Towards cascading genetic risk in Alzheimer’s disease
André Altmann, Leon Aksman, Neil P. Oxtoby, Alexandra L. Young, ADNI, Michael W. Weiner, Paul Aisen, Ronald Petersen, Michael Weiner, Paul Aisen, Ronald Petersen, Clifford R Jack, William Jagust, Susan Landau, Mónica Rivera Mindt, Ozioma C. Okonkwo, Leslie M Shaw, Edward B Lee, Arthur W Toga, Laurel Beckett, Danielle Harvey, Robert C Green, Andrew J. Saykin, Kwangsik Nho, Richard J Perrin, Duygu Tosun, Pallavi Sachdev, Robert C Green, Tom Montine, Cat Conti, Michael W. Weiner, Rachel L. Nosheny, Juliet Fockler, Melanie J. Miller, Catherine Conti, Winnie Kwang, Chengshi Jin, Adam Diaz, Miriam T. Ashford, Derek Flenniken, Adrienne Kormos, Ronald Petersen, Paul Aisen, Michael Rafii, Rema Raman, Gustavo Jimenez‐Maggiora, Michael Donohue, Jennifer Salazar, Andrea Fidell, Virginia Boatwright, Justin Robison, Caileigh Zimmerman, Yuliana Cabrera, Sarah Walter, Taylor Clanton, Elizabeth Shaffer, Caitlin Webb, Lindsey Hergesheimer, Stephanie Smith, Sheila Ogwang, Olusegun Adegoke, Payam Mahboubi, Jeremy Pizzola, Cecily Jenkins, Laurel Beckett, Danielle Harvey, Michael Donohue, Naomi Saito, Adam Diaz, Kedir Adem Hussen, Ozioma C. Okonkwo, Mónica Rivera Mindt, Hannatu Amaza, Mai Seng Thao, Shaniya Parkins, Omobolanle Ayo, Matt Glittenberg, Isabella Hoang, Kaori Kubo Germano, Joe Strong, Trinity Weisensel, Fabiola Magana, Lisa Thomas, Vanessa Guzmán, Adeyinka Ajayi, Joseph Di Benedetto, Sandra Talavera, Clifford R Jack, Joel P. Felmlee, Nick C. Fox, Paul Thompson, Charles DeCarli, Arvin Forghanian-Arani, Bret Borowski, Calvin Reyes, Caitie Hedberg, Chad Ward, Christopher G. Schwarz, Denise Reyes, Jeff Gunter
Abstract
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 interplay between disease stage and genetic risk can lead to a more mechanistic understanding of the transition between ATN stages and a better understanding of the molecular processes leading to Alzheimer's disease, in addition to opening therapeutic windows for targeted interventions.