Impact of APOE ε4 and ε2 on plasma neurofilament light chain and cognition in autosomal dominant Alzheimer's disease

Background 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 epsilon 4 and epsilon 2 variants on age-related plasma NfL increases and cognition in PSEN1 E280A mutation carriers. Methods 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 epsilon 4 or epsilon 2 allele on age-related log-transformed plasma NfL increases. Linear regression models were estimated to explore the impact of APOE epsilon 4 and epsilon 2 variants and plasma NfL on a composite cognitive test score in the ADAD mutation carrier and non-carrier groups. Results Analyses included 788 PSEN1 E280A mutation carriers (169 APOE epsilon 4 + , 114 epsilon 2 +) and 650 mutation non-carriers (165 APOE epsilon 4 + , 80 epsilon 2 +), aged 18-75 years. APOE epsilon 4 allele carriers were distinguished from epsilon 4 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 epsilon 2 allele carriers had lower plasma NfL concentrations than epsilon 2 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. Conclusions APOE epsilon 4 accelerates age-related plasma NfL increases and APOE epsilon 2 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.