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Introduction: Dementia is associated with many comorbidities while being related to Apolipoprotein E (ApoE) polymorphism. However, it is unclear how these clinical illnesses and genetic factors modify the dementia risk. Methods: We enrolled 600 dementia cases and 6000 matched non-dementia controls, with identified ApoE genotype (ε4/ε4, ε4/ε3, and ε3/ε3). Eight comorbidities were selected by medical records, and counted if occurring within 3 years of enrollment. Results: The dementia group had a higher ratio of carrying +4 allele and prevalence of comorbidities than the non-dementia group. Homozygous +4 carriers presented the broken line of dementia risk with the peak age at 65--75 years and odds ratio (OR) up to 6.6. The risk only emerged after 65 years of age in +3/+4 subjects with OR around 1.6--2.4 when aged > 75 years. Cerebrovascular accident (CVA) is the commonest comorbidity (14.6%). CVA, sleep disorder, and functional gastrointestinal disorders remained as significant risk comorbidities for dementia throughout all age groups (OR = 1.7--5.0). When functional gastrointestinal disorder and +4 allele both occurred, the dementia risk exceeded the summation of individual risks OR = 3.7 and 1.9 individually, OR = 6.0 for the combination). Comorbidities could also be predictors of dementia. Conclusion: Combining the genetic and clinical information, we detected cognitive decline and optimize interventions early when the patients present a specific illness in a particular age and carry a specific ApoE allele. Of comorbidities, functional gastrointestinal disorder is the strongest predicting factor for dementia in +4 allele carriers. [ABSTRACT FROM AUTHOR]