An UNC5C Allele Predicts Cognitive Decline and Hippocampal Atrophy in Clinically Normal Older Adults

Article type: Research Article

Authors: Yang, Hyun-Sik^{a; b; c; d} | Chhatwal, Jasmeer P.^{a; c} | Xu, Jishu^d | White, Charles C.^d | Hanseeuw, Bernard^{a; c; e} | Rabin, Jennifer S.^{c; f} | Papp, Kathryn V.^{a; b; c} | Buckley, Rachel F.^{a; b; c; g; h} | Schultz, Aaron P.^{a; c; i} | Properzi, Michael J.^a | Gatchel, Jennifer R.^{c; f; j; k} | Amariglio, Rebecca E.^{a; b; c} | Donovan, Nancy J.^{b; c; f; l} | Mormino, Elizabeth C.^{a; c; m} | Hedden, Trey^{c; i} | Marshall, Gad A.^{a; b; c} | Rentz, Dorene M.^{a; b; c} | Johnson, Keith A.^{a; b; c; i} | De Jager, Philip L.^{d; n} | Sperling, Reisa A.^{a; b; c; *}

Affiliations: [a] Department of Neurology, Massachusetts General Hospital, Boston, MA, USA | [b] Department of Neurology, Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital, Boston, MA, USA | [c] Harvard Medical School, Boston, MA, USA | [d] Cell Circuits Program, Broad Institute of MIT and Harvard, Cambridge, MAs, USA | [e] Department of Neurology, Cliniques Universitaires Saint-Luc, Institute of Neurosciences, Université Catholique de Louvain, Brussels, Belgium | [f] Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA | [g] Florey Institutes of Neuroscience and Mental Health, Melbourne, VIC, Australia | [h] Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, VIC, Australia | [i] Department of Radiology, Massachusetts General Hospital, Boston, MA, USA | [j] Division of Geriatric Psychiatry, McLean Hospital, Belmont, MA, USA | [k] Gerontology Research Unit, Massachusetts General Hospital, Boston, MA, USA | [l] Department of Psychiatry, Brigham and Women’s Hospital, Boston, MA, USA | [m] Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA | [n] Department of Neurology, Center for Translational & Computational Neuroimmunology, Columbia University Medical Center, New York, NY, USA

Correspondence: [*] Correspondence to: Reisa A. Sperling, MD, Brigham and Women’s Hospital, 60 Fenwood Road, Boston, MA 02115, USA. Tel.: +1 617 525 8675; Fax: +1 617 264 5295; E-mail: [email protected].

Abstract: Background:The UNC5C rs3846455G allele has been linked to poor cognitive resilience against age-related neuropathologies, but this association remains to be replicated, and the allele’s effect on hippocampal neurodegeneration needs to be examined. Objective:To further validate the association between rs3846455G and faster cognitive decline, especially among cognitively normal older adults, and to assess whether rs3846455G predicts accelerated hippocampal volume loss in older adults. Methods:We assessed participants in the Harvard Aging Brain Study (HABS), a longitudinal cohort study of older adults who were clinically normal at baseline. To avoid bias from population admixture, analyses were limited to participants of European descent with longitudinal neuroimaging data (n = 174). Linear mixed effect models were used to examine the effect of rs3846455G on longitudinal change of the Preclinical Alzheimer Cognitive Composite (PACC) and MRI-measured bilateral hippocampal volume, adjusting for baseline amyloid-β (Aβ) measured by the cortical Pittsburgh Compound B PET distributed volume ratio. We also tested whether hippocampal atrophy mediates the association between rs3846455G and greater PACC decline through a mediation analysis. Results:rs3846455G was associated with greater PACC decline (β= –0.087/year, 95% CI –0.169 to –0.005, p = 0.039) after controlling for baseline Aβ. Further, rs3846455G predicted accelerated hippocampal atrophy after controlling for baseline Aβ (β= –57.3 mm3/year, 95% CI –102.8 to –11.9, p = 0.014). The association between rs3846455G and greater PACC decline was partially mediated by accelerated hippocampal atrophy (mediated effect (relative scale) = –0.014, 95% CI –0.032 to –6.0×10–4, p = 0.039). Conclusion:UNC5C rs3846455G predicts greater cognitive decline and accelerated hippocampal atrophy in clinically normal older adults.

Keywords: Alzheimer’s disease, amyloid plaques, cognitive reserve, genetics, hippocampus, neuroimaging

DOI: 10.3233/JAD-180788

Journal: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1161-1170, 2019