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Background  Age-related frailty reflects cumulative multisystem physiological and health decline. Frailty increases the risk of adverse brain and cognitive outcomes, including differential decline and dementia. In a longitudinal sample of non-demented older adults, we examine whether (a) the level and/or change in frailty predicts trajectories across three cognitive domains (memory, speed, and executive function (EF)) and (b) prediction patterns are modified by sex or Alzheimer’s genetic risk ( Apolipoprotein E  ( APOE )).    Methods  Participants ( n  = 632;  M  age = 70.7, range 53–95; 3 waves) were from the Victoria Longitudinal Study. After computing a frailty index, we used latent growth modeling and path analysis to test the frailty effects on level and change in three latent variables of cognition. We tested two potential moderators by stratifying by sex and  APOE  risk (ε4+, ε4-).    Results  First, frailty levels predicted speed and EF performance (level) and differential memory change slopes. Second, change in frailty predicted the rate of decline for both speed and EF. Third, sex moderation analyses showed that females were selectively sensitive to (a) frailty effects on memory change and (b) frailty change effects on speed change. In contrast, the frailty effects on EF change were stronger in males. Fourth, genetic moderation analyses showed that  APOE  risk (e4+) carriers were selectively sensitive to frailty effects on memory change.    Conclusion  In non-demented older adults, increasing frailty is strongly associated with the differential decline in cognitive trajectories. For example, higher (worse) frailty was associated with more rapid memory decline than was lower (better) frailty. These effects, however, are moderated by both genetic risk and sex.    Electronic supplementary material  The online version of this article (10.1186/s13195-019-0509-9) contains supplementary material, which is available to authorized users.

Frailty effects on non-demented cognitive trajectories are moderated by sex and Alzheimer’s genetic risk