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[Preprint]. 2025 Jun 25:2025.01.07.25320117.

doi: 10.1101/2025.01.07.25320117.

Evaluating the association of APOE 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); 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, 3319 West End Ave, Rm 819, Nashville, TN 37203, USA.
² Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195-6420, USA.
³ University Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR1219, 146 Rue Léo Saignat 11, Bordeaux, France 33076.
⁴ Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195-6560, USA.
⁵ VA Puget Sound Health Care System, GRECC, 1660 S Columbian Way, Seattle, WA 98108, USA.
⁶ Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston University Medical Center, 85 East Concord Street, 1st floor, Boston, MA 02118, USA.
⁷ Department of Biostatistics, Boston University School of Public Health, Crosstown Building, 801 Massachusetts Avenue 3 Floor, Boston, MA 02118, USA.
⁸ Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, 72 East Concord St., Boston, MA 02118, USA.
⁹ Department of Psychiatry, Washington University in St. Louis, 4444 Forest Park Avenue, St. Louis, MO 63108, USA.
¹⁰ NeuroGenomics and Informatics Center, Washington University in St. Louis, 4444 Forest Park Ave Room 5501, St. Louis, MO 63018, USA.
¹¹ Department of Neurology and Department Psychological & Brain Sciences, Washington University in St Louis, 1 Brookings Drive, St. Louis, MO 63130, USA.
¹² Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, 423 Guardian Drive, Philadelphia, PA 19104-6021, USA.
¹³ Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, 3400 Spruce St., Philadelphia, PA 19104-4238, USA.
¹⁴ Alzheimer's Disease Research Center, University of Wisconsin-Madison, School of Medicine and Public Health, 600 Highland Ave J5/1 Mezzanine, Madison, WI 53792, USA.
¹⁵ Department of Population Health Sciences, University of Wisconsin-Madison, School of Medicine and Public Health, 500 Lincoln Dr., Madison, WI 53706, USA.
¹⁶ Department of Epidemiology, School of Public Health, University of Washington, 3980 15 Ave NE, Seattle, WA 98195, USA.
¹⁷ Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195, USA.
¹⁸ Department of Radiology and Imaging Services, Indiana University School of Medicine, 550 University Blvd, Indianapolis, IN 46202, USA.
¹⁹ Department of Medical and Molecular Genetics, School of Medicine, Indiana University, 975 W Walnut St IB 130, Indianapolis, IN 46202, USA.
²⁰ John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, 1501 NW 10 Ave, Miami, FL 33101, USA.
²¹ Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W Harrison St, Chicago, IL 60612, USA.
²² Cleveland Institute for Computational Biology, Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, 2109 Adelbert Rd, Cleveland, OH 44106, 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, 710 W 168 St #3, New York, NY 10032, USA.
²⁴ Department of Neurology, The Johns Hopkins University School of Medicine, 550 N Broadway #415, Baltimore, MD 21205, USA.
²⁵ Keck School of Medicine, University of Southern California, 1975 Zonal Ave, Los Angeles, CA 90033, USA.
²⁶ Department of Neurology, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, USA.
²⁷ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, USA.
²⁸ Division of Geriatric Medicine, Department of Medicine, Vanderbilt University Medical Center, 1161 21 Ave S, Nashville, TN 37232, USA.

PMID: 39830268
PMCID: PMC11741496
DOI: 10.1101/2025.01.07.25320117

Evaluating the association of APOE genotype and cognitive resilience in SuperAgers

Alaina Durant et al. medRxiv. 2025.

[Preprint]. 2025 Jun 25:2025.01.07.25320117.

doi: 10.1101/2025.01.07.25320117.

Authors

Affiliations

¹ Vanderbilt Memory & Alzheimer's Center, Vanderbilt University Medical Center, 3319 West End Ave, Rm 819, Nashville, TN 37203, USA.
² Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195-6420, USA.
³ University Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR1219, 146 Rue Léo Saignat 11, Bordeaux, France 33076.
⁴ Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195-6560, USA.
⁵ VA Puget Sound Health Care System, GRECC, 1660 S Columbian Way, Seattle, WA 98108, USA.
⁶ Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston University Medical Center, 85 East Concord Street, 1st floor, Boston, MA 02118, USA.
⁷ Department of Biostatistics, Boston University School of Public Health, Crosstown Building, 801 Massachusetts Avenue 3 Floor, Boston, MA 02118, USA.
⁸ Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, 72 East Concord St., Boston, MA 02118, USA.
⁹ Department of Psychiatry, Washington University in St. Louis, 4444 Forest Park Avenue, St. Louis, MO 63108, USA.
¹⁰ NeuroGenomics and Informatics Center, Washington University in St. Louis, 4444 Forest Park Ave Room 5501, St. Louis, MO 63018, USA.
¹¹ Department of Neurology and Department Psychological & Brain Sciences, Washington University in St Louis, 1 Brookings Drive, St. Louis, MO 63130, USA.
¹² Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, 423 Guardian Drive, Philadelphia, PA 19104-6021, USA.
¹³ Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, 3400 Spruce St., Philadelphia, PA 19104-4238, USA.
¹⁴ Alzheimer's Disease Research Center, University of Wisconsin-Madison, School of Medicine and Public Health, 600 Highland Ave J5/1 Mezzanine, Madison, WI 53792, USA.
¹⁵ Department of Population Health Sciences, University of Wisconsin-Madison, School of Medicine and Public Health, 500 Lincoln Dr., Madison, WI 53706, USA.
¹⁶ Department of Epidemiology, School of Public Health, University of Washington, 3980 15 Ave NE, Seattle, WA 98195, USA.
¹⁷ Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195, USA.
¹⁸ Department of Radiology and Imaging Services, Indiana University School of Medicine, 550 University Blvd, Indianapolis, IN 46202, USA.
¹⁹ Department of Medical and Molecular Genetics, School of Medicine, Indiana University, 975 W Walnut St IB 130, Indianapolis, IN 46202, USA.
²⁰ John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, 1501 NW 10 Ave, Miami, FL 33101, USA.
²¹ Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W Harrison St, Chicago, IL 60612, USA.
²² Cleveland Institute for Computational Biology, Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, 2109 Adelbert Rd, Cleveland, OH 44106, 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, 710 W 168 St #3, New York, NY 10032, USA.
²⁴ Department of Neurology, The Johns Hopkins University School of Medicine, 550 N Broadway #415, Baltimore, MD 21205, USA.
²⁵ Keck School of Medicine, University of Southern California, 1975 Zonal Ave, Los Angeles, CA 90033, USA.
²⁶ Department of Neurology, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, USA.
²⁷ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, USA.
²⁸ Division of Geriatric Medicine, Department of Medicine, Vanderbilt University Medical Center, 1161 21 Ave S, Nashville, TN 37232, USA.

PMID: 39830268
PMCID: PMC11741496
DOI: 10.1101/2025.01.07.25320117

Abstract

Introduction: "SuperAgers" are oldest-old adults (ages 80+) whose memory performance more closely resembles middle-aged adults. The present study examined 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 resilience differ across race groups.

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

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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. Abbreviations: ADSP-PHC, Alzheimer’s Disease Sequencing Project – Phenotype Harmonization Consortium; AD, Alzheimer’s Disease; CN, Cognitively Normal; MEM, Memory; EXF, Executive Functioning; LAN, Language.

See this image and copyright information in PMC

References

1. Harrison T. M., Mesulam M. M., Rogalski E. & Weintraub S. Superior Memory and Higher Cortical Volumes in Unusually Successful Cognitive Aging. Journal of the International Neuropsychological Society 18, 1081–1085 (2012). 10.1017/S1355617712000847 - DOI - PMC - PubMed
1. Rogalski E. J. et al. Youthful Memory Capacity in Old Brains: Anatomic and Genetic Clues from the Northwestern SuperAging Project. Journal of Cognitive Neuroscience 25, 29–36 (2013). 10.1162/jocn_a_00300 - DOI - PMC - PubMed
1. de Godoy L. L. et al. Understanding brain resilience in superagers: a systematic review. Neuroradiology 63, 663–683 (2021). 10.1007/s00234-020-02562-1 - DOI - PubMed
1. Dekhtyar M. et al. Neuroimaging markers associated with maintenance of optimal memory performance in late-life. Neuropsychologia 100, 164–170 (2017). 10.1016/j.neuropsychologia.2017.04.037 - DOI - PMC - PubMed
1. Gefen T. et al. Morphometric and histologic substrates of cingulate integrity in elders with exceptional memory capacity. Journal of Neuroscience 35, 1781–1791 (2015). 10.1523/JNEUROSCI.2998-14.2015 - DOI - PMC - PubMed

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This is a preprint.

Evaluating the association of APOE genotype and cognitive resilience in SuperAgers

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Evaluating the association of APOE genotype and cognitive resilience in SuperAgers

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