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Abstract Reduced insulin-like growth factor 2 (IGF2) levels in Alzheimer’s disease (AD) may be the mechanism relating age-related metabolic disorders to dementia. Since Igf2 is an imprinted gene, we examined age and sex differences in the relationship between amyloid-beta 1–42 (Aβ 42 ) accumulation and epigenetic regulation of the Igf2/H19 gene cluster in cerebrum, liver, and plasma of young and old male and female 5xFAD mice, in frontal cortex of male and female AD and non-AD patients, and in HEK293 cell cultures. We show IGF2 levels, Igf2 expression, histone acetylation, and H19 ICR methylation are lower in females than males. However, elevated Aβ 42 levels are associated with Aβ 42 binding to Igf2 DMR2, increased DNA and histone methylation, and a reduction in Igf2 expression and IGF2 levels in 5xFAD mice and AD patients, independent of H19 ICR methylation. Cell culture results confirmed the binding of Aβ 42 to Igf2 DMR2 increased DNA and histone methylation, and reduced Igf2 expression. These results indicate an age- and sex-related causal relationship among Aβ 42 levels, epigenomic state, and Igf2 expression in AD and provide a potential mechanism for Igf2 regulation in normal and pathological conditions, suggesting IGF2 levels may be a useful diagnostic biomarker for Aβ 42 targeted AD therapies.