背景:纵向早发性阿尔茨海默病研究(LEADS)的一个目标是研究早发性(40-64岁)认知障碍的遗传病因。为了这个目标,对LEADS参与者进行已知致病变异的筛查。
方法: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(EOononAD)病例进行全外显子组测序(N=299)。APP中的致病变异频率,PSEN1,PSEN2,GRN,MAPT,并对C9ORF72进行EOAD和EOnonAD评估。在帕金森病进展标志物倡议(PPMI)研究中,对与年龄相似的认知正常对照者进行基因负荷检测。
结果:先前报道的6个基因的致病变异在1.35%的EOAD(3/223)和6.58%的EOononAD(5/76)中被鉴定。在LEADS病例中,没有基因显示出罕见功能变异携带者的富集。
结论:结果表明,LEADS富含新的遗传致病变异,正如以前报道的变体在大多数情况下没有观察到。
结论:测序确定了8个认知受损的致病变异携带者。在PSEN1、GRN、MAPT,C9ORF72APP中没有丰富稀有变体,PSEN1/2,GRN,和MAPT。纵向早发性阿尔茨海默病研究(LEADS)是早发性阿尔茨海默病基因研究的关键资源。
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.