Genetic Determinants of Disease Progression in Alzheimer's Disease

Article type: Research Article

Authors: Wang, Xingbin^{a; b} | Lopez, Oscar L.^{c; d} | Sweet, Robert A.^{c; d; e; g} | Becker, James T.^{c; d} | DeKosky, Steven T.^f | Barmada, Mahmud M.^a | Demirci, F. Yesim^a | Kamboh, M. Ilyas^{a; d; e; *}

Affiliations: [a] Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA | [b] Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA | [c] Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA | [d] Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA, USA | [e] Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA | [f] Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA | [g] VISN 4 Mental Illness Research, Education and Clinical Center (MIRECC), VA Pittsburgh Healthcare System, Pittsburgh, PA, USA

Correspondence: [*] Correspondence to: Professor M. Ilyas Kamboh, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA. E-mail: kamboh@pitt.edu.

Abstract: There is a strong genetic basis for late-onset Alzheimer's disease (LOAD); thus far 22 genes/loci have been identified that affect the risk of LOAD. However, the relationships among the genetic variations at these loci and clinical progression of the disease have not been fully explored. In the present study, we examined the relationships of 22 known LOAD genes to the progression of AD in 680 AD patients recruited from the University of Pittsburgh Alzheimer's Disease Research Center. Patients were classified as “rapid progressors” if the Mini-Mental State Examination (MMSE) changed ≥3 points in 12 months and “slow progressors” if the MMSE changed ≤2 points. We also performed a genome-wide association study in this cohort in an effort to identify new loci for AD progression. Association analysis between single nucleotide polymorphisms (SNPs) and the progression status of the AD cases was performed using logistic regression model controlled for age, gender, dementia medication use, psychosis, and hypertension. While no significant association was observed with either APOE*4 (p = 0.94) or APOE*2 (p = 0.33) with AD progression, we found multiple nominally significant associations (p < 0.05) either within or adjacent to seven known LOAD genes (INPP5D, MEF2C, TREM2, EPHA1, PTK2B, FERMT2, and CASS4) that harbor both risk and protective SNPs. Genome-wide association analyses identified four suggestive loci (PAX3, CCRN4L, PIGQ, and ADAM19) at p < 1E-05. Our data suggest that short-term clinical disease progression in AD has a genetic basis. Better understanding of these genetic factors could help to improve clinical trial design and potentially affect the development of disease modifying therapies.

Keywords: Alzheimer's disease progression, genome-wide association studies, late-onset Alzheimer's disease, Mini-Mental State Examination

DOI: 10.3233/JAD-140729

Journal: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 649-655, 2015