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. 2024 Oct 1;16(1):208.
doi: 10.1186/s13195-024-01572-y.

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

Stephanie Langella  1 , Kyra Bonta  2 , Yinghua Chen  3 , Yi Su  3 , Daniel Vasquez  4 , David Aguillon  4 , Natalia Acosta-Baena  4 , Ana Y Baena  4 , Gloria Garcia-Ospina  4 , Margarita Giraldo-Chica  4 , Victoria Tirado  4   5 , Claudia Muñoz  4 , Silvia Ríos-Romenets  4 , Claudia Guzman-Martínez  4 , Jeremy J Pruzin  3 , Valentina Ghisays  3 , Joseph F Arboleda-Velasquez  6 , Kenneth S Kosik  7 , Pierre N Tariot  3 , Eric M Reiman #  3 , Francisco Lopera #  4 , Yakeel T Quiroz #  8   9
Affiliations

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

Stephanie Langella et al. Alzheimers Res Ther. .

Abstract

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 ε4 and ε2 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 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.

Results: 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.

Conclusions: 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.

Keywords: APOE; Autosomal dominant Alzheimer’s disease; Blood biomarkers; Neurodegeneration; PSEN1.

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Conflict of interest statement

S.L. is supported by a grant from the Alzheimer’s Association (AARF-22–920754). Y.S. reports grants from The Alzheimer’s Association, The BrightFocus Foundation, NIH/NIA, State of Arizona, outside the submitted work. C.V.-C. reports grants from the Alzheimer’s Association (AARF 2019A005859) and the National Institute on Aging (K99AG073452). J.J.P. was supported by the Arizona Department of Health Services (CTR057001). K.S.K. is on the Board of Directors for the Tau Consortium, receives funding from the NIA, the Alzheimer Association, and the Alzheimer’s Drug Discovery Foundation. P.N.T. reports receiving consulting fees from AbbVie, AC Immune, Acadia, Athira, Axsome, Biogen, BioXcel, Corium, Cortexyme, CuraSen, Eisai, Genentech, Immunobrain, Lundbeck, Novo Nordisk, Otsuka & Astex, Merck & Co., Novo Nordisk, Syneos, and T3D Therapeutics. E.M.R. and P.N.T. report grants from National Institute on Aging (P30 AG072980, R01 AG069453, R01 AG055444), Banner Alzheimer’s Foundation and the NOMIS Foundation during the conduct of the study. E.M.R. is a compensated scientific advisor for Alzheon, Aural Analytics, Denali, Retromer Therapeutics, and Vaxxinity, an uncompensated scientific advisor for Lilly, and a cofounder, advisor and shareholder of AlzPATH, which is involved in the development of blood-based biomarkers for Alzheimer’s disease outside the scope of the submitted. In addition, E.M.R. is the inventor of a patent issued to Banner Health, which involves the use of biomarker endpoints in at-risk persons to accelerate the evaluation of Alzheimer’s disease prevention therapies and is outside the submitted work. F.L. was supported by an Anonymous Foundation, and the Administrative Department of Science, Technology and Innovation (Colciencias Colombia;111565741185). E.M.R., F.L., and P.N.T. are principal investigators of the Alzheimer’s Prevention Initiative (API) Autosomal Dominant AD Trial, which is supported by NIA, philanthropy, Genentech, and Roche. E.M.R was supported by grants from the NIA (R01 AG069453, P30 AG072980, RF1AG041705 and R01 AG055444). Y.T.Q. was supported by grants from the National Institute on Aging (R01 AG054671, RF1AG077627, RM1NS132996, U01AG087103), the Alzheimer’s Association, and Massachusetts General Hospital ECOR. Y.T.Q. serves as consultant for Biogen. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Plasma NfL as a function of APOE ε4. A Boxplot showing log-transformed plasma NfL concentrations (pg/mL) in PSEN1 E280A carriers and non-carriers as a function of APOE ε4 group (black: APOE ε4-, red: APOE ε4 +). B Log-transformed plasma NfL concentrations of PSEN1 E280A mutation carriers who are APOE ε4 + and APOE ε4- as a function of age. C Differences in NfL concentrations between APOE ε4 + and ε4- PSEN1 E280A mutation carriers as a function of age. D Log-transformed plasma NfL concentrations of PSEN1 E280A mutation non-carriers who are APOE ε4 + and APOE ε4- as a function of age. E Differences in NfL concentrations between APOE ε4 + and ε4- PSEN1 E280A mutation non-carriers as a function of age. F API composite score plotted by log-transformed plasma NfL concentrations in PSEN1 E280A mutation carriers stratified by APOE ε4 group. G API composite score plotted by log-transformed plasma NfL concentrations in PSEN1 E280A mutation non-carriers stratified by APOE ε4 group. In panels C and E, the shaded areas of each plot represent the 99% credible intervals around the model estimates drawn from the distributions of model fits derived by the Hamiltonian Markov chain Monte Carlo analyses. In panels F and G, plots show regression line with shaded standard error bands
Fig. 2
Fig. 2
Plasma NfL as a function of APOE ε2. A Boxplot showing log-transformed plasma NfL concentrations (pg/mL) in PSEN1 E280A carriers and non-carriers as a function of APOE ε2 group (black: APOE ε2+, red: APOE ε2-). B Log-transformed plasma NfL concentrations of PSEN1 E280A mutation carriers who are APOE ε2 + and APOE ε2- as a function of age. C Differences in NfL concentrations between APOE ε2 + and ε2- PSEN1 E280A mutation carriers as a function of age. D Log-transformed plasma NfL concentrations of PSEN1 E280A mutation non-carriers who are APOE ε2 + and APOE ε2- as a function of age. E Differences in NfL concentrations between APOE ε2 + and ε2- PSEN1 E280A mutation non-carriers as a function of age. F API composite score plotted by log-transformed plasma NfL concentrations in PSEN1 E280A mutation carriers stratified by APOE ε2 group. G API composite score plotted by log-transformed plasma NfL concentrations in PSEN1 E280A mutation non-carriers stratified by APOE ε2 group. In panels C and E, the shaded areas of each plot represent the 99% credible intervals around the model estimates drawn from the distributions of model fits derived by the Hamiltonian Markov chain Monte Carlo analyses. In panels F and G, plots show regression line with shaded standard error bands
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