Alzheimer's disease polygenic risk in early- and late-onset Alzheimer's disease

Julian V Pentchev; Trever Jackson; Naazneen Khan; Thea J Rosewood; Yen-Ning Huang; Kwangsik Nho; Andrew J Saykin; Ani Eloyan; Alexander Taurone; Maryanne Thangarajah; Meghan Riddle; Steven Salloway; Alireza Atri; Lawrence S Honig; Erik C B Johnson; Raymond Scott Turner; Joseph C Masdeu; Tatiana M Foroud; David Clark; Dustin B Hammers; Jeffrey L Dage; Kala Kirby; Bernardino Ghetti; Kathy Newell; Chiadi U Onyike; Gregory S Day; Neill R Graff-Radford; Melissa E Murray; David T Jones; Clifford R Jack Jr; Prashanthi Vemuri; Alexandra Touroutoglou; Ranjan Duara; Ian Grant; Sharon Sha; Thomas S Wingo; Laurel A Beckett; Emily Rogalski; Mario F Mendez; Joel Kramer; Renaud La Joie; Ganna Blazhenets; Lea T Grinberg; Robert Koeppe; David A Wolk; Paul Aisen; Rema Raman; Arthur Toga; Walter A Kukull; Erik Musiek; Kyle B Womack; Maria C Carrillo; Gil D Rabinovici; Bradford C Dickerson; Liana G Apostolova; Kelly N H Nudelman; Longitudinal Early‐Onset Alzheimer's Disease Study Consortium and the Alzheimer's Disease Neuroimaging Initiative

doi:10.1002/alz.71066

Alzheimer's disease polygenic risk in early- and late-onset Alzheimer's disease

Alzheimers Dement. 2026 Jan;22(1):e71066. doi: 10.1002/alz.71066.

Authors

Julian V Pentchev¹, Trever Jackson², Naazneen Khan^{1

3}, Thea J Rosewood^{3

4}, Yen-Ning Huang^{3

4}, Kwangsik Nho^{3

4}, Andrew J Saykin^{1

2

3

4}, Ani Eloyan⁵, Alexander Taurone⁵, Maryanne Thangarajah⁵, Meghan Riddle⁶, Steven Salloway⁶, Alireza Atri⁷, Lawrence S Honig⁸, Erik C B Johnson⁹, Raymond Scott Turner¹⁰, Joseph C Masdeu¹¹, Tatiana M Foroud^{2

3}, David Clark¹, Dustin B Hammers¹, Jeffrey L Dage^{1

2

3}, Kala Kirby¹, Bernardino Ghetti^{3

12}, Kathy Newell^{3

12}, Chiadi U Onyike¹³, Gregory S Day¹⁴, Neill R Graff-Radford¹⁴, Melissa E Murray¹⁵, David T Jones^{16

17}, Clifford R Jack Jr¹⁷, Prashanthi Vemuri¹⁷, Alexandra Touroutoglou¹⁸, Ranjan Duara¹⁹, Ian Grant²⁰, Sharon Sha²¹, Thomas S Wingo²², Laurel A Beckett²³, Emily Rogalski²⁴, Mario F Mendez²⁵, Joel Kramer²⁶, Renaud La Joie²⁶, Ganna Blazhenets²⁶, Lea T Grinberg^{26

27}, Robert Koeppe²⁸, David A Wolk²⁹, Paul Aisen³⁰, Rema Raman³⁰, Arthur Toga³¹, Walter A Kukull³², Erik Musiek³³, Kyle B Womack³³, Maria C Carrillo³⁴, Gil D Rabinovici²⁶, Bradford C Dickerson¹⁸, Liana G Apostolova^{1

2

3

4}, Kelly N H Nudelman^{2

3}; Longitudinal Early‐Onset Alzheimer's Disease Study Consortium and the Alzheimer's Disease Neuroimaging Initiative

Affiliations

¹ Department of Neurology, Indiana University School of Medicine, Indianapolis, USA.
² Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, USA.
³ Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA.
⁴ Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, USA.
⁵ Center for Statistical Sciences, Brown University, Providence, USA.
⁶ Department of Neurology, Alpert Medical School, Brown University, Providence, USA.
⁷ Banner Sun Health Research Institute, Sun City, USA.
⁸ Department of Neurology, Columbia University Irving Medical Center, New York, USA.
⁹ Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, USA.
¹⁰ Department of Neurology, Georgetown University, Washington D.C., USA.
¹¹ Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, USA.
¹² Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, USA.
¹³ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, USA.
¹⁴ Department of Neurology, Mayo Clinic, Jacksonville, USA.
¹⁵ Department of Neuroscience, Mayo Clinic, Jacksonville, USA.
¹⁶ Department of Neurology, Mayo Clinic, Rochester, USA.
¹⁷ Department of Radiology, Mayo Clinic, Rochester, USA.
¹⁸ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
¹⁹ Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami, USA.
²⁰ Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, USA.
²¹ Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, USA.
²² Department of Neurology, University of California, Davis, USA.
²³ Department of Public Health Sciences, University of California, Davis, USA.
²⁴ Department of Neurology, Healthy Aging & Alzheimer's Research Care Center, University of Chicago, Chicago, USA.
²⁵ Department of Neurology, University of California, Los Angeles, USA.
²⁶ Department of Neurology, University of California, San Francisco, USA.
²⁷ Department of Pathology, University of California, San Francisco, USA.
²⁸ Department of Radiology, University of Michigan, Ann Arbor, USA.
²⁹ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
³⁰ Alzheimer's Therapeutic Research Institute, University of Southern California, San Diego, USA.
³¹ Laboratory of Neuro Imaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Los Angeles, USA.
³² Department of Epidemiology, University of Washington, Seattle, USA.
³³ Department of Neurology, Washington University in St. Louis, St. Louis, USA.
³⁴ Medical & Scientific Relations Division, Alzheimer's Association, Chicago, USA.

Abstract

Introduction: The genetic basis of sporadic early-onset Alzheimer's disease (EOAD) remains largely unknown, prompting evaluation of late-onset Alzheimer's disease (LOAD) polygenic risk in EOAD.

Methods: A LOAD polygenic score (PGS) was calculated in the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) study and tested for associations with AD risk, cognitive performance, and imaging and fluid biomarkers.

Results: Though PGS was elevated in LOAD and EOAD, it was not a significant predictor of EOAD adjusting for APOE ε4 carrier status and was not associated with age of EOAD onset (p = 0.106) or with cognitive performance (p = 0.417). In LEADS, greater LOAD PGS was associated with differences in neuroimaging and fluid biomarkers, including elevated synaptosomal-associated protein 25 (SNAP-25) (p = 2.3 × 10^-5).

Discussion: While LOAD polygenic risk contributed minimally to EOAD onset and cognitive dysfunction, PGS association with fluid biomarkers in LEADS suggests a role for LOAD polygenic risk in EOAD pathophysiology.

Highlights: LOAD PGSs were elevated in both LOAD and EOAD compared to controls; however, LOAD PGS did not significantly predict EOAD risk, age at onset, or cognitive performance independent of APOE ε4 in the LEADS. Higher LOAD PGS was associated with lower amyloid PET Centiloids (less brain amyloid deposition) as well as lower CSF biomarker Aβ42 in LEADS (proxy marker suggesting higher brain amyloid deposition) in LEADS; these contradictory findings support the need for larger studies to further investigate whether LOAD PGS is associated with increased amyloid deposition in EOAD. Higher LOAD PGS was also associated with higher levels of CSF synaptosomal-associated protein 25 (SNAP-25), a key component of the SNARE complex, suggesting that LOAD genetic factors may contribute to dysregulation of synaptic transmission and/or pathological protein aggregation in EOAD.

Keywords: Alzheimer's disease; early onset; genetics; polygenic.

MeSH terms

Age of Onset
Aged
Aged, 80 and over
Alzheimer Disease* / cerebrospinal fluid
Alzheimer Disease* / diagnostic imaging
Alzheimer Disease* / genetics
Amyloid beta-Peptides / cerebrospinal fluid
Apolipoprotein E4 / genetics
Biomarkers / cerebrospinal fluid
Brain / diagnostic imaging
Cognitive Dysfunction / genetics
Female
Genetic Predisposition to Disease
Humans
Longitudinal Studies
Male
Middle Aged
Multifactorial Inheritance* / genetics
Neuroimaging
Risk Factors
Synaptosomal-Associated Protein 25 / cerebrospinal fluid

Substances

Biomarkers
Amyloid beta-Peptides
Apolipoprotein E4
Synaptosomal-Associated Protein 25

Abstract

MeSH terms

Substances

Grants and funding