Increased genetic protection against Alzheimer's disease in centenarians

Harold Bae¹, Zeyuan Song^{2

3}, Amanat Ali^{4

5}, Takashi Sasaki⁶, Niccolò Tesi^{7

8

9}, Hannah Lords¹⁰, Anastasia Leshchyk¹⁰, Yukiko Abe⁶, Nobuyoshi Hirose¹¹, Yasumichi Arai^{6

12}, Nir Barzilai^{4

5

13}, Erica F Weiss^{13

14}, Marc Hulsman^{8

9}, Sven van der Lee^{8

9}, Natasja M van Schoor¹⁵, Martijn Huisman¹⁵, Yolande Pijnenburg⁹, Wiesje van der Flier⁹, Marcel Reinders⁷, Henne Holstege^{7

8

9}, Sofiya Milman^{4

5

13}, Thomas T Perls¹⁶, Stacy L Andersen¹⁶, Paola Sebastiani^{2

3}

Affiliations

¹ School of Nutrition and Public Health, College of Health, Oregon State University, Corvallis, OR, USA. harold.bae@oregonstate.edu.
² Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, USA.
³ School of Medicine, Tufts University, Boston, MA, USA.
⁴ Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA.
⁵ Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA.
⁶ Center for Supercentenarian Medical Research, Keio University School of Medicine, Tokyo, Japan.
⁷ Delft Bioinformatics Lab, Delft University of Technology, Mekelweg 2, 2628CD, Delft, The Netherlands.
⁸ Section Genomics of Neurodegenerative Diseases and Aging, Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam, UMC, De Boelelaan 1117, 1081HV, Amsterdam, The Netherlands.
⁹ Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, UMC, De Boelelaan 1117, 1081HV, Amsterdam, The Netherlands.
¹⁰ Division of Computational Biomedicine, Boston University, Boston, MA, USA.
¹¹ Center of Supercentenarian Medical Research, School of Medicine, Keio University, Tokyo, Japan.
¹² Faculty of Nursing, Keio University, Tokyo, Japan.
¹³ Institute for Aging Researchand the Einstein-NSC, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA.
¹⁴ Department of Neurology, Montefiore Medical Center, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA.
¹⁵ Department of Epidemiology and Data Sciences, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081HV, Amsterdam, The Netherlands.
¹⁶ Boston University, Avedisian School of Medicine, Chobanian &, Boston, MA, USA.

PMID: 40615639
DOI: 10.1007/s11357-025-01774-8

Increased genetic protection against Alzheimer's disease in centenarians

Harold Bae et al. Geroscience. 2025.

. 2025 Jul 4.

doi: 10.1007/s11357-025-01774-8. Online ahead of print.

Authors

Affiliations

¹ School of Nutrition and Public Health, College of Health, Oregon State University, Corvallis, OR, USA. harold.bae@oregonstate.edu.
² Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, USA.
³ School of Medicine, Tufts University, Boston, MA, USA.
⁴ Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA.
⁵ Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA.
⁶ Center for Supercentenarian Medical Research, Keio University School of Medicine, Tokyo, Japan.
⁷ Delft Bioinformatics Lab, Delft University of Technology, Mekelweg 2, 2628CD, Delft, The Netherlands.
⁸ Section Genomics of Neurodegenerative Diseases and Aging, Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam, UMC, De Boelelaan 1117, 1081HV, Amsterdam, The Netherlands.
⁹ Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, UMC, De Boelelaan 1117, 1081HV, Amsterdam, The Netherlands.
¹⁰ Division of Computational Biomedicine, Boston University, Boston, MA, USA.
¹¹ Center of Supercentenarian Medical Research, School of Medicine, Keio University, Tokyo, Japan.
¹² Faculty of Nursing, Keio University, Tokyo, Japan.
¹³ Institute for Aging Researchand the Einstein-NSC, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA.
¹⁴ Department of Neurology, Montefiore Medical Center, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA.
¹⁵ Department of Epidemiology and Data Sciences, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081HV, Amsterdam, The Netherlands.
¹⁶ Boston University, Avedisian School of Medicine, Chobanian &, Boston, MA, USA.

PMID: 40615639
DOI: 10.1007/s11357-025-01774-8

Abstract

We constructed a polygenic protective score specific to Alzheimer's disease (AD PPS) based on the current literature among the participants enrolled in five studies of healthy aging and extreme longevity in the USA, Europe, and Asia. This AD PPS did not include variants on apolipoprotein E (APOE) gene. Comparisons of AD PPS in different data sets of healthy agers and centenarians showed that centenarians have stronger genetic protection against AD compared to individuals without familial longevity. The current study also shows evidence that this genetic protection increases with increasingly older ages in centenarians (centenarians who died before reaching age 105 years, semi-supercentenarians who reached age 105 to 109 years, and supercentenarians who reached age 110 years and older). However, the genetic protection was of modest size: the average increase in AD PPS was approximately one additional protective allele per 5 years of gained lifetime. Additionally, we show that the higher AD PPS was associated with better cognitive function and decreased mortality. Taken together, this analysis suggests that individuals who achieve the most extreme ages, on average, have the greatest protection against AD. This finding is robust to different genetic backgrounds with important implications for universal applicability of therapeutics that target this AD PPS.

Keywords: Alzheimer’s disease; Centenarians; Cognitive function; Extreme longevity; Polygenic risk score.

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Conflict of interest statement

Declarations. Competing interests: The authors declare no competing interests.

Update of

Increased Genetic Protection Against Alzheimer's Disease in Centenarians.
Bae H, Song Z, Ali A, Sasaki T, Tesi N, Lords H, Leshchyk A, Abe Y, Hirose N, Arai Y, Barzilai N, Weiss EF, Hulsman M, van der Lee S, van Schoor NM, Huisman M, Pijnenburg Y, van der Flier W, Reinders M, Holstege H, Milman S, Perls TT, Andersen SL, Sebastiani P. Bae H, et al. bioRxiv [Preprint]. 2025 Jun 3:2025.06.02.657442. doi: 10.1101/2025.06.02.657442. bioRxiv. 2025. Update in: Geroscience. 2025 Jul 4. doi: 10.1007/s11357-025-01774-8. PMID: 40501936 Free PMC article. Updated. Preprint.

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Increased genetic protection against Alzheimer's disease in centenarians

Affiliations

Increased genetic protection against Alzheimer's disease in centenarians

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous