From the Clinical Memory Research Unit (P.S.I., A.K., O.H., N.M.-C.), Faculty of Medicine, Lund University, Sweden; Department of Psychiatry and Behavioral Sciences (P.S.I.), University of California, San Francisco; Memory Clinic (O.H.), Department of Neurology (N.M.-C.), Skåne University Hospital, and Wallenberg Center for Molecular Medicine (N.M.-C.), Lund University, Sweden.
Neurology. 2023 Jul 4;101(1):e20-e29. doi: 10.1212/WNL.0000000000207305. Epub 2023 Apr 21.
There is considerable heterogeneity in the association between increasing β-amyloid (Aβ) pathology and early cognitive dysfunction in preclinical Alzheimer disease (AD). At this stage, some individuals show no signs of cognitive dysfunction, while others show clear signs of decline. The factors explaining this heterogeneity are particularly important for understanding progression in AD but remain largely unknown. In this study, we examined an array of genetic variants that may influence the relationships among Aβ, brain structure, and cognitive performance in 2 large cohorts.
In 2,953 cognitively unimpaired participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) study, interactions between genetic variants and 18F-Florbetapir PET standardized uptake value ratio (SUVR) to predict the Preclinical Alzheimer Cognitive Composite (PACC) were assessed. Genetic variants identified in the A4 study were evaluated in the Alzheimer Disease Neuroimaging Initiative (ADNI, N = 527) for their association with longitudinal cognition and brain atrophy in both cognitively unimpaired participants and those with mild cognitive impairment.
In the A4 study, 4 genetic variants significantly moderated the association between Aβ load and cognition. Minor alleles of 3 variants were associated with additional decreases in PACC scores with increasing Aβ SUVR (rs78021285, β = -2.29, SE = 0.40, = 0.02, nearest gene ; rs71567499, β = -2.16, SE = 0.38, = 0.02, nearest gene ; and rs10974405, β = -1.68, SE = 0.29, = 0.02, nearest gene ). The minor allele of rs7825645 was associated with less decrease in PACC scores with increasing Aβ SUVR (β = 0.71, SE = 0.13, = 0.04, nearest gene ). The genetic variant rs76366637, in linkage disequilibrium with rs78021285, was available in both the A4 and ADNI. In the A4, rs76366637 was strongly associated with reduced PACC scores with increasing Aβ SUVR (β = -1.01, SE = 0.21, = -4.90, < 0.001). In the ADNI, rs76366637 was associated with accelerated cognitive decline (χ = 15.3, = 0.004) and atrophy over time (χ = 26.8, < 0.001), with increasing Aβ SUVR.
Patterns of increased cognitive dysfunction and accelerated atrophy due to specific genetic variation may explain some of the heterogeneity in cognition in preclinical and prodromal AD. The genetic variant near associated with lower cognitive scores in the A4 and accelerated cognitive decline and brain atrophy in the ADNI may help to identify those at the highest risk of accelerated progression of AD.
β-淀粉样蛋白（Aβ）病理学与临床前阿尔茨海默病（AD）早期认知功能障碍之间的相关性存在很大的异质性。在这个阶段，一些人没有表现出认知功能障碍的迹象，而另一些人则表现出明显的衰退迹象。解释这种异质性的因素对于了解 AD 的进展非常重要，但仍知之甚少。在这项研究中，我们在两个大型队列中检查了一系列可能影响 Aβ、大脑结构和认知表现之间关系的遗传变异。
在来自抗淀粉样蛋白治疗无症状 AD（A4）研究的 2953 名认知正常的参与者中，评估了遗传变异与 18F-氟比替派 PET 标准化摄取值比（SUVR）之间的相互作用，以预测临床前 AD 认知综合评分（PACC）。在 ADNI（N=527）中评估了在 A4 研究中确定的遗传变异与认知正常参与者和轻度认知障碍参与者的纵向认知和大脑萎缩的相关性。
在 A4 研究中，有 4 个遗传变异显著调节了 Aβ负荷与认知之间的关系。随着 Aβ SUVR 的增加，3 个变异的次要等位基因与 PACC 评分的进一步下降相关（rs78021285，β=-2.29，SE=0.40， =0.02，最接近基因；rs71567499，β=-2.16，SE=0.38， =0.02，最接近基因；和 rs10974405，β=-1.68，SE=0.29， =0.02，最接近基因）。rs7825645 的次要等位基因与随着 Aβ SUVR 的增加，PACC 评分的下降幅度较小相关（β=0.71，SE=0.13， =0.04，最接近基因）。rs76366637 是与 rs78021285 连锁不平衡的遗传变异，在 A4 和 ADNI 中均可用。在 A4 中，rs76366637 与随着 Aβ SUVR 的增加，PACC 评分的降低显著相关（β=-1.01，SE=0.21， =-4.90， < 0.001）。在 ADNI 中，rs76366637 与认知能力的加速下降（χ=15.3， =0.004）和随时间的大脑萎缩（χ=26.8， < 0.001）相关，随着 Aβ SUVR 的增加。
由于特定遗传变异导致的认知功能障碍和萎缩加速的模式可能解释了临床前和前驱 AD 中认知异质性的部分原因。与 A4 中较低认知评分相关并在 ADNI 中加速认知下降和大脑萎缩的与附近的遗传变异可能有助于识别那些 AD 进展加速风险最高的人。
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