From the ICM Paris Brain Institute (L.X., B.G., A.L., G.«F., F.D., J.S.G., O.C., N.V., B.D., M.-C.P.), CNRS UMR7225, INSERM U1127, Sorbonne University, Hôpital de la Pitié-Salpêtrière; Univ. Lille (B.G.-B., P.A., J.-C.L.), Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE-Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement; Inria (J.S.G., O.C.), Aramis-Project Team, Paris; Centre d'Acquisition et Traitement des Images (CATI platform) (G.M., M.-O.H.), cati-neuroimaging.com, Paris; Centre des Maladies Cognitives et Comportementales (M.L., M.-O.H., B.D.), IM2A, AP-HP, Sorbonne Université, Hôpital de la Salpêtrière; Department of Neurology (N.V., B.D.), Hôpital Pitié-Salpêtrière, AP-HP Sorbonne Université; Sorbonne Université (M.-O.H.), CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, LIB; and AP-HP (M.-O.H.), Hôpital Pitié-Salpêtrière, Médecine Nucléaire, Paris, France.
Neurology. 2022 Aug 1;99(5):e462-e475. doi: 10.1212/WNL.0000000000200544.
Brain amyloid deposition, a major risk factor for Alzheimer disease (AD), is currently estimated by measuring CSF or plasma amyloid peptide levels or by PET imaging. Assessing genetic risks relating to amyloid deposition before any accumulation has occurred would allow for earlier intervention in persons at increased risk for developing AD. Previous work linking amyloid burden and genetic risk relied almost exclusively on , a major AD genetic risk factor. Here, we ask whether a polygenic risk score (PRS) that incorporates an optimized list of common variants linked to AD and excludes is associated with brain amyloid load in cognitively unimpaired older adults.
We included 291 asymptomatic older participants from the INveStIGation of AlzHeimer's PredicTors (INSIGHT pre-AD) cohort who underwent amyloid imaging, including 83 amyloid-positive (+) participants. We used an Alzheimer's (A) PRS composed of 33 AD risk variants excluding and selected the 17 variants that showed the strongest association with amyloid positivity to define an optimized (oA) PRS. Participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study (228 participants, 90 amyloid [+]) were tested as a validation cohort. Finally, 2,300 patients with AD and 6,994 controls from the European Alzheimer's Disease Initiative (EADI) were evaluated.
A-PRS was not significantly associated with amyloid burden in the INSIGHT or ADNI cohorts with or without correction for the genotype. However, oA-PRS was significantly associated with amyloid status independently of adjustment (INSIGHT odds ratio [OR]: 5.26 [1.71-16.88]; ADNI OR: 3.38 [1.02-11.63]). Of interest, oA-PRS accurately discriminated amyloid (+) and (-) ε4 carriers (INSIGHT OR: 181.6 [7.53-10,674.6]; ADNI OR: 44.94 [3.03-1,277]). A-PRS and oA-PRS showed a significant association with disease status in the EADI cohort (OR: 1.68 [1.53-1.85] and 2.06 [1.73-2.45], respectively). Genes assigned to oA-PRS variants were enriched in ontologies related to β-amyloid metabolism and deposition.
PRSs relying on AD genetic risk factors excluding may improve risk prediction for brain amyloid, allowing stratification of cognitively unimpaired individuals at risk of AD independent of their status.
脑淀粉样蛋白沉积是阿尔茨海默病（AD）的主要危险因素，目前通过测量 CSF 或血浆淀粉样肽水平或 PET 成像来估计。在淀粉样蛋白沉积发生之前评估与沉积相关的遗传风险，将允许对 AD 发病风险增加的个体进行更早的干预。以前将淀粉样蛋白负担与遗传风险联系起来的工作几乎完全依赖于 APOE ε4，这是 AD 的一个主要遗传风险因素。在这里，我们询问是否一种包含与 AD 相关的常见变异体的优化列表并排除 APOE ε4 的多基因风险评分（PRS）与认知未受损的老年人的脑淀粉样蛋白负荷相关。
我们纳入了来自 INveStIGation of AlzHeimer's PredicTors (INSIGHT pre-AD) 队列的 291 名无症状老年参与者，他们接受了淀粉样蛋白成像，包括 83 名淀粉样蛋白阳性（+）参与者。我们使用了一种由 33 个 AD 风险变异体组成的阿尔茨海默病 (A) PRS，不包括 APOE ε4，并且选择了与淀粉样蛋白阳性相关性最强的 17 个变异体来定义优化的（oA）PRS。来自阿尔茨海默病神经影像学倡议 (ADNI) 研究的 228 名参与者（90 名淀粉样蛋白[+]）作为验证队列进行了测试。最后，对来自欧洲阿尔茨海默病倡议 (EADI) 的 2300 名 AD 患者和 6994 名对照者进行了评估。
APRS 与 INSIGHT 或 ADNI 队列中的淀粉样蛋白负荷无显著相关性，无论是否对 APOE ε4 基因型进行校正。然而，oA-PRS 与淀粉样蛋白状态独立于 APOE ε4 调整显著相关（INSIGHT 比值比 [OR]：5.26 [1.71-16.88]；ADNI OR：3.38 [1.02-11.63]）。有趣的是，oA-PRS 准确地区分了淀粉样蛋白（+）和（-）ε4 携带者（INSIGHT OR：181.6 [7.53-10,674.6]；ADNI OR：44.94 [3.03-1,277]）。APRS 和 oA-PRS 在 EADI 队列中与疾病状态显著相关（OR：1.68 [1.53-1.85]和 2.06 [1.73-2.45]）。分配给 oA-PRS 变异体的基因在与 β-淀粉样蛋白代谢和沉积相关的本体论中富集。
依赖于 AD 遗传风险因素并排除 APOE ε4 的 PRS 可能会改善脑淀粉样蛋白的风险预测，允许对 AD 发病风险增加的认知未受损个体进行分层，而无需考虑其 APOE ε4 状态。
