Stephanie A Schultz1, Elizabeth A Boots1, Burcu F Darst1, Henrik Zetterberg1, Kaj Blennow1, Dorothy F Edwards1, Rebecca L Koscik1, Cynthia M Carlsson1, Catherine L Gallagher1, Barbara B Bendlin1, Sanjay Asthana1, Mark A Sager1, Kirk J Hogan1, Bruce P Hermann1, Dane B Cook1, Sterling C Johnson1, Corinne D Engelman1, Ozioma C Okonkwo2. 1. From the Geriatric Research Education and Clinical Center (S.A.S., E.A.B., C.M.C., C.L.G., B.B.B., S.A., S.C.J., O.C.O.) and Research Service (D.B.C.), William S. Middleton Memorial VA Hospital, Madison, WI; Wisconsin Alzheimer's Disease Research Center (S.A.S., E.A.B., D.F.E., R.L.K., C.M.C., B.B.B., S.A., M.A.S., B.P.H., S.C.J., C.D.E., O.C.O.), Madison; Departments of Population Health Sciences (B.F.D., C.D.E.), Kinesiology (D.F.E., D.B.C.), Neurology (C.L.G.), and Anesthesiology (K.J.H.), University of Wisconsin School of Medicine and Public Health, Madison; Clinical Neurochemistry Laboratory (H.Z., K.B.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, Queen Square, London, UK; and Wisconsin Alzheimer's Institute (D.F.E., C.M.C., C.L.G., B.B.B., S.A., M.A.S., K.J.H., B.P.H., S.C.J., C.D.E., O.C.O.), Madison. 2. From the Geriatric Research Education and Clinical Center (S.A.S., E.A.B., C.M.C., C.L.G., B.B.B., S.A., S.C.J., O.C.O.) and Research Service (D.B.C.), William S. Middleton Memorial VA Hospital, Madison, WI; Wisconsin Alzheimer's Disease Research Center (S.A.S., E.A.B., D.F.E., R.L.K., C.M.C., B.B.B., S.A., M.A.S., B.P.H., S.C.J., C.D.E., O.C.O.), Madison; Departments of Population Health Sciences (B.F.D., C.D.E.), Kinesiology (D.F.E., D.B.C.), Neurology (C.L.G.), and Anesthesiology (K.J.H.), University of Wisconsin School of Medicine and Public Health, Madison; Clinical Neurochemistry Laboratory (H.Z., K.B.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, Queen Square, London, UK; and Wisconsin Alzheimer's Institute (D.F.E., C.M.C., C.L.G., B.B.B., S.A., M.A.S., K.J.H., B.P.H., S.C.J., C.D.E., O.C.O.), Madison. ozioma@medicine.wisc.edu.
Abstract
OBJECTIVE: To examine whether a polygenic risk score (PRS) derived from APOE4, CLU, and ABCA7 is associated with CSF biomarkers of Alzheimer disease (AD) pathology and whether higher cardiorespiratory fitness (CRF) modifies the association between the PRS and CSF biomarkers. METHODS: Ninety-five individuals from the Wisconsin Registry for Alzheimer's Prevention were included in these cross-sectional analyses. They were genotyped for APOE4, CLU, and ABCA7, from which a PRS was calculated for each participant. The participants underwent lumbar puncture for CSF collection. β-Amyloid 42 (Aβ42), Aβ40, total tau (t-tau), and phosphorylated tau (p-tau) were quantified by immunoassays, and Aβ42/Aβ40 and tau/Aβ42 ratios were computed. CRF was estimated from a validated equation incorporating sex, age, body mass index, resting heart rate, and self-reported physical activity. Covariate-adjusted regression analyses were used to test for associations between the PRS and CSF biomarkers. In addition, by including a PRS×CRF term in the models, we examined whether these associations were modified by CRF. RESULTS: A higher PRS was associated with lower Aβ42/Aβ40 (p < 0.001), higher t-tau/Aβ42 (p = 0.012), and higher p-tau/Aβ42 (p = 0.040). Furthermore, we observed PRS × CRF interactions for Aβ42/Aβ40 (p = 0.003), t-tau/Aβ42 (p = 0.003), and p-tau/Aβ42 (p = 0.001). Specifically, the association between the PRS and these CSF biomarkers was diminished in those with higher CRF. CONCLUSIONS: In a late-middle-aged cohort, CRF attenuates the adverse influence of genetic vulnerability on CSF biomarkers. These findings support the notion that increased cardiorespiratory fitness may be beneficial to those at increased genetic risk for AD.
OBJECTIVE: To examine whether a polygenic risk score (PRS) derived from APOE4, CLU, and ABCA7 is associated with CSF biomarkers of Alzheimer disease (AD) pathology and whether higher cardiorespiratory fitness (CRF) modifies the association between the PRS and CSF biomarkers. METHODS: Ninety-five individuals from the Wisconsin Registry for Alzheimer's Prevention were included in these cross-sectional analyses. They were genotyped for APOE4, CLU, and ABCA7, from which a PRS was calculated for each participant. The participants underwent lumbar puncture for CSF collection. β-Amyloid 42 (Aβ42), Aβ40, total tau (t-tau), and phosphorylated tau (p-tau) were quantified by immunoassays, and Aβ42/Aβ40 and tau/Aβ42 ratios were computed. CRF was estimated from a validated equation incorporating sex, age, body mass index, resting heart rate, and self-reported physical activity. Covariate-adjusted regression analyses were used to test for associations between the PRS and CSF biomarkers. In addition, by including a PRS×CRF term in the models, we examined whether these associations were modified by CRF. RESULTS: A higher PRS was associated with lower Aβ42/Aβ40 (p < 0.001), higher t-tau/Aβ42 (p = 0.012), and higher p-tau/Aβ42 (p = 0.040). Furthermore, we observed PRS × CRF interactions for Aβ42/Aβ40 (p = 0.003), t-tau/Aβ42 (p = 0.003), and p-tau/Aβ42 (p = 0.001). Specifically, the association between the PRS and these CSF biomarkers was diminished in those with higher CRF. CONCLUSIONS: In a late-middle-aged cohort, CRF attenuates the adverse influence of genetic vulnerability on CSF biomarkers. These findings support the notion that increased cardiorespiratory fitness may be beneficial to those at increased genetic risk for AD.
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