Cerebral hypoperfusion is thought to contribute to cognitive decline in Alzheimer’s disease, but the natural trajectory of cerebral perfusion in cognitively healthy adults has not been well-studied. This longitudinal study is consisted of 950 participants (40—89 years), who were cognitively unimpaired at their first visit. We investigated the age-related changes in cerebral perfusion, and their associations with APOE-genotype, biological sex, and cardiometabolic measurements. During the follow-up period (range 0.13—8.24 years), increasing age was significantly associated with decreasing cerebral perfusion, in total gray-matter (β=−1.43), hippocampus (−1.25), superior frontal gyrus (−1.70), middle frontal gyrus (−1.99), posterior cingulate (−2.46), and precuneus (−2.14), with all P-values < 0.01. Compared with male-ɛ4 carriers, female-ɛ4 carriers showed a faster decline in global and regional cerebral perfusion with increasing age, whereas the age-related decline in cerebral perfusion was similar between male- and female-ɛ4 non-carriers. Worse cardiometabolic profile (i.e., increased blood pressure, body mass index, total cholesterol, and blood glucose) was associated with lower cerebral perfusion at all the visits. When time-varying cardiometabolic measurements were adjusted in the model, the synergistic effect of sex and APOE-ɛ4 on age-related cerebral perfusion-trajectories became largely attenuated. Our findings demonstrate that APOE-genotype and sex interactively impact cerebral perfusion-trajectories in mid- to late-life. This effect may be partially explained by cardiometabolic alterations.

脑灌注不足被认为会导致阿尔茨海默病的认知能力下降，但认知健康成人脑灌注的自然轨迹尚未得到充分研究。这项纵向研究由 950 名参与者（40-89 岁）组成，他们在第一次访问时没有认知障碍。我们调查了与年龄相关的脑灌注变化，以及它们与APOE-基因型、生物学性别和心脏代谢测量。在随访期间（范围 0.13-8.24 岁），年龄增加与脑灌注减少显着相关，总灰质（β=-1.43）、海马（-1.25）、额上回（-1.70）、额中回 (-1.99)、后扣带回 (-2.46) 和楔前叶 (-2.14)，所有 P 值 < 0.01。与男性-ɛ4携带者相比，女性-ɛ4携带者随着年龄的增长，全球和区域脑灌注下降更快，而男性和女性-ɛ4非携带者之间与年龄相关的脑灌注下降相似。在所有就诊中，较差的心脏代谢特征（即血压、体重指数、总胆固醇和血糖升高）与较低的脑灌注相关。与年龄相关的脑灌注轨迹上的APOE -ɛ4 大大减弱。我们的研究结果表明，APOE基因型和性别交互影响中年至晚年的脑灌注轨迹。这种效应可以部分地通过心脏代谢改变来解释。