Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Indiana Alzheimer's Disease Research Center, Indianapolis, Indiana, USA.
Alzheimers Dement. 2023 Nov;19 Suppl 9(Suppl 9):S64-S73. doi: 10.1002/alz.13482. Epub 2023 Oct 6.
One goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants.
LEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study.
Previously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases.
Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases.
Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research.
纵向早发性阿尔茨海默病研究（LEADS）的目标之一是研究早发性（40-64 岁）认知障碍的遗传病因。为此，LEADS 参与者接受了已知致病性变异的筛查。
对 LEADS 淀粉样蛋白阳性早发性阿尔茨海默病（EOAD）或阴性早发性非 AD（EOnonAD）病例进行全外显子组测序（N=299）。评估 APP、PSEN1、PSEN2、GRN、MAPT 和 C9ORF72 中的致病性变异频率在 EOAD 和 EOnonAD 中的频率。与帕金森病进展标志物倡议（PPMI）研究中的相似年龄认知正常对照相比，对病例进行了基因负担测试。
在六个基因中，以前报道的致病性变异在 1.35%的 EOAD（3/223）和 6.58%的 EOnonAD（5/76）中被发现。没有基因显示 LEADS 病例中罕见功能变异携带者的富集。
结果表明，LEADS 富含新的遗传致病变异，因为以前报道的变异在大多数病例中未观察到。
测序确定了 8 名认知障碍的致病性变异携带者。在 PSEN1、GRN、MAPT 和 C9ORF72 中发现了致病性变异。APP、PSEN1/2、GRN 和 MAPT 中未富集罕见变异。纵向早发性阿尔茨海默病研究（LEADS）是早发性阿尔茨海默病遗传研究的重要资源。
