A comprehensive genome-wide association study (GWAS) has validated the identification of the Plexin-A 4 (PLXNA4) gene as a novel susceptibility factor for Alzheimer’s disease (AD). Nonetheless, the precise role of PLXNA4 gene polymorphisms in the pathophysiology of AD remains to be established. Consequently, this study is aimed at exploring the relationship between PLXNA4 gene polymorphisms and neuroimaging phenotypes intimately linked to AD. This study encompassed 812 subjects with PLXNA4 genotype data, procured from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Employing a tagging strategy, we identified five common variant sites within the PLXNA4 gene and assessed their associations with glucose metabolism, atrophy in AD-related brain regions (including the medial temporal lobe, hippocampus, and parahippocampal gyrus), and intracerebral Aβ deposition. We conducted a comprehensive analysis using a multiple linear regression model, with neuroimaging phenotypes as the dependent variable and PLXNA4 gene polymorphisms as the independent variable while incorporating APOE e4 carrier status, education level, age, and gender as covariates. The subjects were stratified into three groups based on their disease status: the Alzheimer’s disease (AD) group, the mild cognitive impairment (MCI) group, and the cognitively normal healthy control (CN) group. Within each group, we examined the associations between PLXNA4 gene polymorphisms and various neuroimaging phenotypes. Our study identified significant associations between the rs156676-A and rs78036292-G alleles and the baseline volumes of the anterior cingulate and middle temporal gyrus, respectively, across the entire population. After 1 year of follow-up, a significant correlation was observed between the rs6467431-G allele and accelerated volumetric atrophy of the parahippocampal gyrus in the overall population. Additionally, at the 2-year follow-up, significant correlations were observed between three PLXNA4 loci (rs1863015, rs6467431, rs67468325) and volumetric atrophy in the anterior cingulate, middle temporal gyrus, and hippocampus across the entire population. Specifically, the rs1863015-G allele notably accelerated atrophy of the left middle temporal gyrus and bilateral hippocampus, whereas the A alleles of rs6467431 and rs67468325 markedly accelerated atrophy specifically in the bilateral hippocampus. Subgroup analysis further validated these findings. Additionally, in the baseline CN group, the rs78036292 allele showed a significant correlation with intracerebral Aβ deposition, while in the 2-year follow-up CN group, rs67468325 was significantly associated with alterations in glucose metabolism rates in the right cingulate gyrus. Our findings indicate that PLXNA4 genotypes may modulate the development of AD through their regulation of intracerebral Aβ deposition. Additionally, PLXNA4 genotypes are strongly associated with AD-related brain atrophy and glucose metabolism, suggesting that they may alter susceptibility to AD by modulating neurodegenerative biomarkers.