APOE ε4 carriership status enhances age-related changes in Alzheimer’s disease plasma biomarkers concentrations

Alzheimer’s disease (AD) plasma biomarkers are cost-effective tools to detect early stage amyloid pathology. We investigated how interactions between AD genetic risk (apolipoprotein E (APOE) ε4, AD polygenic risk score (excluding APOE; PRSAD)), age, and sex affected AD plasma biomarkers concentrations in a population-based cohort. We included 5913 participants from the Netherlands Twin Register age 30 – 80 (64.1% females, 29.8% ε4 carriers) and measured plasma phosphorylated-tau-217 (p-tau217), amyloid-β−42/40 (Aβ−42/40), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP).

We showed that the PRSAD did not associate with biomarker concentrations over age. In ε4 carriers, decreases in Aβ−42/40 became steeper after age 50, and increases in p-tau217 and GFAP became steeper after age 55 and 60 compared to non-carriers, respectively. Analyses in a separate longitudinal cohort (EMIF-AD) confirmed that p-tau217 concentration changes in ε4 carriers reflect AD pathology.

These results highlight the potential of plasma biomarkers, especially p-tau217, for early detection of preclinical AD pathology. Funding for blood sample collection was obtained from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organisation for Health Research and Development (ZonMW) grants 904-61-090, 985-10-002, 904-61-193,480-04-004, 400-05-717, Addiction-31160008, 016-115-035, 400-07-080, Middelgroot-911-09-032, NWO-Groot 480-15-001/674; the European Community’s Fifth and Seventh Framework Program (FP5- LIFE QUALITY-CT-2002-2006, FP7- HEALTH-F4-2007-2013, grant 01254: GenomEUtwin, grant 01413: ENGAGE). R.R., C.T. and Ad.B. receive funding from the CANTATE project.

The CANTATE project is funded by the Alzheimer Drug Discovery Foundation. Research of C.T. is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE), Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831434) EPND (IMI 2 Joint Undertaking (JU), grant No. 101034344) and JPND (bPRIDE), National MS Society (Progressive MS alliance), Alzheimer Association, Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, and Alzheimer Netherlands. C.T. is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health~Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106).

C.T. is recipient of TAP-dementia, a ZonMw funded project (#10510032120003) in the context of the Dutch National Dementia Strategy. C.T. has research contracts with Acumen, ADx Neurosciences, AC-Immune, Alamar, Aribio, Axon Neurosciences, Beckman-Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, C2N diagnostics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Instant Nano Biosensors, Merck, Muna, Nitrase Therapeutics, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Sysmex, Toyama, Vaccinex, Vivoryon. She is editor in chief of Alzheimer Research and Therapy, and serves on editorial boards of Molecular Neurodegeneration, Alzheimer’s & Dementia, Neurology: Neuroimmunology & Neuroinflammation, Medidact Neurologie/Springer, and is committee member to define guidelines for Cognitive disturbances, and one for acute Neurology in the Netherlands.

She has consultancy/speaker contracts for Aribio, Biogen, Beckman-Coulter, Cognition Therapeutics, Danaher, Eisai, Eli Lilly, Janssen, Merck, Neurogen Biomarking, Nordic Biosciences, Novo Nordisk, Novartis, Olink, Quanterix, Roche, Sanofi and Veravas. B.B., L.B., D.W., L.L., R.P., P.J.V., S.Mvd.L. and Ed.G. have nothing to disclose. Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands Rebecca Z.