ABCA7 deletion lowers age at onset of Alzheimer's disease and interacts with APOE ε4 synergistically in African-ancestry populations

Bilcag Akgun¹, Alexander V Gulyayev¹, Motunrayo Coker², Kara L Hamilton-Nelson¹, Oladotun Olalusi^{2

3}, Larry D Adams¹, Kazeem Akinwande², Patrice G Whitehead¹, Samuel Diala², Mayowa Ogunronbi², Renee A Laux⁴, Albert Akpalu⁵, Takiyah D Starks⁶, Fred S Sarfo⁷, Jenny Chavez⁸, Kamada Lwere⁹, Gary W Beecham¹⁰, Joshua O Akinyemi¹¹, Reginald Obiako¹², David Ndetei¹³, Allison Caban-Holt⁶, Biniyam Ayele^{1

14}, Paula Ogrocki^{15

16}, Anthony J Griswold^{1

17}, Andrew F Zaman¹, Pedro R Mena¹, Izri M Martinez¹, Susan H Blanton^{1

17}, Njideka Okubadejo¹⁸, Albertino Damasceno¹⁹, Rajesh Kalaria²⁰, Michael L Cuccaro^{1

17}, Katalina F McInerney²¹; African Dementia Consortium (AfDC); Alzheimer's Disease Sequencing Project (ADSP); William S Bush^{4

22}, Brian W Kunkle^{1

17}, Adesola Ogunniyi^{2

3}, Jeffery M Vance^{1

17

21}, Rufus O Akinyemi^{2

3}, Jonathan L Haines^{4

22}, Christiane Reitz⁸, Goldie S Byrd⁶, Farid Rajabli^{1

17}, Margaret A Pericak-Vance^{1

17

21}

Affiliations

¹ John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA.
² Neuroscience and Ageing Research Unit, Institute for Advanced Medical Research & Training, College of Medicine, University of Ibadan, Ibadan, Nigeria.
³ Department of Neurology, University College Hospital, Ibadan, Nigeria.
⁴ Department of Population & Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
⁵ Department of Medicine, University of Ghana Medical School/Korle Bu Teaching Hospital, Accra, Ghana.
⁶ Department of Social Sciences and Health Policy, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
⁷ Department of Medicine, Kwame Nkrumah University of Science & Technology, Kumasi, Ghana.
⁸ Gertrude H. Sergievsky Center, Taub Institute for Research on the Aging Brain, Departments of Neurology, Psychiatry, and Epidemiology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
⁹ Makerere University College of Health Sciences, Kampala, Uganda.
¹⁰ Department of Biostatistics and Data Science, Wake Forest School University of Medicine, Winston-Salem, North Carolina, USA.
¹¹ Department of Epidemiology and Medical Statistics, College of Medicine, University of Ibadan, Ibadan, Nigeria.
¹² Department of Medicine, Ahmadu Bello University, Zaria, Nigeria.
¹³ Africa Mental Health Research and Training Foundation/Department of Psychiatry, University of Nairobi, Nairobi, Kenya.
¹⁴ College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
¹⁵ Department of Neurology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
¹⁶ Department of Neurology, Case Western Reserve University, School of Medicine, Cleveland, Ohio, USA.
¹⁷ Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA.
¹⁸ Department of Medicine, College of Medicine, University of Lagos, Lagos, Nigeria.
¹⁹ Faculty of Medicine, Eduardo Mondlane University, Maputo, Mozambique.
²⁰ Translational and Clinical Research Institute, Newcastle University, Newcastle, UK.
²¹ Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA.
²² Cleveland Institute for Computational Biology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.

PMID: 40832784
PMCID: PMC12365657
DOI: 10.1002/alz.70583

ABCA7 deletion lowers age at onset of Alzheimer's disease and interacts with APOE ε4 synergistically in African-ancestry populations

Bilcag Akgun et al. Alzheimers Dement. 2025 Aug.

. 2025 Aug;21(8):e70583.

doi: 10.1002/alz.70583.

Authors

Affiliations

¹ John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA.
² Neuroscience and Ageing Research Unit, Institute for Advanced Medical Research & Training, College of Medicine, University of Ibadan, Ibadan, Nigeria.
³ Department of Neurology, University College Hospital, Ibadan, Nigeria.
⁴ Department of Population & Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
⁵ Department of Medicine, University of Ghana Medical School/Korle Bu Teaching Hospital, Accra, Ghana.
⁶ Department of Social Sciences and Health Policy, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
⁷ Department of Medicine, Kwame Nkrumah University of Science & Technology, Kumasi, Ghana.
⁸ Gertrude H. Sergievsky Center, Taub Institute for Research on the Aging Brain, Departments of Neurology, Psychiatry, and Epidemiology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
⁹ Makerere University College of Health Sciences, Kampala, Uganda.
¹⁰ Department of Biostatistics and Data Science, Wake Forest School University of Medicine, Winston-Salem, North Carolina, USA.
¹¹ Department of Epidemiology and Medical Statistics, College of Medicine, University of Ibadan, Ibadan, Nigeria.
¹² Department of Medicine, Ahmadu Bello University, Zaria, Nigeria.
¹³ Africa Mental Health Research and Training Foundation/Department of Psychiatry, University of Nairobi, Nairobi, Kenya.
¹⁴ College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
¹⁵ Department of Neurology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
¹⁶ Department of Neurology, Case Western Reserve University, School of Medicine, Cleveland, Ohio, USA.
¹⁷ Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA.
¹⁸ Department of Medicine, College of Medicine, University of Lagos, Lagos, Nigeria.
¹⁹ Faculty of Medicine, Eduardo Mondlane University, Maputo, Mozambique.
²⁰ Translational and Clinical Research Institute, Newcastle University, Newcastle, UK.
²¹ Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA.
²² Cleveland Institute for Computational Biology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.

PMID: 40832784
PMCID: PMC12365657
DOI: 10.1002/alz.70583

Abstract

Introduction: Apolipoprotein E (APOE) and ABCA7 genes are among the strongest heritable risk factors for Alzheimer's disease (AD) in African-ancestry (AA) populations. APOE 𝜀4 affects both risk and age at onset (AAO), with lower risk in AA populations. This study evaluates the independent and interactive effects of the AA-specific ABCA7 frameshift deletion and APOE 𝜀4 allele on AAO.

Methods: We analyzed 3510 AA individuals, including AD cases and controls. Cox regression models assessed the effects of ABCA7 deletion, APOE genotypes, and their interactive influence on AAO.

Results: APOE ε3/ε4 carriers with the ABCA7 deletion had a significantly shorter survival compared to ε3/ε4 carriers without the deletion. No significant differences were found between deletion carriers and non-carriers with APOE ε3/ε3 or ε4/ε4 genotypes.

Discussion: Our study showed that the ABCA7 deletion lowered the AAO of AD in APOE ε3/ε4 carriers from AA populations. These findings suggest that the AA-specific ABCA7 deletion and the APOE ε4 allele have synergistic effects on AAO.

Highlights: AA-specific ABCA7 deletion lowers AAO of AD in APOE ε3/ε4 carriers from AA populations. Findings suggest an interaction between ABCA7 deletion and APOE ε4 on AAO. APOE ε4 has a strong, dose-dependent effect on AAO of AD in AA individuals. ABCA7 deletion impact on AAO of AD is stronger in females with APOE ε3/ε4.

Keywords: ABCA7; APOE; African ancestry; Alzheimer's disease; age at onset.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest. Author disclosures are available in the Supporting Information.

Figures

**FIGURE 1**
Cox regression survival plot illustrating adjusted survival probabilities for individuals with (red line) and without (green line) the *ABCA7* deletion.

**FIGURE 2**
Cox regression survival plot for *APOE‐*‐*ABCA7* interaction model: ε4/ε4_Del(+) (dark red), ε4/ε4_Del(−) (pink), ε3/ε4_Del(+) (orange), ε3/ε4_Del(−) (yellow), ε3/ε3_Del(+) (dark green), and ε3/ε3_Del(−) (light green).

See this image and copyright information in PMC

References

1. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261:921‐923. - PubMed
1. Corder EH, Saunders AM, Risch NJ, et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. 1994;7:180‐184. - PubMed
1. Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta‐analysis. APOE and Alzheimer disease meta analysis consortium. JAMA. 1997;278:1349‐1356. - PubMed
1. Tang MX, Cross P, Andrews H, et al. Incidence of AD in African‐Americans, Caribbean Hispanics, and Caucasians in northern Manhattan. Neurology. 2001;56:49‐56. - PubMed
1. Tang MX, Stern Y, Marder K, et al. The APOE‐epsilon4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics. JAMA. 1998;279:751‐755. - PubMed

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ABCA7 deletion lowers age at onset of Alzheimer's disease and interacts with APOE ε4 synergistically in African-ancestry populations

Affiliations

ABCA7 deletion lowers age at onset of Alzheimer's disease and interacts with APOE ε4 synergistically in African-ancestry populations

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

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