Evaluating the association of apolipoprotein E genotype and cognitive resilience in SuperAgers

Alaina Durant¹, Shubhabrata Mukherjee², Michael L Lee², Seo-Eun Choi², Phoebe Scollard^{2

3}, Brandon S Klinedinst², Emily H Trittschuh^{4

5}, Jesse Mez⁶, Lindsay A Farrer^{6

7

8}, Katherine A Gifford^{1

8}, Carlos Cruchaga^{9

10}, Jason Hassenstab¹¹, Adam C Naj^{12

13}, Li-San Wang¹³, Sterling C Johnson^{14

15}, Corinne D Engelman^{14

15}, Walter A Kukull¹⁶, C Dirk Keene¹⁷, Andrew J Saykin^{18

19}, Michael L Cuccaro²⁰, Brian W Kunkle²⁰, Margaret A Pericak-Vance²⁰, Eden R Martin²⁰, David A Bennett²¹, Lisa L Barnes²¹, Julie A Schneider²¹, William S Bush²², Jonathan L Haines²², Richard Mayeux²³, Badri N Vardarajan²³, Marilyn S Albert²⁴, Paul M Thompson²⁵, Angela L Jefferson^{1

26}; Alzheimer's Disease Neuroimaging Initiative (ADNI)*Alzheimer's Disease Genetics Consortium (ADGC)The Alzheimer's Disease Sequencing Project (ADSP); Paul K Crane², Logan Dumitrescu^{1

26

27}, Derek B Archer^{1

26

27}, Timothy J Hohman^{1

26

27}, Leslie S Gaynor^{1

28}

Affiliations

¹ Vanderbilt Memory & Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
² Department of Medicine, University of Washington, Seattle, Washington, USA.
³ Bordeaux Population Health Research Center, University Bordeaux, Inserm, Bordeaux, France.
⁴ Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
⁵ VA Puget Sound Health Care System, GRECC, Seattle, Washington, USA.
⁶ Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston University Medical Center, Boston, Massachusetts, USA.
⁷ Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
⁸ Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.
⁹ Department of Psychiatry, Washington University in St. Louis, St. Louis, Missouri, USA.
¹⁰ NeuroGenomics and Informatics Center, Washington University in St. Louis, St. Louis, Missouri, USA.
¹¹ Department of Neurology and Department Psychological & Brain Sciences, Washington University in St Louis, St. Louis, Missouri, USA.
¹² Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
¹³ Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
¹⁴ Alzheimer's Disease Research Center, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin, USA.
¹⁵ Department of Population Health Sciences, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin, USA.
¹⁶ Department of Neurology, WashU Medicine, St. Louis, Missouri, USA.
¹⁷ Department of Laboratory Medicine and Pathology, University of Washington, St. Seattle, Washington, USA.
¹⁸ Department of Radiology and Imaging Services, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹⁹ Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
²⁰ John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA.
²¹ Rush Alzheimer's Disease Center, Rush University Medical Center, St. Chicago, Illinois, USA.
²² Cleveland Institute for Computational Biology, Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
²³ Department of Neurology, The Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University Medical Center and The New York Presbyterian Hospital, New York, New York, USA.
²⁴ Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²⁵ Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
²⁶ Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²⁷ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²⁸ Division of Geriatric Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

PMID: 41542929
PMCID: PMC12809718
DOI: 10.1002/alz.71024

Evaluating the association of apolipoprotein E genotype and cognitive resilience in SuperAgers

Alaina Durant et al. Alzheimers Dement. 2026 Jan.

. 2026 Jan;22(1):e71024.

doi: 10.1002/alz.71024.

Authors

Affiliations

¹ Vanderbilt Memory & Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
² Department of Medicine, University of Washington, Seattle, Washington, USA.
³ Bordeaux Population Health Research Center, University Bordeaux, Inserm, Bordeaux, France.
⁴ Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
⁵ VA Puget Sound Health Care System, GRECC, Seattle, Washington, USA.
⁶ Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston University Medical Center, Boston, Massachusetts, USA.
⁷ Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
⁸ Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.
⁹ Department of Psychiatry, Washington University in St. Louis, St. Louis, Missouri, USA.
¹⁰ NeuroGenomics and Informatics Center, Washington University in St. Louis, St. Louis, Missouri, USA.
¹¹ Department of Neurology and Department Psychological & Brain Sciences, Washington University in St Louis, St. Louis, Missouri, USA.
¹² Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
¹³ Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
¹⁴ Alzheimer's Disease Research Center, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin, USA.
¹⁵ Department of Population Health Sciences, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin, USA.
¹⁶ Department of Neurology, WashU Medicine, St. Louis, Missouri, USA.
¹⁷ Department of Laboratory Medicine and Pathology, University of Washington, St. Seattle, Washington, USA.
¹⁸ Department of Radiology and Imaging Services, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹⁹ Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
²⁰ John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA.
²¹ Rush Alzheimer's Disease Center, Rush University Medical Center, St. Chicago, Illinois, USA.
²² Cleveland Institute for Computational Biology, Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
²³ Department of Neurology, The Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University Medical Center and The New York Presbyterian Hospital, New York, New York, USA.
²⁴ Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²⁵ Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
²⁶ Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²⁷ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²⁸ Division of Geriatric Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

PMID: 41542929
PMCID: PMC12809718
DOI: 10.1002/alz.71024

Abstract

Introduction: "SuperAgers" are oldest-old adults (ages 80+) whose memory performance more closely resembles middle-aged adults. The present study examined apolipoprotein E (APOE) allele frequency in non-Hispanic Black (NHB) and non-Hispanic White (NHW) SuperAgers compared to controls and Alzheimer's disease dementia cases.

Methods: In 18,080 participants from eight cohorts, harmonized clinical diagnostics and memory, executive function, and language domain scores were used to identify SuperAgers, cases, and controls across age-defined bins.

Results: NHW SuperAgers had significantly lower frequency of APOE-ε4 alleles and higher frequency of APOE-ε2 alleles compared to all cases and controls, including oldest-old controls. Similar patterns were found in a small yet substantial sample of NHB SuperAgers; however, not all comparisons with controls reached significance.

Discussion: We demonstrated strong evidence that APOE allele frequency relates to SuperAger status. Further research is needed with a larger sample of NHB SuperAgers to determine if mechanisms conferring cognitive resilience differ across race groups.

Highlights: Apolipoprotein E (APOE) allele frequency differs between SuperAgers and cases APOE allele frequency differs between non-Hispanic White SuperAgers and controls The relationship of APOE and non-Hispanic Black SuperAger status is unclear.

Keywords: APOE genotype; Alzheimer's disease; SuperAgers; cognitive aging; cognitive resilience.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest. Author disclosures are available in the supporting information.

Figures

**FIGURE 1**
Flow diagram for participant classification of SuperAgers, cases, and controls. (A) Flowchart depicting inclusion and exclusion criteria for identifying SuperAgers, AD dementia cases, controls. (B) Flowchart depicting selection order of SuperAgers, cases, and controls. Age range of participants indicated by line segment with arrows on each end. Age of participant classification is indicated by position of shorter, labeled line segments. Closed circles at the end of line segments indicate inclusion of age, such that age range is less‐than‐or‐equal‐to or greater‐than‐or‐equal‐to the age with which the circle aligns, while open circles indicate exclusion of age, such that age range is less‐than or greater‐than the age with which the circle aligns. Sequence of selection is indicated by line height, higher lines indicating earlier selection. AD, Alzheimer's disease; ADSP‐PHC, Alzheimer's Disease Sequencing Project – Phenotype Harmonization Consortium; CN, cognitively normal; EXF, executive functioning; LAN, language; MEM, memory.

**FIGURE 2**
*APOE* allele frequency in NHW and NHB SuperAgers compared to cases and controls. Bar charts depicting *APOE*‐ε2 and *APOE*‐ε4 allele frequency for SuperAgers, cases, and controls across age‐defined subgroups. Participant classification is indicated by the X‐axis, while percent frequency is indicated by the Y‐axis. (A) *APOE*‐ε2 allele frequency in NHW participants. (B) *APOE*‐ε4 allele frequency in NHW participants. (C) *APOE*‐ε2 allele frequency in NHB participants. (D) *APOE*‐ε4 allele frequency in NHB participants. Asterisks denote significant differences in allele frequency compared to SuperAgers determined by logistic regression models covarying for sex and years of education (* $\leq$ 0.05, ** $\leq$ 0.01, *** $\leq$ 0.001). APOE, apolipoprotein E; NHW, non‐Hispanic White; NHB, non‐Hispanic Black.

See this image and copyright information in PMC

Update of

Evaluating the association of APOE genotype and cognitive resilience in SuperAgers.
Durant A, Mukherjee S, Lee ML, Choi SE, Scollard P, Klinedinst BS, Trittschuh EH, Mez J, Farrer LA, Gifford KA, Cruchaga C, Hassenstab J, Naj AC, Wang LS, Johnson SC, Engelman CD, Kukull WA, Keene CD, Saykin AJ, Cuccaro ML, Kunkle BW, Pericak-Vance MA, Martin ER, Bennett DA, Barnes LL, Schneider JA, Bush WS, Haines JL, Mayeux R, Vardarajan BN, Albert MS, Thompson PM, Jefferson AL; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer’s Disease Genetics Consortium (ADGC); Alzheimer’s Disease Sequencing Project (ADSP); Crane PK, Dumitrescu L, Archer DB, Hohman TJ, Gaynor LS. Durant A, et al. medRxiv [Preprint]. 2025 Jun 25:2025.01.07.25320117. doi: 10.1101/2025.01.07.25320117. medRxiv. 2025. Update in: Alzheimers Dement. 2026 Jan;22(1):e71024. doi: 10.1002/alz.71024. PMID: 39830268 Free PMC article. Updated. Preprint.

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Evaluating the association of apolipoprotein E genotype and cognitive resilience in SuperAgers

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Evaluating the association of apolipoprotein E genotype and cognitive resilience in SuperAgers

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Conflict of interest statement

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