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Abstract: The clinical implications of WMHs in aMCI are inconclusive. Moreover, clinical interactions between APOE genotypes and WMHs remain unclear. This study was conducted to investigate the relationship between WMHs and cognitive functions and how this relationship interacted with APOE genotype in people with aMCI. This study included a total of 1472 patients with aMCI from the Clinical Research Center for Dementia of South Korea (CREDOS) and divided them into 3 groups according to the severity of WMHs as assessed by visual ratings of brain magnetic resonance images. The associations of WMHs with the various cognitive domains and with APOE epsilon 4 (ɛ4) status were evaluated. After multivariable adjustments, the severity of WMHs was independently associated with semantic/phonemic verbal fluency and Stroop test-color reading, while APOE ɛ4 status was associated with verbal and visual memory-immediate, delayed recall, and recognition. Moreover, there were interaction between WMHs and APOE ɛ4 status in semantic verbal fluency (animal, P =0.033; supermarket, P =0.047)/Stroop test-color reading (P =0.024). WMHs independently deleteriously affected frontal executive functions in aMCI patients, regardless of APOE ɛ4 presence. Furthermore, APOE ɛ4 possession caused a rapid decline in frontal executive functions with the increase in the WMHs severity (vs. absence), suggesting that WMHs and APOE ɛ4 genotypes synergistically contribute to frontal executive dysfunctions in aMCI. [Copyright &y& Elsevier]