No association between APOE genotype and lipid lowering with cognitive function in a randomized controlled trial of evolocumab
Open accessAbstract
APOE encodes a cholesterol transporter, and the ε4 allele is associated with higher circulating cholesterol levels, ß-amyloid burden, and risk of Alzheimer's disease. Prior studies demonstrated no significant differences in objective or subjective cognitive function for patients receiving the PCSK9 inhibitor evolocumab vs. placebo added to statin therapy. There is some evidence that cholesterol-lowering medications may confer greater cognitive benefits in APOE ε4 carriers. Thus, the purpose of this study was to determine whether APOE genotype moderates the relationships between evolocumab use and cognitive function. APOE-genotyped patients (N = 13,481; 28% ε4 carriers) from FOURIER, a randomized, placebo-controlled trial of evolocumab added to statin therapy in patients with stable atherosclerotic cardiovascular disease followed for a median of 2.2 years, completed the Everyday Cognition Scale (ECog) to self-report cognitive changes from the end of the trial compared to its beginning; a subset (N = 835) underwent objective cognitive testing using the Cambridge Neuropsychological Test Automated Battery as part of the EBBINGHAUS trial. There was a dose-dependent relationship between APOE ε4 genotype and patient-reported memory decline on the ECog in the placebo arm (p = .003 for trend across genotypes; ε4/ε4 carriers vs. non-carriers: OR = 1.46, 95% CI [1.03, 2.08]) but not in the evolocumab arm (p = .50, OR = 1.18, 95% CI [.83,1.66]). However, the genotype by treatment interaction was not significant (p = .30). In the subset of participants who underwent objective cognitive testing with the CANTAB, APOE genotype did not significantly modify the relationship between treatment arm and CANTAB performance after adjustment for demographic and medical covariates, (p's>.05). Although analyses were limited by the low population frequency of the ε4/ε4 genotype, this supports the cognitive safety of evolocumab among ε4 carriers, guiding future research on possible benefits of cholesterol-lowering medications in people at genetic risk for Alzheimer's disease.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In some trials, PCSK9 inhibitors including evolocumab do not show effects on cognitive decline and complaints.
“in some trials, PCSK9 inhibitors including evolocumab do not show the effects on cognitive decline and complain in a large clinical trial [33, 34].”
From Blood PCSK9 Impacts Alzheimer's Disease Risk in an <i>APOE</i> Genotype‐Dependent Manner: A Prospective Cohort Study (2026) · cites this paper as [33]
Another study did not show interactive effects with APOE ε4 genotype for cognitive decline and complaints in a large clinical trial.
“Another study did not show the interactive effects with APOE ɛ4 genotype for cognitive decline and complain in a large clinical trial [33].”
From Blood PCSK9 Impacts Alzheimer's Disease Risk in an <i>APOE</i> Genotype‐Dependent Manner: A Prospective Cohort Study (2026) · cites this paper as [33]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease
Sabatine, M. S., Giugliano, R. P., Keech, A. C., Honarpour, N., Wiviott, S. D., Murphy, S. A., Kuder, J. F., Wang, H., Liu, T., Wasserman, S. M., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1615664 · Cited by 6,138 · see citing works
Self-citationMutations in PCSK9 cause autosomal dominant hypercholesterolemia
Abifadel, M., Varret, M., Rabès, J.-P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., et al. (2003) · Nature Genetics · doi:10.1038/ng1161 · Cited by 2,985 · see citing works
Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database
Bertram, L., McQueen, M. B., Mullin, K., Blacker, D., & Tanzi, R. E. (2007) · Nature Genetics · doi:10.1038/ng1934 · Cited by 1,857 · see citing works
Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance
Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., Fagan, A. M., Morris, J. C., Mawuenyega, K. G., Cruchaga, C., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002156 · Cited by 1,227 · see citing works
<i>APOE</i> predicts amyloid‐beta but not tau Alzheimer pathology in cognitively normal aging
Morris, J. C., Roe, C. M., Xiong, C., Fagan, A. M., Goate, A. M., Holtzman, D. M., & Mintun, M. A. (2010) · Annals of Neurology · doi:10.1002/ana.21843 · Cited by 830 · see citing works
(1985) · PubMed · Cited by 706 · see citing works
Giugliano, R. P., Pedersen, T. R., Park, J.-G., De Ferrari, G. M., Gaciong, Z. A., Ceska, R., Toth, K., Gouni-Berthold, I., Lopez-Miranda, J., Schiele, F., et al. (2017) · The Lancet · doi:10.1016/s0140-6736(17)32290-0 · Cited by 682 · see citing works
Self-citationThe measurement of everyday cognition (ECog): Scale development and psychometric properties.
Farias, S. T., Mungas, D., Reed, B., Cahn, D. A., Jagust, W. J., Baynes, K., & DeCarli, C. S. (2008) · Neuropsychology · doi:10.1037/0894-4105.22.4.531 · Cited by 637 · see citing works
Coon, K. D., Myers, A. J., Craig, D. W., Webster, J. A., Pearson, J. V., Lince, D. H., Zismann, V. L., Beach, T. G., Leung, D., Bryden, L., et al. (2007) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v68n0419 · Cited by 569 · see citing works
Cardiovascular disease and distribution of cognitive function in elderly people: the Rotterdam study
Breteler, M. M. B., Claus, J. J., Grobbee, D. E., & Albert Hofman, D. (1994) · BMJ · doi:10.1136/bmj.308.6944.1604 · Cited by 539 · see citing works
Cognitive function in a randomized trial of evolocumab
Giugliano, R. P., Mach, F., Zavitz, K., Kurtz, C., Im, K., Kanevsky, E., Schneider, J., Wang, H., Keech, A., Pedersen, T. R., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1701131 · Cited by 492 · see citing works
Self-citationThe effects of apolipoprotein E on non-impaired cognitive functioning: A meta-analysis
Wisdom, N. M., Callahan, J. L., & Hawkins, K. A. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.02.003 · Cited by 416 · see citing works
Martins, I. J., Hone, E., Foster, J. K., Sünram-Lea, S. I., Gnjec, A., Fuller, S. J., Nolan, D., Gandy, S. E., & Martins, R. N. (2006) · Molecular Psychiatry · doi:10.1038/sj.mp.4001854 · Cited by 388 · see citing works
Statin‐Associated Memory Loss: Analysis of 60 Case Reports and Review of the Literature
Wagstaff, L. R., Mitton, M. W., McLendon-Arvik, B., & Doraiswamy, P. M. (2003) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1592/phco.23.7.871.32720 · Cited by 365 · see citing works
Effects of lovastatin on cognitive function and psychological well-being
Muldoon, M. F., Barger, S. D., Ryan, C. M., Flory, J. D., Lehoczky, J. P., Matthews, K. A., & Manuck, S. B. (2000) · The American Journal of Medicine · doi:10.1016/s0002-9343(00)00353-3 · Cited by 290 · see citing works
The role of APOE -ε4 in longitudinal cognitive decline
Bretsky, P., Guralnik, J. M., Launer, L. J., Albert, M., & Seeman, T. E. (2003) · Neurology · doi:10.1212/01.wnl.0000055875.26908.24 · Cited by 257 · see citing works
Statins and Cognitive Function: A Systematic Review
Richardson, K., Schoen, M., French, B., Umscheid, C. A., Mitchell, M. D., Arnold, S. E., Heidenreich, P. A., Rader, D. J., & deGoma, E. M. (2013) · Annals of Internal Medicine · doi:10.7326/0003-4819-159-10-201311190-00007 · Cited by 250 · see citing works
Effect of<i>APOE</i>genotype on amyloid plaque load and gray matter volume in Alzheimer disease
Drzezga, A., Grimmer, T., Henriksen, G., Mühlau, M., Perneczky, R., Miederer, I., Praus, C., Sorg, C., Wohlschläger, A., Riemenschneider, M., et al. (2009) · Neurology · doi:10.1212/wnl.0b013e3181a2e8d0 · Cited by 248 · see citing works
Muldoon, M. F., Ryan, C. M., Sereika, S. M., Flory, J. D., & Manuck, S. B. (2004) · The American Journal of Medicine · doi:10.1016/j.amjmed.2004.07.041 · Cited by 247 · see citing works
Do Statins Impair Cognition? A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Ott, B. R., Daiello, L. A., Dahabreh, I. J., Springate, B. A., Bixby, K., Murali, M., & Trikalinos, T. A. (2015) · Journal of General Internal Medicine · doi:10.1007/s11606-014-3115-3 · Cited by 240 · see citing works
Self-citationLongitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele
Caselli, R. J., Reiman, E. M., Osborne, D., Hentz, J. G., Baxter, L. C., Hernandez, J. L., & Alexander, G. (2004) · Neurology · doi:10.1212/01.wnl.0000129533.26544.bf · Cited by 231 · see citing works
Égerházi, A., Berecz, R., Bartók, E., & Degrell, I. (2007) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2007.01.011 · Cited by 214 · see citing works
Farias, S. T., Mungas, D., Harvey, D. J., Simmons, A. L., Reed, B., & DeCarli, C. S. (2011) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2011.02.007 · Cited by 202 · see citing works
Evidence for benefit of statins to modify cognitive decline and risk in Alzheimer’s disease
Geifman, N., Brinton, R. D., Kennedy, R. E., Schneider, L. S., & Butte, A. J. (2017) · Alzheimer's Research & Therapy · doi:10.1186/s13195-017-0237-y · Cited by 191 · see citing works
Cardiac disease and cognitive impairment: a systematic review
Eggermont, L. H. P., de Boer, K., Muller, M., Jaschke, A. C., Otto Kamp, B., & Scherder, E. (2012) · Heart · doi:10.1136/heartjnl-2012-301682 · Cited by 180 · see citing works
Sabatine, M. S., Giugliano, R. P., Keech, A., Honarpour, N., Wang, H., Liu, T., Wasserman, S. M., Scott, R., Sever, P. S., & Pedersen, T. R. (2016) · American Heart Journal · doi:10.1016/j.ahj.2015.11.015 · Cited by 176 · see citing works
Self-citationKalmijn, S., Feskens, E. J. M., Launer, L. J., & Kromhout, D. (1996) · Stroke · doi:10.1161/01.str.27.12.2230 · Cited by 159 · see citing works
<i>APOE</i> genotype and cognitive decline in a middle-aged cohort
Blair, C. K., Folsom, A. R., Knopman, D. S., Bray, M. S., Mosley, T. H., & Boerwinkle, E. (2005) · Neurology · doi:10.1212/01.wnl.0000149643.91367.8a · Cited by 143 · see citing works
Prevention and Treatment of Dementia or Alzheimer’s Disease by Statins: A Meta-Analysis
Zhou, B., Teramukai, S., & Fukushima, M. (2007) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000099037 · Cited by 100 · see citing works
Cognition After Lowering LDL-Cholesterol With Evolocumab
Gencer, B., Mach, F., Guo, J., Im, K., Ruzza, A., Wang, H., Kurtz, C. E., Pedersen, T. R., KEECH, A. C., Ott, B. R., et al. (2020) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2020.03.039 · Cited by 94 · see citing works
Self-citationO’Connell, E. M., & Lohoff, F. W. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00609 · Cited by 93 · see citing works
Increased PCSK9 cerebrospinal fluid concentrations in Alzheimer’s disease
Zimetti, F., Caffarra, P., Ronda, N., Favari, E., Adorni, M. P., Zanotti, I., Bernini, F., Barocco, F., Spallazzi, M., Galimberti, D., et al. (2016) · Journal of Alzheimer's Disease · doi:10.3233/jad-160411 · Cited by 75 · see citing works
Adorni, M. P., Ruscica, M., Ferri, N., Bernini, F., & Zimetti, F. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00120 · Cited by 67 · see citing works
Baxter, L. C., Caselli, R. J., Johnson, S. C., Reiman, E. M., & Osborne, D. (2003) · Neurobiology of Aging · doi:10.1016/s0197-4580(03)00006-x · Cited by 67 · see citing works
Lenehan, M. E., Summers, M. J., Saunders, N. L., Summers, J. J., & Vickers, J. C. (2015) · Assessment · doi:10.1177/1073191115581474 · Cited by 65 · see citing works
Picard, C., Poirier, A., Bélanger, S., Labonté, A., Auld, D., Poirier, J., & on behalf of the PREVENT-AD Research Group (2019) · PLOS ONE · doi:10.1371/journal.pone.0220254 · Cited by 59 · see citing works
Subjective Memory Complaints in APOE ɛ 4 Carriers are Associated with High Amyloid-β Burden
Zwan, M. D., Villemagne, V. L., Doré, V., Buckley, R. F., Bourgeat, P., Veljanoski, R., Salvado, O., Williams, R., Margison, L., Rembach, A., et al. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-150446 · Cited by 53 · see citing works
Abuelezz, S. A., & Hendawy, N. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119310 · Cited by 50 · see citing works
Zhao, X.-S., Wu, Q., Peng, J., Pan, L.-H., Ren, Z., Liu, H.-T., Jiang, Z.-S., Wang, G.-X., Tang, Z.-H., & Liu, L.-S. (2017) · Molecular Medicine Reports · doi:10.3892/mmr.2016.6055 · Cited by 46 · see citing works
APOE ε4 Genotype and the Risk for Subjective Cognitive Impairment in Elderly Persons
Krell‐Roesch, J., Woodruff, B. K., Acosta, J. I., Locke, D. E. C., Hentz, J. G., Stonnington, C. M., Stokin, G. B., Nagle, C., Michel, B. F., Sambuchi, N., et al. (2015) · Journal of Neuropsychiatry · doi:10.1176/appi.neuropsych.14100268 · Cited by 12 · see citing works
Early neurological and cognitive impairments in subclinical cerebrovascular disease
Atanassova, P. A., Massaldjieva, R., Dimitrov, B. D., Aleksandrov, A., Semerdjieva, M. A., Tsvetkova, S., Chalakova, N. T., & Chompalov, K. A. (2016) · Neurology India · doi:10.4103/0028-3886.185359 · Cited by 7 · see citing works
Potential Link Between Proprotein Convertase Subtilisin/Kexin Type 9 and Alzheimer’s Disease
Oldham, C. E., & Lopez, D. (2018) · International Journal of Biomedical Investigation · doi:10.31531/2581-4745.1000106 · Cited by 5 · see citing works
Jonnal (2000) · doi:10.1002/1096-8628(20001204)96:6
Flagged first, then by citations
Cited by
Sorted by citations
Palaniappan, L. P., Allen, N. B., Almarzooq, Z., Anderson, C. A. M., Arora, P. K., Avery, C. L., Baker-Smith, C. M., Bansal, N., Currie, M. E., Earlie, R. S., et al. (2026) · Circulation · doi:10.1161/cir.0000000000001412 · Cited by 312 · see citing works
Goldstein, L. B., Toth, P. P., Dearborn, J. L., Giugliano, R. P., Hirsh, B. J., Peña, J. M., Selim, M. H., & Woo, D. (2023) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atv.0000000000000164 · Cited by 95 · see citing works
Self-citationBorràs, C., Mercer, A., Sirisi, S., Alcolea, D. A., Escolá‐Gil, J. C., Blanco‐Vaca, F., & Tondo, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169356 · Cited by 41 · see citing works
PCSK9 Inhibitors in the Management of Cardiovascular Risk: A Practical Guidance
Jia, X., Rifai, M. A., Saeed, A., Ballantyne, C. M., & Virani, S. S. (2022) · Vascular Health and Risk Management · doi:10.2147/vhrm.s275739 · Cited by 33 · see citing works
Ups and downs in PCSK9 inhibition in the cardiovascular arena: a review
McClintick, D. J., & Giugliano, R. P. (2023) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000897 · Cited by 7 · see citing works
Self-citationPleiotropic Effects of PCSK9 Inhibitors on Cardio-Cerebrovascular Diseases
Li, Z., Zhu, L., Xu, Y., Zhang, Y., Liu, Y., Sun, H., Li, S., Wang, M., Jiang, T., Zhou, J., et al. (2024) · Biomedicines · doi:10.3390/biomedicines12122729 · Cited by 6 · see citing works
Suswidiantoro, V., Puteri, M. U., Kato, M., Ariestanti, D. M., James, R. J., & Saputri, F. C. (2025) · Life · doi:10.3390/life15121851 · Cited by 4 · see citing works
APOE genotype and the effect of statins on lipid outcomes: A meta‐analysis
Asiimwe, I. G., Gebru, T. G., Jorgensen, A., & Pirmohamed, M. (2026) · British Journal of Clinical Pharmacology · doi:10.1002/bcp.70493 · Cited by 5 · see citing works
Tao, Q., Ang, T. F. A., Huang, J., Itchapurapu, I. S., Mez, J., Alosco, M., Au, R., Farrer, L. A., Zhang, X., Qiu, W. Q., et al. (2026) · Health Science Reports · doi:10.1002/hsr2.71810 · Cited by 1 · see citing works
Chen, L., Peng, H., Wang, B., Yu, W., Ding, X., Gao, M., & Yu, Y. (2023) · Medicine · doi:10.1097/md.0000000000034247 · Cited by 1 · see citing works
Wang, J. D. J., Teo, A. Y. T., Xiao, B., Chao, Y., Zhou, Z. D., Tan, B. J.-W., Chan, L.-L., Rosalie, E., & Tan, E.-K. (2026) · Translational Neurodegeneration · doi:10.1186/s40035-026-00568-y
- Authors
- Korthauer, L. E., Giugliano, R. P., Guo, J., Sabatine, M. S., Sever, P., Keech, A., Atar, D., Kurtz, C., Ruff, C. T., Mach, F., & Ott, B. R.
- Affiliations
- Brown University (US)
- Brigham and Women's Hospital (US)
- Imperial College London (GB)
- The University of Sydney (AU)
- Oslo University Hospital (NO)
- Amgen (United States) (US)
- Corresponding author
- Korthauer, Laura E.
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2022-04-11
- Volume
- 17
- Issue
- 4
- Pages
- e0266615
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC9000128
- OpenAlex
- W4223434464
- Cited by
- 11
- References
- 43
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 1 · 2023: 3 · 2022: 2
- FWCI
- 1.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
- Funders
- amgen
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- APOE ε4, evolocumab, PCSK9 inhibitors, cognitive function, memory decline, Alzheimer's disease risk, genetic moderation, cholesterol-lowering therapy, statin therapy, atherosclerotic cardiovascular disease, Everyday Cognition Scale, CANTAB, FOURIER trial
- MeSH terms
- Proprotein Convertase 9, Alzheimer Disease, Anticholesteremic Agents, Cognition, Genotype, Humans, Neuropsychological Tests, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Apolipoprotein E4, Antibodies, Monoclonal, Humanized
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
