| Title: |
Towards cascading genetic risk in Alzheimer’s disease |
| Authors: |
Altmann, Andre; Aksman, Leon M; Oxtoby, Neil P; Young, Alexandra L; Weiner, Michael; Aisen, Paul; Petersen, Ronald; Jack, Clifford R; Jagust, William; Landau, Susan; Rivera-Mindt, Monica; Okonkwo, Ozioma; Shaw, Leslie M; Lee, Edward B; Toga, Arthur W; Beckett, Laurel; Harvey, Danielle; Green, Robert C; Saykin, Andrew J; Nho, Kwangsik; Perrin, Richard J; Tosun, Duygu; Sachdev, Pallavi; Montine, Tom; Conti, Cat; Weiner, Michael W; Nosheny, Rachel; Fockler, Juliet; Miller, Melanie J; Conti, Catherine; Kwang, Winnie; Jin, Chengshi; Diaz, Adam; Ashford, Miriam; Flenniken, Derek; Kormos, Adrienne; Rafii, Michael; Raman, Rema; Jimenez, Gustavo; Donohue, Michael; Salazar, Jennifer; Fidell, Andrea; Boatwright, Virginia; Robison, Justin; Zimmerman, Caileigh; Cabrera, Yuliana; Walter, Sarah; Clanton, Taylor; Shaffer, Elizabeth; Webb, Caitlin; Hergesheimer, Lindsey; Smith, Stephanie; Ogwang, Sheila; Adegoke, Olusegun; Mahboubi, Payam; Pizzola, Jeremy; Jenkins, Cecily; Saito, Naomi; Hussen, Kedir Adem; Amaza, Hannatu; Thao, Mai Seng; Parkins, Shaniya; Ayo, Omobolanle; Glittenberg, Matt; Hoang, Isabella; Germano, Kaori Kubo; Strong, Joe; Weisensel, Trinity; Magana, Fabiola; Thomas, Lisa; Guzman, Vanessa; Ajayi, Adeyinka; Benedetto, Joseph Di; Talavera, Sandra; Felmlee, Joel; Fox, Nick C; Thompson, Paul; DeCarli, Charles; Forghanian-Arani, Arvin; Borowski, Bret; Reyes, Calvin; Hedberg, Caitie; Ward, Chad; Schwarz, Christopher; Reyes, Denise; Gunter, Jeff; Moore-Weiss, John |
| Source: |
Brain, vol 147, iss 8 |
| Publisher Information: |
eScholarship, University of California |
| Publication Year: |
2024 |
| Collection: |
University of California: eScholarship |
| Subject Terms: |
4202 Epidemiology (for-2020); 42 Health Sciences (for-2020); Aging (rcdc); Alzheimer's Disease (rcdc); Neurodegenerative (rcdc); Acquired Cognitive Impairment (rcdc); Neurosciences (rcdc); Human Genome (rcdc); Brain Disorders (rcdc); Dementia (rcdc); Genetics (rcdc); Prevention (rcdc); Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) (rcdc); 2.1 Biological and endogenous factors (hrcs-rac); Neurological (hrcs-hc); Humans (mesh); Alzheimer Disease (mesh); Male (mesh); Female (mesh); Aged (mesh); tau Proteins (mesh); Genetic Predisposition to Disease (mesh); Disease Progression (mesh); Biomarkers (mesh); Aged; 80 and over (mesh); Apolipoproteins E (mesh); Positron-Emission Tomography (mesh); Genome-Wide Association Study (mesh); Multifactorial Inheritance (mesh) |
| Time: |
2680 - 2690 |
| Description: |
Alzheimer's disease typically progresses in stages, which have been defined by the presence of disease-specific biomarkers: amyloid (A), tau (T) and neurodegeneration (N). This progression of biomarkers has been condensed into the ATN framework, in which each of the biomarkers can be either positive (+) or negative (-). Over the past decades, genome-wide association studies have implicated ∼90 different loci involved with the development of late-onset Alzheimer's disease. Here, we investigate whether genetic risk for Alzheimer's disease contributes equally to the progression in different disease stages or whether it exhibits a stage-dependent effect. Amyloid (A) and tau (T) status was defined using a combination of available PET and CSF biomarkers in the Alzheimer's Disease Neuroimaging Initiative cohort. In 312 participants with biomarker-confirmed A-T- status, we used Cox proportional hazards models to estimate the contribution of APOE and polygenic risk scores (beyond APOE) to convert to A+T- status (65 conversions). Furthermore, we repeated the analysis in 290 participants with A+T- status and investigated the genetic contribution to conversion to A+T+ (45 conversions). Both survival analyses were adjusted for age, sex and years of education. For progression from A-T- to A+T-, APOE-e4 burden showed a significant effect [hazard ratio (HR) = 2.88; 95% confidence interval (CI): 1.70-4.89; P < 0.001], whereas polygenic risk did not (HR = 1.09; 95% CI: 0.84-1.42; P = 0.53). Conversely, for the transition from A+T- to A+T+, the contribution of APOE-e4 burden was reduced (HR = 1.62; 95% CI: 1.05-2.51; P = 0.031), whereas the polygenic risk showed an increased contribution (HR = 1.73; 95% CI: 1.27-2.36; P < 0.001). The marginal APOE effect was driven by e4 homozygotes (HR = 2.58; 95% CI: 1.05-6.35; P = 0.039) as opposed to e4 heterozygotes (HR = 1.74; 95% CI: 0.87-3.49; P = 0.12). The genetic risk for late-onset Alzheimer's disease unfolds in a disease stage-dependent fashion. A better understanding of the ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
qt6ht7760t; https://escholarship.org/uc/item/6ht7760t; https://escholarship.org/content/qt6ht7760t/qt6ht7760t.pdf |
| DOI: |
10.1093/brain/awae176 |
| Availability: |
https://escholarship.org/uc/item/6ht7760t; https://escholarship.org/content/qt6ht7760t/qt6ht7760t.pdf; https://doi.org/10.1093/brain/awae176 |
| Rights: |
CC-BY |
| Accession Number: |
edsbas.9F8BCF36 |
| Database: |
BASE |