APOE ε4 influences cognitive decline positively in APP and negatively in PSEN1 mutation carriers with autosomal‐dominant Alzheimer's disease

• Published in: European journal of neurology Vol. 29; no. 12; pp. 3580 - 3589
• Main Authors: Almkvist, Ove, Johansson, Charlotte, Laffita‐Mesa, Jose, Thordardottir, Steinunn, Graff, Caroline
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.12.2022; John Wiley and Sons Inc
• Subjects: Age; Alleles; Alzheimer Disease - epidemiology; Alzheimer's disease; APOE; Apolipoprotein E; Apolipoprotein E4 - genetics; APP/PSEN1; autosomal‐dominant Alzheimer's disease; Chronology; cognition; Cognitive ability; Cognitive Dysfunction - diagnosis; Demographics; Disease Progression; Education; Humans; longitudinal; Medicin och hälsovetenskap; Movement Disorders; Mutation; Neurodegenerative diseases; Original; Pleiotropy; Presenilin-1 - genetics; autosomal-dominant Alzheimer's disease; APOE; cognition; longitudinal; APP/PSEN1
• ISSN: 1351-5101; 1468-1331; 1468-1331
• DOI: 10.1111/ene.15536

Background and purpose The aim was to investigate the effect of APOE ε4 allele on cognitive decline in adAD. Presence of the APOE ε4 allele reduces age of symptom onset, increases disease progression, and lowers cognitive performance in sporadic Alzheimer's disease (AD), while the impact of the APOE ε4 allele in autosomal‐dominant AD (adAD) is incompletely known. Methods Mutation carriers (MCs; n = 39) and non‐carriers (NCs; n = 40) from six adAD families harbouring a mutation in the APP (28 MCs and 25 NCs) or the PSEN1 genes (11 MCs and 15 NCs) underwent repeated cognitive assessments. A timeline of disease course was defined as years to expected age of clinical onset (YECO) based on history of disease onset in each family. The MC and NC groups were comparable with regard to demographics and prevalence of the APOE ε4 allele. The relationship between cognitive decline and YECO, YECO2, education, APOE, and APOE‐by‐YECO interaction was analysed using linear mixed‐effects models. Results The trajectory of cognitive decline was significantly predicted by linear and quadratic YECO and education in MCs and was determined by age and education in NCs. Adding APOE ε4 allele (presence/absence) as a predictor did not change the results in the MC and NC groups. The outcome also remained the same for MCs and NCs after adding the APOE‐by‐YECO interaction as a predictor. Analyses of APP and PSEN1 MCs separately showed favourable APOE‐by‐YECO interaction in APP (less steep decline) and unfavourable interaction in PSEN1 (steeper decline), linked to the APOE ε4 allele. Conclusion The APOE ε4 allele influences cognitive decline positively in APP and negatively in PSEN1 mutation carriers with adAD, indicating a possible antagonistic pleiotropy. Presence of the APOE ε4 allele influences cognitive decline positively in APP mutation carriers (MCs) and negatively in PSEN1 MCs. In contrast, the opposite pattern was obtained when APOE ε4 was absent. These findings indicate a possible antagonistic pleiotropy.