Arenaza-Urquijo Eider M, Salvadó Gemma, Operto Gregory, Minguillón Carolina, Sánchez-Benavides Gonzalo, Crous-Bou Marta, Grau-Rivera Oriol, Sala-Vila Aleix, Falcón Carles, Suárez-Calvet Marc, Zetterberg Henrik, Blennow Kaj, Gispert Juan Domingo, Molinuevo José Luis
From the Barcelonaβeta Brain Research Center (E.M.A.-U., G.S., G.O., C.M., G.S.-B., M.C.-B., O.G.-R., A.S.-V, C.F., M.S.-C., J.D.G., J.L.M.), Pasqual Maragall Foundation; IMIM (Hospital del Mar Medical Research Institute) (E.M.A.-U., G.S., G.O., C.M., G.S.-B., M.C.-B., O.G.-R., A.S.-V, C.F., M.S.-C., J.D.G., J.L.M.), Barcelona; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (E.M.A.-U., G.S., G.O., C.M., G.S.-B., M.C.-B., O.G.-R., M.S.-C., J.L.M.), Madrid, Spain; Department of Epidemiology (M.C.-B.), Harvard TH Chan School of Public Health, Boston, MA; Servei de Neurologia (O.G.-R., M.S.-C.), Hospital del Mar, Barcelona; Investigación Biomédica en Red Bioingeniería, Biomateriales y Nanomedicina (C.F., J.D.G.), Madrid, Spain; Clinical Neurochemistry Laboratory (H.Z., K.B.), Sahlgrenska University Hospital, Mölndal; Department of Psychiatry and Neurochemistry (H.Z., K.B.), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Department of Neurodegenerative Disease (H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (H.Z.), London; and Universitat Pompeu Fabra (J.D.G., J.L.M.), Barcelona, Spain.
Neurology. 2020 Oct 13;95(15):e2065-e2074. doi: 10.1212/WNL.0000000000010527. Epub 2020 Jul 31.
To evaluate the hypothesis that proximity to parental age at onset (AAO) in sporadic Alzheimer disease (AD) is associated with greater AD and neural injury biomarker alterations during midlife and to assess the role of nonmodifiable and modifiable factors.
This observational study included 290 cognitively unimpaired (CU) participants with a family history (FH) of clinically diagnosed sporadic AD (age 49-73 years) from the Alzheimer's and Families (ALFA) study. [F]flutemetamol-PET standardized uptake value ratios, CSF β-amyloid ratio, and phosphorylated tau were used as AD biomarkers. Hippocampal volumes and CSF total tau were used as neural injury biomarkers. Mental and vascular health proxies were calculated. In multiple regression models, we assessed the effect of proximity to parental AAO and its interaction with age on AD and neural injury biomarkers. Then, we evaluated the effects of FH load (number of parents affected), sex, ε4, education, and vascular and mental health.
Proximity to parental AAO was associated with β-amyloid, but not with neural injury biomarkers, and interacted with sex and age, showing that women and older participants had increased β-amyloid. FH load and ε4 showed independent contributions to β-amyloid load. Education and vascular and mental health proxies were not associated with AD biomarkers. However, lower mental health proxies were associated with decreased hippocampal volumes with age.
The identification of the earliest biomarker changes and modifiable factors to be targeted in early interventions is crucial for AD prevention. Proximity to parental AAO may offer a timeline for detection of incipient β-amyloid changes in women. In risk-enriched middle-aged cohorts, mental health may be a target for early interventions.
NCT02485730.
This study provides Class II evidence that in CU adults with FH of sporadic AD, proximity to parental AAO was associated with β-amyloid but not with neural injury biomarkers.
评估散发性阿尔茨海默病（AD）患者发病时父母年龄（AAO）相近与中年期AD及神经损伤生物标志物改变程度更大之间存在关联这一假设，并评估不可改变和可改变因素的作用。
这项观察性研究纳入了来自阿尔茨海默病与家族研究（ALFA研究）的290名认知未受损（CU）且有临床诊断散发性AD家族史（FH）的参与者（年龄49 - 73岁）。使用[F]氟代甲磺酸去甲肾上腺素正电子发射断层扫描（[F]flutemetamol - PET）标准化摄取值比率、脑脊液β - 淀粉样蛋白比率和磷酸化tau蛋白作为AD生物标志物。海马体积和脑脊液总tau蛋白用作神经损伤生物标志物。计算了心理和血管健康指标。在多元回归模型中，我们评估了与父母AAO相近程度及其与年龄的相互作用对AD和神经损伤生物标志物的影响。然后，我们评估了FH负荷（受影响父母的数量）、性别、ε4、教育程度以及血管和心理健康的影响。
与父母AAO相近程度与β - 淀粉样蛋白有关，但与神经损伤生物标志物无关，且与性别和年龄存在相互作用，表明女性和年龄较大的参与者β - 淀粉样蛋白增加。FH负荷和ε4对β - 淀粉样蛋白负荷有独立影响。教育程度以及血管和心理健康指标与AD生物标志物无关。然而，较低的心理健康指标与年龄增长导致的海马体积减小有关。
识别早期生物标志物变化以及早期干预中可针对的可改变因素对于AD预防至关重要。与父母AAO相近程度可能为检测女性早期β - 淀粉样蛋白变化提供一个时间线。在风险较高的中年队列中，心理健康可能是早期干预的一个目标。
NCT02485730。
本研究提供二级证据表明，在有散发性AD家族史的认知未受损成年人中（CU），与父母AAO相近程度与β - 淀粉样蛋白有关，但与神经损伤生物标志物无关。
