disease polygenic risk scores (AD-PRS) can capture non- APOE common-variant burden across lipid transport, endosomal trafficking, innate immune signaling, complement activity, microglial regulation, mitochondrial stress, and neurovascular integrity. Recent perioperative cohort studies have begun to test preoperative APOE-based and polygenic neurocognitive risk in surgical patients. Large delirium genetics studies also show a strong signal at the APOE locus and support overlap between delirium risk and Alzheimer’s disease-related common-variant architecture. These findings support an APOE-aware framework in which APOE genotype is modeled separately from non- APOE AD-PRS. In clinical use, this genomic layer should be combined with baseline cognition, frailty, vascular comorbidity, surgery-related risk, and circulating biomarkers such as neurofilament light chain. This review summarizes the loci, molecular pathways, and translational model designs that can move preoperative genomic profiling from association to perioperative risk stratification.

Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), represent a growing societal challenge due to their irreversible progression and significant impact on patients, caregivers, and healthcare systems. Despite advances in clinical and imaging-based diagnostics, these diseases are often detected at advanced stages, limiting the effectiveness of therapeutic interventions. Recent breakthroughs in genomic and transcriptomic technologies, including whole-genome sequencing, single-cell RNA sequencing (scRNA-seq), and CRISPR-based screens, have revolutionized the field, offering new avenues for early diagnosis and personalized prognosis. Genomic approaches have elucidated disease-specific genetic risk factors and molecular pathways, while transcriptomic studies have identified stage-specific biomarkers that correlate with disease progression and severity. Furthermore, genome-wide association studies (GWAS), polygenic risk scores (PRS), and spatial transcriptomics are enabling the stratification of patients based on their risk profiles and prognostic trajectories. Advances in functional genomics have uncovered actionable targets, such as ATXN2 in ALS and TREM2 in AD, paving the way for tailored therapeutic strategies. Despite these achievements, challenges remain in translating genomic discoveries into clinical practice due to disease heterogeneity and the complexity of neurodegenerative pathophysiology. Future integration of genetic technologies holds promise for transforming diagnostic and prognostic paradigms, offering hope for improved patient outcomes and precision medicine approaches.