Langella Stephanie, Bonta Kyra, Chen Yinghua, Su Yi, Vasquez Daniel, Aguillon David, Acosta-Baena Natalia, Baena Ana Y, Garcia-Ospina Gloria, Giraldo-Chica Margarita, Tirado Victoria, Muñoz Claudia, Ríos-Romenets Silvia, Guzman-Martínez Claudia, Pruzin Jeremy J, Ghisays Valentina, Arboleda-Velasquez Joseph F, Kosik Kenneth S, Tariot Pierre N, Reiman Eric M, Lopera Francisco, Quiroz Yakeel T
Massachusetts General Hospital, Harvard Medical School, 39 1st Avenue, Suite 101, Charlestown, Boston, MA, USA.
Yale University, New Haven, CT, USA.
Alzheimers Res Ther. 2024 Oct 1;16(1):208. doi: 10.1186/s13195-024-01572-y.
Apolipoprotein E (APOE) genotypes have been suggested to influence cognitive impairment and clinical onset in presenilin-1 (PSEN1) E280A carriers for autosomal dominant Alzheimer's disease (ADAD). Less is known about their impact on the trajectory of biomarker changes. Neurofilament light chain (NfL), a marker of neurodegeneration, begins to accumulate in plasma about 20 years prior to the clinical onset of ADAD. In this study we investigated the impact of APOE ε4 and ε2 variants on age-related plasma NfL increases and cognition in PSEN1 E280A mutation carriers.
We analyzed cross-sectional data from PSEN1 E280A mutation carriers and non-carriers recruited from the Alzheimer's Prevention Initiative Registry of ADAD. All participants over 18 years with available APOE genotype, plasma NfL, and neuropsychological evaluation were included in this study. APOE genotypes and plasma NfL concentrations were characterized for each participant. Cubic spline models using a Hamiltonian Markov chain Monte Carlo method were used to characterize the respective impact of at least one APOE ε4 or ε2 allele on age-related log-transformed plasma NfL increases. Linear regression models were estimated to explore the impact of APOE ε4 and ε2 variants and plasma NfL on a composite cognitive test score in the ADAD mutation carrier and non-carrier groups.
Analyses included 788 PSEN1 E280A mutation carriers (169 APOE ε4 + , 114 ε2 +) and 650 mutation non-carriers (165 APOE ε4 + , 80 ε2 +), aged 18-75 years. APOE ε4 allele carriers were distinguished from ε4 non-carriers by greater age-related NfL elevations in the ADAD mutation carrier group, beginning about three years after the mutation carriers' estimated median age at mild cognitive impairment onset. APOE ε2 allele carriers had lower plasma NfL concentrations than ε2 non-carriers in both the ADAD mutation carrier and non-carrier groups, unrelated to age, and an attenuated relationship between higher NfL levels on cognitive decline in the ADAD mutation carrier group.
APOE ε4 accelerates age-related plasma NfL increases and APOE ε2 attenuates the relationship between higher plasma NfL levels and cognitive decline in ADAD. NfL may be a useful biomarker to assess clinical efficacy of APOE-modifying drugs with the potential to help in the treatment and prevention of ADAD.
载脂蛋白E（APOE）基因型被认为会影响常染色体显性遗传性阿尔茨海默病（ADAD）的早老素1（PSEN1）E280A携带者的认知障碍和临床发病情况。关于它们对生物标志物变化轨迹的影响，人们了解较少。神经丝轻链（NfL）是神经退行性变的标志物，在ADAD临床发病前约20年开始在血浆中积累。在本研究中，我们调查了APOE ε4和ε2变体对PSEN1 E280A突变携带者年龄相关血浆NfL升高及认知的影响。
我们分析了从ADAD的阿尔茨海默病预防倡议登记处招募的PSEN1 E280A突变携带者和非携带者的横断面数据。本研究纳入了所有18岁以上且有可用APOE基因型、血浆NfL和神经心理学评估的参与者。对每位参与者的APOE基因型和血浆NfL浓度进行了特征描述。使用哈密顿马尔可夫链蒙特卡罗方法的三次样条模型用于描述至少一个APOE ε4或ε2等位基因对年龄相关的对数转换血浆NfL升高的各自影响。估计线性回归模型以探讨APOE ε4和ε2变体以及血浆NfL对ADAD突变携带者和非携带者组综合认知测试分数的影响。
分析纳入了788名PSEN1 E280A突变携带者（169名APOE ε4携带者，114名ε2携带者）和650名非突变携带者（165名APOE ε4携带者，80名ε2携带者），年龄在18 - 75岁之间。在ADAD突变携带者组中，APOE ε4等位基因携带者与非携带者相比，年龄相关的NfL升高更明显，大约在突变携带者估计的轻度认知障碍发病中位年龄后三年开始。在ADAD突变携带者组和非携带者组中，APOE ε2等位基因携带者的血浆NfL浓度均低于非携带者，且与年龄无关，并且在ADAD突变携带者组中，较高的NfL水平与认知下降之间的关系减弱。
APOE ε4加速年龄相关的血浆NfL升高，而APOE ε2减弱ADAD中较高血浆NfL水平与认知下降之间的关系。NfL可能是一种有用的生物标志物，可用于评估具有帮助治疗和预防ADAD潜力的APOE修饰药物的临床疗效。
