Assessment of the Genetic Architecture of Alzheimer’s Disease Risk in Rate of Memory Decline

Article type: Research Article

Authors: Del-Aguila, Jorge L.^{a; b} | Fernández, Maria Victoria^{a; b} | Schindler, Suzanne^{d; e} | Ibanez, Laura^{a; b} | Deming, Yuetiva^{a; b} | Ma, Shengmei^{a; b} | Saef, Ben^{a; b} | Black, Kathleen^{a; b} | Budde, John^{a; b} | Norton, Joanne^{a; b} | Chasse, Rachel^{a; b} | Alzheimer’s Disease Neuroimaging Initiative (ADNI)¹ | Harari, Oscar^a | Goate, Alison^c | Xiong, Chengjie^d | Morris, John C.^{d; e} | Cruchaga, Carlos^{a; b; d; *}

Affiliations: [a] Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA | [b] Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA | [c] Mount Sinai School of Medicine, New York, NY, USA | [d] Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA | [e] Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA

Correspondence: [*] Correspondence to: Carlos Cruchaga, PhD, Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO 63110, USA. Tel.: +1 314 286 0546; Fax: +1 314 362 2244; E-mail: ccruchaga@wustl.edu.

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

Abstract: Many genetic studies for Alzheimer’s disease (AD) have been focused on the identification of common genetic variants associated with AD risk and not on other aspects of the disease, such as age at onset or rate of dementia progression. There are multiple approaches to untangling the genetic architecture of these phenotypes. We hypothesized that the genetic architecture of rate of progression is different than the risk for developing AD dementia. To test this hypothesis, we used longitudinal clinical data from ADNI and the Knight-ADRC at Washington University, and we calculated PRS (polygenic risk score) based on the IGAP study to compare the genetic architecture of AD risk and dementia progression. Dementia progression was measured by the change of Clinical Dementia Rating Sum of Boxes (CDR)-SB per year. Out of the 21 loci for AD risk, no association with the rate of dementia progression was found. The PRS rate was significantly associated with the rate of dementia progression (β= 0.146, p = 0.03). In the case of rare variants, TREM2 (β= 0.309, p = 0.02) was also associated with the rate of dementia progression. TREM2 variant carriers showed a 23% faster rate of dementia compared with non-variant carriers. In conclusion, our results indicate that the recently identified common and rare variants for AD susceptibility have a limited impact on the rate of dementia progression in AD patients.

Keywords: Alzheimer’s disease risk, Clinical Dementia Rating sum of boxes, International Genomics of Alzheimer’s Project (IGAP), polygenic risk score, progression

DOI: 10.3233/JAD-170834

Journal: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 745-756, 2018