Aamand Rasmus, Rasmussen Peter M, Andersen Katrine Schilling, de Paoli Stine, Weitzberg Eddie, Christiansen Michael, Lund Torben E, Østergaard Leif
Department of Clinical Medicine, Center of Functionally Integrative Neuroscience (CFIN), Aarhus University, 8000 Aarhus, Denmark.
Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden.
PNAS Nexus. 2024 Aug 23;3(9):pgae369. doi: 10.1093/pnasnexus/pgae369. eCollection 2024 Sep.
APOE-ɛ4 is a genetic risk factor for Alzheimer's disease (AD). AD is associated with reduced cerebral blood flow (CBF) and with microvascular changes that limit the transport of oxygen from blood into brain tissue: reduced microvascular cerebral blood volume and high relative transit time heterogeneity (RTH). Healthy APOE-ɛ4 carriers reveal brain regions with CBF compared with carriers of the common ɛ3 allele. Such asymptomatic hyperemia may reflect : a vascular disease entity characterized by suboptimal tissue oxygen uptake, rather than limited blood flow per se. Here, we used perfusion MRI to show that elevated regional CBF is accompanied by reduced capillary blood volume in healthy APOE-ɛ4 carriers (carriers) aged 30-70 years compared with similarly aged APOE-ɛ3 carriers (noncarriers). Younger carriers have elevated hippocampal RTH and more extreme RTH values throughout both white matter (WM) and cortical gray matter (GM) compared with noncarriers. Older carriers have reduced WM CBF and more extreme GM RTH values than noncarriers. Across all groups, lower WM and hippocampal RTH correlate with higher educational attainment, which is associated with lower AD risk. Three days of dietary nitrate supplementation carriers' WM CBF but caused older carriers to score on two of six aggregate neuropsychological scores. The intervention improved late recall in younger carriers and in noncarriers. The APOE-ɛ4 gene is associated with microvascular changes that may impair tissue oxygen extraction. We speculate that vascular risk factor control is particularly important for APOE-ɛ4 carriers' healthy aging.
APOE-ɛ4是阿尔茨海默病（AD）的一种遗传风险因素。AD与脑血流量（CBF）减少以及微血管变化有关，这些变化限制了氧气从血液向脑组织的输送：微血管脑血容量减少和相对转运时间异质性（RTH）升高。与常见的ɛ3等位基因携带者相比，健康的APOE-ɛ4携带者显示出脑区CBF增加。这种无症状性充血可能反映了一种以组织氧摄取不理想为特征的血管疾病实体，而非血流量本身受限。在此，我们使用灌注磁共振成像显示，与年龄相仿的APOE-ɛ3携带者（非携带者）相比，30至70岁的健康APOE-ɛ4携带者（携带者）区域CBF升高伴随着毛细血管血容量减少。与非携带者相比，年轻携带者海马体RTH升高，在整个白质（WM）和皮质灰质（GM）中RTH值更极端。年长携带者的WM CBF低于非携带者，GM RTH值更极端。在所有组中，较低的WM和海马体RTH与较高的教育程度相关，而较高的教育程度与较低的AD风险相关。三天的膳食硝酸盐补充增加了携带者的WM CBF，但导致年长携带者在六项综合神经心理学评分中的两项得分较低。该干预改善了年轻携带者和非携带者的延迟回忆。APOE-ɛ4基因与可能损害组织氧提取的微血管变化有关。我们推测，控制血管风险因素对APOE-ɛ4携带者的健康衰老尤为重要。
