Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory and cognitive impairment, as well as mental and behavioral abnormalities (Masters et al., 2015). The clinical features of AD mainly include progressive memory, cognitive, and emotional dysfunction, as well as behavioral abnormalities. The typical pathological manifestations of AD include amyloid deposition (amyloid β-protein, Aβ), neurofibrillary tangle (NFT) formation, neuronal number reduction, axonal abnormalities, synaptic abnormalities, and granular vacuolar degeneration (Masters et al., 2015). AD can be divided into familial AD and sporadic AD. Familial AD is hereditary and accounts for approximately 4–8% of AD cases. Familial AD is caused mainly by mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes (Hoogmartens et al., 2021), which lead to Aβ_1-42/Aβ_1-40 overexpression and deposition in brain tissue. The etiology of sporadic AD is currently unclear, but the following hypotheses have been proposed: Aβ toxicity hypothesis, tau protein phosphorylation hypothesis, oxidative stress hypothesis, neuroinflammation hypothesis, mitochondrial dysfunction hypothesis, cholinergic damage hypothesis, and apolipoprotein E (ApoE) hypothesis (Zetterberg and Mattsson, 2014).

Parkinson’s disease (PD) is another common neurodegenerative disease. Diffusion weighted magnetic resonance imaging (dw-MRI), particularly diffusion tensor imaging (DTI), has confirmed a reduction in fractional anisotropy (FA) and an increase in mean diffusivity in the substantia nigra in PD patients (Monnot et al., 2017). In addition to a large reduction in the striatal binding ratio (SBR) and dopamine transporter (DAT) levels, cortical and subcortical VMAT2 neurons are reduced in PD (Zhou, 2021a). There are currently several hypotheses regarding the pathogenesis of PD as follows: oxidative stress hypothesis, neuroinflammation hypothesis, neurotoxicity hypothesis, and mitochondrial dysfunction hypothesis (Morris et al., 2024). The main clinical manifestations of PD include motor and nonmotor symptoms. The main motor symptoms include increased overall muscle tension, muscle rigidity, reduced voluntary movement, slow movements, and stiff facial expressions, and these symptoms are often accompanied by static tremors (Magrinelli et al., 2016); PD patients may also experience nonmotor symptoms, such as low mood, anxiety, sleep disorders, cognitive impairment, and fatigue.

It has been reported that the prevalence rate of comorbid mild cognitive impairment (MCI) in PD patients is approximately 20–30%, while for long-term PD with dementia (PDD) patients, the rate can reach 80% (Zhou, 2021a). Additionally, the annual progression rate of PD-MCI to PDD incidence is approximately 11%, and the rate of PDD conversion is greater than 90% after a long time (>15 years) (Zhou, 2021b). Moreover, approximately 50% of AD patients have Lewy bodies, Aβ, and tau lesions in the brain (Azar et al., 2020). With the development of AD, alterations in the activity of enzymes associated with various neurotransmitters (DA, Ach, and GABA) may occur, resulting in imbalances among different neurotransmitter systems, impaired motor function, and even the appearance of PD symptoms, such as motor disorders (Wang et al., 2021). At present, there is no effective option for the treatment of patients with AD and comorbid PD.

Epithelial growth factor receptor (EGFR) is a multifunctional glycoprotein with tyrosine kinase activity that belongs to the ErbB receptor family, which includes HER1 (erbB1 and EGFR), HER2 (erbB2 and NEU), HER3 (erbB3), and HER4 (erbB4) (Sabbah et al., 2020). EGFR, which is widely distributed on the cell membranes of various tissues in the human body, is a receptor for epithelial growth factor (EGF) that promotes cell proliferation and signal transduction. Activated EGFR can alleviate glutamate-induced neurotoxicity and thus exert a neuroprotective effect (Abe and Saito, 1992). EGFR are known to improve both behavioral and pathologic hallmarks of neurodegenerative diseases via autophagy induction and rescuing reactive astrocyte (Romano and Bucci, 2020; Tavassoly et al., 2020). Extensive Aβ_1–42 production and tau phosphorylation form because of overexpressed EGFR leading to sustained phosphorylation of the downstream signaling axis (Jayaswamy et al., 2023). In transgenic Drosophila and transgenic mouse models, EGFR is the preferred target for treating Aβ-induced memory loss, suggesting that EGFR plays a key role in maintaining neuronal structure and function (Sibilia and Wagner, 1995). In addition, the EGFR signaling pathway and its related genes play important roles in the death of DA neurons (Kim et al., 2017; Jin et al., 2020). EGFR aggregates to form dimers when activated by ligands, subsequently regulating downstream signaling pathways through TK activation and phosphorylation of tyrosine residues in the CTD. According to KEGG pathway analysis, EGFR-mediated regulation of AD and comorbid PD may involve the RAS/RAF/MAPK pathway and PI3K/Akt pathway (Gao et al., 2023; Nowell et al., 2023). In the RAS/RAF/MAPK pathway, when EGFR activates Ras, it promotes the conversion of plasma membrane RAS-GDP to the RAS-GTP active form, which activates the Raf protein kinase. Activated Raf activates ERK kinase, which amplifies signals to induce the ERK cascade through positive feedback, subsequently promoting the proliferation of nerve cells and axonal growth (Zhang et al., 2021; Chun et al., 2022). The PI3K/Akt signaling pathway regulates glucose homeostasis and energy metabolism in the brain through the insulin signaling pathway, thereby affecting synaptic function, learning, and working memory (De Felice et al., 2022). mTOR is the initiator protein of autophagy. The PI3K/Akt signaling pathway affects the autophagic function of nerve cells through mTOR, mediating the degradation of pathological proteins, the accumulation of neurocytotoxic substances, neuronal survival, axonal regeneration, and synaptic plasticity (Liu et al., 2017; Yang et al., 2023). The PI3K/Akt signaling pathway regulates the activity of GSK-3β, resulting in the hyperphosphorylation of pathological proteins in neurodegenerative diseases (L'Episcopo et al., 2016).

The structure of EGFR is divided into an N-terminal domain (NTD), a single transmembrane domain (TM), and a C-terminal intracellular domain. The N-terminus of EGFR (EGFR_NTD), a ligand-binding domain that receives external signals, is divided into the following four subregions: region I is responsible for binding ligands; region II interacts with ligands through conserved amino acid residues (Sabbah et al., 2020); and regions III and IV are involved in the formation of intramolecular disulfide bonds. The transmembrane (TM) domain is a transmembrane hydrophobic region, consisting of 23 amino acid residues, which forms an α-helical structure and anchors EGFR to the cell membrane. The C-terminal intracellular carboxy-terminal region, which has a conserved tyrosine kinase core, can be further divided into the near-membrane (JM) region, tyrosine kinase (TK) region, and C-terminal domain (CTD) region. The JM region regulates the dimerization of EGFR after it binds to ligands, which is followed by ATP binding and TK activation; ultimately, the CTD undergoes autophosphorylation and regulates intracellular signal transduction pathways (Shao and Zhu, 2019).

In the present study, changes in the expression profiles of genes in brain tissue samples from AD and PD patients were analyzed. DEGs in both AD and PD patients were identified. Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed, and a protein–protein interaction network (Genomes) was constructed. The MCODE plugin, CytoHubba plug-in, and CytoNCA algorithms were used to identify key genes related to AD and comorbid PD (Nayan et al., 2023; Zhou et al., 2023). A connectivity map (CMap) was generated to identify the optimal drug for treating AD and comorbid PD. Finally, molecular docking was performed with AutoDock to evaluate the interactions between the key proteins involved in AD and comorbid PD, as well as between the key proteins and optimal drugs, providing a theoretical basis for improving the quality of life of patients with AD and comorbid PD.

AD and PD are the most common neurodegenerative diseases in humans. AD is a degenerative disease of the central nervous system whose main pathological feature is the formation of Aβ plaques and neurofibrillary tangles in the brain, which affect cognitive function, memory, ability to perform life activities, emotions, and personality. PD involves the loss of dopaminergic neurons in the substantia nigra pars compacta and the formation of Lewy bodies in dopaminergic neurons and Lewy neurites in multiple brain areas, resulting in motor dysfunction. In the advanced stage of AD, pathological characteristics associated with both AD and PD may be present in the brain tissue of patients and have dual impacts on physical health and quality of life.

In the present study, the brain tissue sample gene expression data from the GSE120063 (AD) and GSE7621 (PD) datasets were analyzed, and UMAP analysis revealed little difference between the samples from the AD and PD groups. DEGs in the datasets were identified according to the following criteria: p < 0.05 and |LogFC| > 0.585. A total of 3,784 DEGs and 2,201 DEGs were identified in the AD and PD datasets, respectively. There were 625 overlapping DEGs, with 231 upregulated DEGs and 300 downregulated DEGs. To assess the relationships among the genes, the PPI network was analyzed with the CytoNCA algorithm, MCODE module, and CytoHubba plug-in, which suggested that EGFR may be a potential receptor in AD and comorbid PD. EGFR expression was significantly increased in the AD and PD datasets. Enrichment analysis revealed that 54 proteins that directly interact with EGFR were enriched in the signal transduction biological process and in cancer pathways, such as the MAPK signaling pathway.

Semagacestat (BRD-K65592642) was among the small molecule drug candidates for AD and PD identified by CMap. Semagacestat is the most widely studied gamma-secretase inhibitor, and it blocks hybrid β sheet formation between substrates and presenilin 1 to inhibit substrate cleavage (Tagami et al., 2017; Hur, 2022). Stable isotope labeling kinetics have shown that semagacestat decreases the levels of Aβ_1-38, Aβ_1-40, and Aβ_1-42 in cerebrospinal fluid but increases the levels of Aβ_1-15 and/or Aβ_1-16 (Hölttä et al., 2016); however, no decrease in the level of Aβ_1-42 or Aβ_1-40 in cerebrospinal fluid has been detected in phase III trials. Moreover, the use of semagacestat was stopped in August 2010 due to adverse reactions in phase III trials (Lleó et al., 2015). The failure of the clinical evaluation of semagacestat may be caused by multiple factors, one of which is thought to be related to its half-life (2–3 h). Due to its short half-life, semagacestat must reach a high concentration to inhibit Aβ production, which can also inhibit the cleavage of Notch and other substrates, resulting in side effects (De Strooper, 2014; Yang et al., 2021).

According to molecular docking analysis of EGF and semagacestat, the binding energy between semagacestat and EGFR_NTD was −7.8 k/mol, which is less than −5 k/mol, indicating a high binding affinity between semagacestat and EGFR_NTD. Semagacestat was found to be embedded in the cavity formed by the EGFR_NTD domain I, II, and III regions, which agreed with a previous study (Sabbah et al., 2020). Seven hydrogen bonds and one hydrophobic bond formed between semagacestat and EGFR_NTD, and these bonds are key for the effect of semagacestat on the activity of EGFR_NTD (Zhou et al., 2022; Zheng et al., 2023). Although semamacestat can inhibit the activity of gamma-secretase and potentially improve the pathology of AD combined with PD through EGFR, it can also exacerbate side effects by inhibiting the cleavage of Notch. Therefore, the structure of sematacestat can be optimized based on the structure of the EGFR_NTD_semagacestat complex to improve the substrate-selective design. Despite these many unresolved questions, the present study revealed the molecular basis for the recognition and mechanism of action of semagacestat and EGFR, suggesting that semamacestat may improve the pathology of AD and comorbid PD through EGFR, which may ultimately lead to potent therapeutics targeting AD and comorbid PD.

In summary, the present study utilized bioinformatics methods to analyze gene expression in AD and PD patients. According to the enrichment analysis of the DEGs in AD and PD patients, as well as the PPI network map analysis, EGFR may be a key receptor in patients with AD and comorbid PD. According to the GSEA algorithm in CMap, semagacestat is a potential small molecule drug for the treatment of AD and comorbid PD. Molecular docking analysis revealed information about the interaction and binding between semagacestat and EGFR, which may provide a rationale for further analysis of EGFR inhibitors designed on the basis of the semagacestat structure. Thus, the present study provides a novel strategy for the development of drugs for the treatment of AD and comorbid PD.

The present results suggested that EGFR may be a key receptor in AD and comorbid PD. EGFR may mediate the development of AD and PD through cancer-related pathways, such as the Ras/Raf/MAPK and PI3K/Akt pathways. Semagacestat (BRD-K65592642) is a potential candidate drug for treating AD complicated with PD. Molecular docking analysis of the interaction between semagacestat and EGFR suggested that modification of the semagacestat structure may be a novel strategy for the development of more effective drugs for AD and comorbid PD.

Publicly available datasets were analyzed in this study. These data may be found in the GSE122063 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE122063) and GSE7621 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE7621) datasets.

Ethical approval was not required for the studies involving humans because GEO belong to public databases. The patients involved in the database have obtained ethical approval. Users can download relevant data for free for research and publish relevant articles. Our study is based on open source data, so there are no ethical issues and other conflicts of interest. The studies were conducted in accordance with the local legislation and institutional requirements. The human samples used in this study were acquired from gifted from another research group. Written informed consent to participate in this study was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and the institutional requirements.

XZ: Conceptualization, Funding acquisition, Methodology, Project administration, Visualization, Writing – original draft, Writing – review & editing. ZL: Investigation, Methodology, Writing – review & editing. GB: Investigation, Writing – review & editing. DB: Writing – review & editing. PZ: Writing – review & editing. XW: Writing – review & editing. GJ: Conceptualization, Data curation, Project administration, Writing – review & editing.