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While amyloid accumulation starts early, individuals with substantial amyloid burden may remain cognitively normal, implying that amyloid alone is not sufficient for early risk assessment.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Given the genetic susceptibility of AD, a multi\u2010factorial pseudotime approach was proposed to integrate amyloid imaging and genotype data for estimating a risk score. Validation involved association with cognitive decline and survival analysis across risk\u2010stratified groups, focusing on patients with mild cognitive impairment (MCI).<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Our risk score outperformed amyloid composite standardized uptake value ratio in correlation with cognitive scores. MCI subjects with lower pseudotime risk score showed substantial delayed onset of AD and slower cognitive decline. Moreover, pseudotime risk score demonstrated strong capability in risk stratification within traditionally defined subgroups such as early MCI, apolipoprotein E (<jats:italic>APOE<\/jats:italic>) \u03b54+ MCI, <jats:italic>APOE<\/jats:italic> \u03b54\u2013 MCI, and amyloid+ MCI.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>Our risk score holds great potential to improve the precision of early risk assessment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Accurate early risk assessment is critical for the success of clinical trials.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>A new risk score was built from integrating amyloid imaging and genetic data.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Our risk score demonstrated improved capability in early risk 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