The study investigates the protective mechanisms against Alzheimer's disease (AD) in individuals carrying the *APOEε4* allele, which is a significant risk factor for AD. The researchers used whole-genome sequencing data from multiple cohorts to identify rare coding variants that segregate exclusively among cognitively unaffected *APOEε4* carriers. They found 510 rare coding variants in 476 genes, with two variants in the *FN1* gene (fibronectin-1) being particularly noteworthy. Pathway analysis of these genes showed significant enrichment in extracellular matrix (ECM)-related processes, suggesting that functional modifications in ECM proteins might protect against *APOEε4*-mediated AD pathology. The researchers prioritized *FN1* and *COL6A2* genes, which are known to be expressed at the blood–brain barrier (BBB) and are enriched in ECM-related gene ontology terms. An independent analysis in a large cohort of 7185 *APOEε4* homozygous carriers found that the *FN1* variant rs140926439 was protective against AD, reducing the risk by 71% and delaying the age at onset by 3.37 years. Postmortem brain analysis showed that cognitively unaffected *APOEε4* carriers had lower FN1 deposition and less reactive gliosis compared to those with AD, suggesting that FN1 might be a downstream driver of *APOEε4*-mediated AD pathology. To validate these findings, the researchers used zebrafish models with loss-of-function (LOF) mutations in *fn1b* (the ortholog of human *FN1*). They found that LOF of *fn1b* reduced gliosis, enhanced gliovascular remodeling, and potentiated the microglial response, indicating that pathological accumulation of FN1 could impair toxic protein clearance, which is ameliorated with *FN1* LOF. The study concludes that vascular deposition of FN1 is related to the pathogenicity of *APOEε4*, and LOF variants in *FN1* may reduce *APOEε4*-related AD risk, providing novel clues for potential therapeutic interventions targeting the ECM to mitigate AD risk.The study investigates the protective mechanisms against Alzheimer's disease (AD) in individuals carrying the *APOEε4* allele, which is a significant risk factor for AD. The researchers used whole-genome sequencing data from multiple cohorts to identify rare coding variants that segregate exclusively among cognitively unaffected *APOEε4* carriers. They found 510 rare coding variants in 476 genes, with two variants in the *FN1* gene (fibronectin-1) being particularly noteworthy. Pathway analysis of these genes showed significant enrichment in extracellular matrix (ECM)-related processes, suggesting that functional modifications in ECM proteins might protect against *APOEε4*-mediated AD pathology. The researchers prioritized *FN1* and *COL6A2* genes, which are known to be expressed at the blood–brain barrier (BBB) and are enriched in ECM-related gene ontology terms. An independent analysis in a large cohort of 7185 *APOEε4* homozygous carriers found that the *FN1* variant rs140926439 was protective against AD, reducing the risk by 71% and delaying the age at onset by 3.37 years. Postmortem brain analysis showed that cognitively unaffected *APOEε4* carriers had lower FN1 deposition and less reactive gliosis compared to those with AD, suggesting that FN1 might be a downstream driver of *APOEε4*-mediated AD pathology. To validate these findings, the researchers used zebrafish models with loss-of-function (LOF) mutations in *fn1b* (the ortholog of human *FN1*). They found that LOF of *fn1b* reduced gliosis, enhanced gliovascular remodeling, and potentiated the microglial response, indicating that pathological accumulation of FN1 could impair toxic protein clearance, which is ameliorated with *FN1* LOF. The study concludes that vascular deposition of FN1 is related to the pathogenicity of *APOEε4*, and LOF variants in *FN1* may reduce *APOEε4*-related AD risk, providing novel clues for potential therapeutic interventions targeting the ECM to mitigate AD risk.