Elizabeth A Boots1, Stephanie A Schultz1, Lindsay R Clark1, Annie M Racine1, Burcu F Darst1, Rebecca L Koscik1, Cynthia M Carlsson1, Catherine L Gallagher1, Kirk J Hogan1, Barbara B Bendlin1, Sanjay Asthana1, Mark A Sager1, Bruce P Hermann1, Bradley T Christian1, Dena B Dubal1, Corinne D Engelman1, Sterling C Johnson1, Ozioma C Okonkwo2. 1. From the Geriatric Research Education and Clinical Center (E.A.B., S.A.S., L.R.C., C.M.C., C.L.G., B.B.B., S.A., S.C.J., O.C.C.), William S. Middleton Memorial Veterans Hospital; Wisconsin Alzheimer's Disease Research Center (E.A.B., S.A.S., L.R.C., A.M.R., C.M.C., C.L.G., B.B.B., S.A., M.A.S., B.P.H., B.T.C., S.C.J., O.C.O.), Wisconsin Alzheimer's Institute (L.R.C., R.L.K., C.M.C., K.J.H., B.B.B., S.A., M.A.S., B.P.H., C.D.E., S.C.J., O.C.O.), Department of Population Health Sciences (B.F.D., C.D.E.), Department of Neurology (C.L.G., B.P.H.), Department of Anesthesiology (K.J.H.), Department of Radiology (M.A.S.), and Department of Medical Physics (B.T.C.), University of Wisconsin School of Medicine and Public Health, Madison; and Department of Neurology (D.B.D.), University of California, San Francisco. 2. From the Geriatric Research Education and Clinical Center (E.A.B., S.A.S., L.R.C., C.M.C., C.L.G., B.B.B., S.A., S.C.J., O.C.C.), William S. Middleton Memorial Veterans Hospital; Wisconsin Alzheimer's Disease Research Center (E.A.B., S.A.S., L.R.C., A.M.R., C.M.C., C.L.G., B.B.B., S.A., M.A.S., B.P.H., B.T.C., S.C.J., O.C.O.), Wisconsin Alzheimer's Institute (L.R.C., R.L.K., C.M.C., K.J.H., B.B.B., S.A., M.A.S., B.P.H., C.D.E., S.C.J., O.C.O.), Department of Population Health Sciences (B.F.D., C.D.E.), Department of Neurology (C.L.G., B.P.H.), Department of Anesthesiology (K.J.H.), Department of Radiology (M.A.S.), and Department of Medical Physics (B.T.C.), University of Wisconsin School of Medicine and Public Health, Madison; and Department of Neurology (D.B.D.), University of California, San Francisco. ozioma@medicine.wisc.edu.
Abstract
OBJECTIVE: To examine the influence of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on longitudinal cognitive trajectories in a large, cognitively healthy cohort enriched for Alzheimer disease (AD) risk and to understand whether β-amyloid (Aβ) burden plays a moderating role in this relationship. METHODS: One thousand twenty-three adults (baseline age 54.94 ± 6.41 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent BDNF genotyping and cognitive assessment at up to 5 time points (average follow-up 6.92 ± 3.22 years). A subset (n = 140) underwent 11C-Pittsburgh compound B (PiB) scanning. Covariate-adjusted mixed-effects regression models were used to elucidate the effect of BDNF on cognitive trajectories in 4 cognitive domains, including verbal learning and memory, speed and flexibility, working memory, and immediate memory. Secondary mixed-effects regression models were conducted to examine whether Aβ burden, indexed by composite PiB load, modified any observed BDNF-related cognitive trajectories. RESULTS: Compared to BDNF Val/Val homozygotes, Met carriers showed steeper decline in verbal learning and memory (p = 0.002) and speed and flexibility (p = 0.017). In addition, Aβ burden moderated the relationship between BDNF and verbal learning and memory such that Met carriers with greater Aβ burden showed even steeper cognitive decline (p = 0.033). CONCLUSIONS: In a middle-aged cohort with AD risk, carriage of the BDNF Met allele was associated with steeper decline in episodic memory and executive function. This decline was exacerbated by greater Aβ burden. These results suggest that the BDNF Val66Met polymorphism may play an important role in cognitive decline and could be considered as a target for novel AD therapeutics.
OBJECTIVE: To examine the influence of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on longitudinal cognitive trajectories in a large, cognitively healthy cohort enriched for Alzheimer disease (AD) risk and to understand whether β-amyloid (Aβ) burden plays a moderating role in this relationship. METHODS: One thousand twenty-three adults (baseline age 54.94 ± 6.41 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent BDNF genotyping and cognitive assessment at up to 5 time points (average follow-up 6.92 ± 3.22 years). A subset (n = 140) underwent 11C-Pittsburgh compound B (PiB) scanning. Covariate-adjusted mixed-effects regression models were used to elucidate the effect of BDNF on cognitive trajectories in 4 cognitive domains, including verbal learning and memory, speed and flexibility, working memory, and immediate memory. Secondary mixed-effects regression models were conducted to examine whether Aβ burden, indexed by composite PiB load, modified any observed BDNF-related cognitive trajectories. RESULTS: Compared to BDNF Val/Val homozygotes, Met carriers showed steeper decline in verbal learning and memory (p = 0.002) and speed and flexibility (p = 0.017). In addition, Aβ burden moderated the relationship between BDNF and verbal learning and memory such that Met carriers with greater Aβ burden showed even steeper cognitive decline (p = 0.033). CONCLUSIONS: In a middle-aged cohort with AD risk, carriage of the BDNF Met allele was associated with steeper decline in episodic memory and executive function. This decline was exacerbated by greater Aβ burden. These results suggest that the BDNF Val66Met polymorphism may play an important role in cognitive decline and could be considered as a target for novel AD therapeutics.
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