Interaction Between BDNF Val66Met and APOE4 on Biomarkers of Alzheimer’s Disease and Cognitive Decline

Article type: Research Article

Authors: Stonnington, Cynthia M.^* | Velgos, Stefanie N.^{b; c} | Chen, Yinghua^f | Syed, Sameena^{a; d; e} | Huentelman, Mattⁱ | Thiyyagura, Pradeep^f | Lee, Wendy^f | Richholt, Ryanⁱ | Caselli, Richard J.^g | Locke, Dona E.C.^a | Lu, Bai^h | Reiman, Eric M.^{f; i} | Su, Yi^f | Chen, Kewei^f

Affiliations: [a] Department of Psychiatry and Psychology, Mayo Clinic, Scottsdale, AZ, USA | [b] Mayo Clinic Graduate School of Biomedical Sciences, Clinical and Translational Science Track, Scottsdale, AZ, USA | [c] Translational neuroscience and Aging Laboratory, Mayo Clinic, Scottsdale, AZ, USA | [d] Midwestern University, Glendale, AZ, USA | [e] Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USA | [f] Banner Alzheimer’s Institute, Phoenix, AZ, USA | [g] Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA | [h] School of Pharmaceutical Sciences, Tsinghua University, Haidian Qu, Beijing Shi, China | [i] The Translational Genomics Research Institute, Phoenix, AZ, USA

Correspondence: [*] Correspondence to: Cynthia M. Stonnington, MD, Department of Psychiatry and Psychology, Mayo Clinic, 13400 E. Shea Boulevard, Scottsdale, AZ 85259, USA. Tel.: +1 480 301 4853; E-mail: [email protected].

Abstract: Background:Whether brain-derived neurotrophic factor (BDNF) Met carriage impacts the risk or progression of Alzheimer’s disease (AD) is unknown. Objective:To evaluate the interaction of BDNF Met and APOE4 carriage on cerebral metabolic rate for glucose (CMRgl), amyloid burden, hippocampus volume, and cognitive decline among cognitively unimpaired (CU) adults enrolled in the Arizona APOE cohort study. Methods:114 CU adults (mean age 56.85 years, 38% male) with longitudinal FDG PET, magnetic resonance imaging, and cognitive measures were BDNF and APOE genotyped. A subgroup of 58 individuals also had Pittsburgh B (PiB) PET imaging. We examined baseline CMRgl, PiB PET amyloid burden, CMRgl, and hippocampus volume change over time, and rate of change in cognition over an average of 15 years. Results:Among APOE4 carriers, BDNF Met carriers had significantly increased amyloid deposition and accelerated CMRgl decline in regions typically affected by AD, but without accompanying acceleration of cognitive decline or hippocampal volume changes and with higher baseline frontal CMRgl and slower frontal decline relative to the Val/Val group. The BDNF effects were not found among APOE4 non-carriers. Conclusion:Our preliminary studies suggest that there is a weak interaction between BDNF Met and APOE4 on amyloid-β plaque burden and longitudinal PET measurements of AD-related CMRgl decline in cognitively unimpaired late-middle-aged and older adults, but with no apparent effect upon rate of cognitive decline. We suggest that cognitive effects of BDNF variants may be mitigated by compensatory increases in frontal brain activity—findings that would need to be confirmed in larger studies.

Keywords: Amyloid, APOE4, BDNF, cognition, fluorodeoxyglucose F18, positron emission tomography

DOI: 10.3233/JAD-200132

Journal: Journal of Alzheimer's Disease, vol. 78, no. 2, pp. 721-734, 2020