Mantyh William G, Cochran J Nicholas, Taylor Jared W, Broce Iris J, Geier Ethan G, Bonham Luke W, Anderson Ashlyn G, Sirkis Daniel W, Joie Renaud La, Iaccarino Leonardo, Chaudhary Kiran, Edwards Lauren, Strom Amelia, Grant Harli, Allen Isabel E, Miller Zachary A, Gorno-Tempini Marilu L, Kramer Joel H, Miller Bruce L, Desikan Rahul S, Rabinovici Gil D, Yokoyama Jennifer S
Department of Neurology University of Minnesota Minneapolis Minnesota USA.
HudsonAlpha Institute for Biotechnology Huntsville Alabama USA.
Alzheimers Dement (Amst). 2023 Sep 28;15(4):e12482. doi: 10.1002/dad2.12482. eCollection 2023 Oct-Dec.
Early-onset Alzheimer's disease (AD) is highly heritable, yet only 10% of cases are associated with known pathogenic mutations. For early-onset AD patients without an identified autosomal dominant cause, we hypothesized that their early-onset disease reflects further enrichment of the common risk-conferring single nucleotide polymorphisms associated with late-onset AD. We applied a previously validated polygenic hazard score for late-onset AD to 193 consecutive patients diagnosed at our tertiary dementia referral center with symptomatic early-onset AD. For comparison, we included 179 participants with late-onset AD and 70 healthy controls. Polygenic hazard scores were similar in early- versus late-onset AD. The polygenic hazard score was not associated with age-of-onset or disease biomarkers within early-onset AD. Early-onset AD does not represent an extreme enrichment of the common single nucleotide polymorphisms associated with late-onset AD. Further exploration of novel genetic risk factors of this highly heritable disease is warranted. There is a unique genetic architecture of early- versus late-onset Alzheimer's disease (AD).Late-onset AD polygenic risk is not an explanation for early-onset AD.Polygenic risk of late-onset AD does not predict early-onset AD biology.Unique genetic architecture of early- versus late-onset AD parallels AD heterogeneity.
早发型阿尔茨海默病（AD）具有高度遗传性，但仅有10%的病例与已知的致病突变相关。对于未发现常染色体显性病因的早发型AD患者，我们推测他们的早发型疾病反映了与晚发型AD相关的常见风险单核苷酸多态性的进一步富集。我们将先前验证的晚发型AD多基因风险评分应用于在我们的三级痴呆转诊中心连续诊断的193例有症状的早发型AD患者。作为对照，我们纳入了179例晚发型AD患者和70名健康对照。早发型和晚发型AD的多基因风险评分相似。在早发型AD中，多基因风险评分与发病年龄或疾病生物标志物无关。早发型AD并不代表与晚发型AD相关的常见单核苷酸多态性的极端富集。有必要进一步探索这种高度遗传性疾病的新遗传危险因素。早发型和晚发型阿尔茨海默病（AD）存在独特的遗传结构。晚发型AD的多基因风险不能解释早发型AD。晚发型AD的多基因风险不能预测早发型AD的生物学特性。早发型和晚发型AD的独特遗传结构与AD的异质性相似。
