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Amyloid precursor protein (<i>APP</i>), presenilin 1 (<i>PSEN1</i>), and presenilin 2 (<i>PSEN2</i>) are associated with autosomal-dominant early-onset Alzheimer’s disease (AD). Most mutations have been identified in the <i>PSEN1</i> gene. We discovered a <i>PSEN1</i> mutation (Tyr389His) in a Korean patient with early-onset AD who presented memory decline at 41 years of age followed by language, memory, and visuospatial dysfunctions. As this is the third such patient identified in Korea, this mutation may be involved in AD pathogenesis, suggesting that routine screening is necessary in this population. Altered intra-molecular interactions with the mutated amino acid may result in the destabilization of γ-secretase. In the future, a panel incorporating genes with relatively high-frequency rare variants, along with the <i>APOE4</i> gene, may predict the onset of AD and facilitate customized treatment.