Department of Neurology and Neurological Sciences, Functional Imaging in Neuropsychiatric Disorders (FIND) Lab, Stanford University, Stanford, California.
Department of Neurosurgery, Stanford University, Stanford, California.
JAMA Neurol. 2020 Jul 1;77(7):849-862. doi: 10.1001/jamaneurol.2020.0414.
Identification of genetic factors that interact with the apolipoprotein e4 (APOE4) allele to reduce risk for Alzheimer disease (AD) would accelerate the search for new AD drug targets. Klotho-VS heterozygosity (KL-VSHET+ status) protects against aging-associated phenotypes and cognitive decline, but whether it protects individuals who carry APOE4 from AD remains unclear.
To determine if KL-VSHET+ status is associated with reduced AD risk and β-amyloid (Aβ) pathology in individuals who carry APOE4.
DESIGN, SETTING, AND PARTICIPANTS: This study combined 25 independent case-control, family-based, and longitudinal AD cohorts that recruited referred and volunteer participants and made data available through public repositories. Analyses were stratified by APOE4 status. Three cohorts were used to evaluate conversion risk, 1 provided longitudinal measures of Aβ CSF and PET, and 3 provided cross-sectional measures of Aβ CSF. Genetic data were available from high-density single-nucleotide variant microarrays. All data were collected between September 2015 and September 2019 and analyzed between April 2019 and December 2019.
The risk of AD was evaluated through logistic regression analyses under a case-control design. The risk of conversion to mild cognitive impairment (MCI) or AD was evaluated through competing risks regression. Associations with Aβ, measured from cerebrospinal fluid (CSF) or brain positron emission tomography (PET), were evaluated using linear regression and mixed-effects modeling.
Of 36 530 eligible participants, 13 782 were excluded for analysis exclusion criteria or refusal to participate. Participants were men and women aged 60 years and older who were non-Hispanic and of Northwestern European ancestry and had been diagnosed as being cognitively normal or having MCI or AD. The sample included 20 928 participants in case-control studies, 3008 in conversion studies, 556 in Aβ CSF regression analyses, and 251 in PET regression analyses. The genotype KL-VSHET+ was associated with reduced risk for AD in individuals carrying APOE4 who were 60 years or older (odds ratio, 0.75 [95% CI, 0.67-0.84]; P = 7.4 × 10-7), and this was more prominent at ages 60 to 80 years (odds ratio, 0.69 [95% CI, 0.61-0.79]; P = 3.6 × 10-8). Additionally, control participants carrying APOE4 with KL-VS heterozygosity were at reduced risk of converting to MCI or AD (hazard ratio, 0.64 [95% CI, 0.44-0.94]; P = .02). Finally, in control participants who carried APOE4 and were aged 60 to 80 years, KL-VS heterozygosity was associated with higher Aβ in CSF (β, 0.06 [95% CI, 0.01-0.10]; P = .03) and lower Aβ on PET scans (β, -0.04 [95% CI, -0.07 to -0.00]; P = .04).
The genotype KL-VSHET+ is associated with reduced AD risk and Aβ burden in individuals who are aged 60 to 80 years, cognitively normal, and carrying APOE4. Molecular pathways associated with KL merit exploration for novel AD drug targets. The KL-VS genotype should be considered in conjunction with the APOE genotype to refine AD prediction models used in clinical trial enrichment and personalized genetic counseling.
确定与载脂蛋白 E4 (APOE4) 等位基因相互作用以降低阿尔茨海默病 (AD) 风险的遗传因素将加速寻找新的 AD 药物靶点。Klotho-VS 杂合性 (KL-VSHET+ 状态) 可预防与衰老相关的表型和认知能力下降，但它是否能保护携带 APOE4 的个体免受 AD 影响仍不清楚。
确定 KL-VSHET+ 状态是否与携带 APOE4 的个体的 AD 风险降低和 β-淀粉样蛋白 (Aβ) 病理相关。
设计、地点和参与者：本研究结合了 25 个独立的病例对照、基于家庭的纵向 AD 队列，这些队列招募了转诊和志愿者参与者，并通过公共存储库提供数据。分析按 APOE4 状态分层。三个队列用于评估转换风险，一个提供纵向 Aβ CSF 和 PET 测量，三个提供 Aβ CSF 的横断面测量。遗传数据来自高密度单核苷酸变异微阵列。所有数据均于 2015 年 9 月至 2019 年 9 月收集，并于 2019 年 4 月至 2019 年 12 月分析。
通过病例对照设计下的逻辑回归分析评估 AD 的发病风险。通过竞争风险回归评估向轻度认知障碍 (MCI) 或 AD 的转换风险。使用线性回归和混合效应模型评估与 Aβ 的关联，该 Aβ 通过脑脊液 (CSF) 或脑正电子发射断层扫描 (PET) 测量。
在 36530 名符合条件的参与者中，有 13782 人因分析排除标准或拒绝参与而被排除。参与者为年龄在 60 岁及以上的男女，非西班牙裔，北欧血统，被诊断为认知正常或患有 MCI 或 AD。样本包括 20928 名病例对照研究参与者、3008 名转换研究参与者、556 名 Aβ CSF 回归分析参与者和 251 名 PET 回归分析参与者。基因型 KL-VSHET+与携带 APOE4 的 60 岁及以上个体的 AD 风险降低相关（比值比，0.75 [95% CI，0.67-0.84]；P=7.4×10-7），在 60 至 80 岁年龄组更为明显（比值比，0.69 [95% CI，0.61-0.79]；P=3.6×10-8）。此外，携带 APOE4 且 KL-VS 杂合的对照参与者发生 MCI 或 AD 的风险降低（风险比，0.64 [95% CI，0.44-0.94]；P=0.02）。最后，在携带 APOE4 且年龄在 60 至 80 岁的对照参与者中，KL-VS 杂合与 CSF 中 Aβ 升高（β，0.06 [95% CI，0.01-0.10]；P=0.03）和 PET 扫描上 Aβ 降低相关（β，-0.04 [95% CI，-0.07 至 -0.00]；P=0.04）。
基因型 KL-VSHET+ 与 60 至 80 岁认知正常且携带 APOE4 的个体的 AD 风险降低和 Aβ 负担相关。与 KL 相关的分子途径值得探索，以寻找新的 AD 药物靶点。在 AD 预测模型中，应考虑 KL-VS 基因型与 APOE 基因型相结合，以在临床试验富集和个性化遗传咨询中细化 AD 预测模型。
