Abstract
Although APOE ε4 carriers are at substantially higher risk of developing Alzheimer’s disease than noncarriers1, controversial evidence suggests that APOE ε4 might confer some advantages, explaining the survival of this gene (antagonistic pleiotropy)2,3. In a population-based cohort born in one week in 1946 (assessed aged 69–71 years), we assessed differential effects of APOE ε4 and β-amyloid pathology (quantified using 18F-Florbetapir-PET) on visual working memory (object–location binding). In 398 cognitively normal participants, APOE ε4 and β-amyloid had opposing effects on object identification, predicting better and poorer recall, respectively. ε4 carriers also recalled locations more precisely, with a greater advantage at higher β-amyloid burden. These results provide evidence of superior visual working memory in ε4 carriers, showing that some benefits of this genotype are demonstrable in older age, even in the preclinical stages of Alzheimer’s disease.
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Data availability
All data from NSHD are curated and stored by the Lifelong Health and Aging Unit at UCL. Anonymized data will be shared by request from qualified investigators (https://skylark.ucl.ac.uk/NSHD/doku.php).
Code availability
Code for the 2D-mixture model (MATLAB) is freely available at https://doi.org/10.5281/zenodo.3752705. Code for statistical analyses conducted in Stata is provided in Supplementary Information.
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Acknowledgements
This study was principally funded by grants from Alzheimer’s Research UK (nos. ARUK-PG2014-1946 and ARUK-PG2017-1946), the Medical Research Council Dementias Platform UK (no. CSUB19166) and the Selfridges Group Foundation (no. PR/ylr/18575). Genetic analyses were funded by the Brain Research Trust (no. UCC14191). The Florbetapir amyloid tracer was kindly provided by AVID Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly), who had no part in the design of the study. NSHD is funded by the Medical Research Council (nos. MC_UU_12019/06 and MC_UU_12019/08). The funders of the study had no role in study design, data collection, analysis, interpretation, report writing or the decision to submit the article for publication. T.D.P. was supported by a Wellcome Trust Clinical Research Fellowship (no. 200109/Z/15/Z). A.K. was supported by a Wolfson Clinical Research Fellowship. C.H.S. is supported by an Alzheimer’s Society Junior Fellowship (no. AS-JF-17-011). N.C.F. acknowledges support from the UK Dementia Research Institute at University College London, the National Institute for Health Research (Senior Investigator award) and University College London Hospitals Biomedical Research Centre. J.M.S. is supported by University College London Hospitals Biomedical Research Centre, Engineering and Physical Sciences Research Council (no. EP/J020990/1), British Heart Foundation (no. PG/17/90/33415) and EU’s Horizon 2020 research and innovation program (no. 666992). We thank participants both for their contributions to Insight 46 and for their commitments to research over the past seven decades. We are grateful to the radiographers and nuclear medicine physicians (A. Groves, J. Bomanji and I. Kayani) at the UCL Institute of Nuclear Medicine, and to the staff at the Leonard Wolfson Experimental Neurology Centre at UCL. We thank D. Marcus and R. Herrick for assistance with XNAT, P. Curran for assistance with data sharing with the MRC Unit for Lifelong Health and Ageing, the DRC trials team for assistance with imaging quality control, M. White for his work on data connectivity and J. Dickson, A. Barnes and D. Thomas for help with imaging.
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J.M.S., S.J.C., M.R. and N.C.F. conceptualized and led the Insight 46 study. Y.P. and M.H. designed the visual working memory experiment. K.L., I.M.P. and S.-N.J. collected data for the visual working memory test. T.D.P., C.A.L., A.K., S.E.K. and S.M.B. collected clinical and neuroimaging data. H.M.-S. and A.W. were responsible for study coordination and data management. K.L., S.M.D.H., J.M.S. and S.J.C. conceived the manuscript. J.G. and M.H. developed the 2D-mixture model. K.L. analyzed data and drafted the initial manuscript. J.M.N. provided statistical support. D.M.C., I.B.M., C.H.S. and W.C. generated neuroimaging outcomes. K.L., S.M.D.H., J.G., M.H., J.M.S. and S.J.C. aided in manuscript preparation and interpretation. All authors revised and approved the manuscript.
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Peer review information Nature Aging thanks Duke Han, Miranka Wirth and the other, anonymous reviewer(s) for their contribution to the peer review of this work.
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43587_2021_117_MOESM1_ESM.pdf
Supplementary analyses and discussion in nine subsections, incorporating Tables 1–5 and Figs. 1–6; code for statistical analyses reported in the main manuscript and supplementary analyses; and visual representation of the raw response locations for each trial.
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Lu, K., Nicholas, J.M., Pertzov, Y. et al. Dissociable effects of APOE ε4 and β-amyloid pathology on visual working memory. Nat Aging 1, 1002–1009 (2021). https://doi.org/10.1038/s43587-021-00117-4
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DOI: https://doi.org/10.1038/s43587-021-00117-4
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