Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, Centre for Ageing and Health (AGECAP), University of Gothenburg, Sweden.
Region Västra Götaland, Sahlgrenska University Hospital, Psychiatry, Cognition and Old Age Psychiatry Clinic, Gothenburg, Sweden.
J Gerontol A Biol Sci Med Sci. 2021 May 22;76(6):983-990. doi: 10.1093/gerona/glab030.
The effect of Alzheimer's disease (AD) polygenic risk scores (PRS) on amyloid and tau pathophysiology and neurodegeneration in cognitively unimpaired older adults is not known in detail. This study aims to investigate non-APOE AD-PRS and APOE ε4 in relation to AD pathophysiology evaluated by cerebrospinal fluid (CSF) biomarkers in a population-based sample of 70-year olds. A total of 303 dementia-free individuals from the Gothenburg H70 Birth Cohort Studies were included. Genotyping was performed using the NeuroChip, and AD-PRS were calculated. CSF levels of amyloid-β (Aβ42), total tau (t-tau), phosphorylated tau (p-tau), neurogranin (Ng), and neurofilament light (NfL) were measured with enzyme-linked immunosorbent assay. Associations were found between non-APOE PRS and both NfL (p = .001) and Aβ42 (p = .02), and between APOE ε4 and Aβ42 (p = 1e-10), t-tau (p = 5e-4), and p-tau (p = .002). Similar results were observed when only including individuals with CDR = 0, except for no evidence of an association between non-APOE PRS and Aβ42. There was an interaction between non-APOE PRS and Aβ42 pathology status in relation to NfL (p = .005); association was only present in individuals without Aβ42 pathology (p = 3e-4). In relation to Aβ42, there was a borderline interaction (p = .06) between non-APOE PRS and APOE ε4; association was present in ε4 carriers only (p = .03). Similar results were observed in individuals with CDR = 0 (n = 246). In conclusion, among cognitively healthy 70-year olds from the general population, genetic risk of AD beyond the APOE locus was associated with NfL in individuals without Aβ42 pathology, and with Aβ42 in APOE ε4 carriers, suggesting these associations are driven by different mechanisms.
阿尔茨海默病（AD）多基因风险评分（PRS）对认知正常的老年人淀粉样蛋白和 tau 病理生理学和神经退行性变的影响尚不清楚。本研究旨在调查非 APOE AD-PRS 和 APOE ε4 与通过脑脊液（CSF）生物标志物评估的 AD 病理生理学在基于人群的 70 岁样本中的关系。共有 303 名来自哥德堡 H70 出生队列研究的无痴呆个体被纳入研究。使用 NeuroChip 进行基因分型，并计算 AD-PRS。通过酶联免疫吸附测定法测量 CSF 中淀粉样蛋白-β（Aβ42）、总 tau（t-tau）、磷酸化 tau（p-tau）、神经颗粒蛋白（Ng）和神经丝轻链（NfL）的水平。发现非 APOE PRS 与 NfL（p =.001）和 Aβ42（p =.02）以及 APOE ε4 与 Aβ42（p = 1e-10）、t-tau（p = 5e-4）和 p-tau（p =.002）之间存在关联。当仅包括 CDR = 0 的个体时，观察到类似的结果，除了非 APOE PRS 与 Aβ42 之间没有关联的证据。非 APOE PRS 与 Aβ42 病理状态与 NfL 之间存在交互作用（p =.005）；仅在没有 Aβ42 病理的个体中存在关联（p = 3e-4）。与 Aβ42 相关，非 APOE PRS 与 APOE ε4 之间存在边缘交互作用（p =.06）；仅在 ε4 携带者中存在关联（p =.03）。在 CDR = 0 的个体（n = 246）中也观察到类似的结果。总之，在来自普通人群的认知健康 70 岁老年人中，AD 的遗传风险除了 APOE 座标外，与无 Aβ42 病理个体的 NfL 相关，与 APOE ε4 携带者的 Aβ42 相关，这表明这些关联是由不同的机制驱动的。
