Andrew P Merluzzi1, Cynthia M Carlsson2, Sterling C Johnson2, Suzanne E Schindler2, Sanjay Asthana2, Kaj Blennow2, Henrik Zetterberg2, Barbara B Bendlin2. 1. From the Department of Medicine (A.P.M., C.M.C., S.C.J., S.A., B.B.B.), Wisconsin Alzheimer's Disease Research Center, and Neuroscience and Public Policy Program (A.P.M.), University of Wisconsin; Geriatric Research Education and Clinical Center (C.M.C., S.C.J., S.A.), William S. Middleton Memorial Veteran's Hospital; Wisconsin Alzheimer's Institute (S.C.J.), Madison; Department of Neurology (S.E.S.), Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO; Department of Psychiatry and Neurochemistry (K.B., H.Z.), Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg; Clinical Neurochemistry Laboratory (K.B., H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; Institute of Neurology (H.Z.), University College London, Queen Square; and UK Dementia Research Institute (H.Z.), London. andrewmerluzzi@gmail.com. 2. From the Department of Medicine (A.P.M., C.M.C., S.C.J., S.A., B.B.B.), Wisconsin Alzheimer's Disease Research Center, and Neuroscience and Public Policy Program (A.P.M.), University of Wisconsin; Geriatric Research Education and Clinical Center (C.M.C., S.C.J., S.A.), William S. Middleton Memorial Veteran's Hospital; Wisconsin Alzheimer's Institute (S.C.J.), Madison; Department of Neurology (S.E.S.), Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO; Department of Psychiatry and Neurochemistry (K.B., H.Z.), Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg; Clinical Neurochemistry Laboratory (K.B., H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; Institute of Neurology (H.Z.), University College London, Queen Square; and UK Dementia Research Institute (H.Z.), London.
Abstract
OBJECTIVE: To test the hypothesis that cognitively unimpaired individuals with Alzheimer disease (AD) neuropathology differ from individuals with AD dementia on biomarkers of neurodegeneration, synaptic dysfunction, and glial activation. METHODS: In a cross-sectional study, adult participants >70 years old (n = 79, age 77.1 ± 5.3 years) underwent comprehensive cognitive evaluation and CSF collection, which was assayed for markers of amyloid, phosphorylated tau (p-tau), neurodegeneration (neurofilament light protein [NFL] and total tau), synaptic dysfunction (neurogranin), and glial activation (chitinase-3-like protein 1 [YKL-40]). Participants were divided into 3 groups based on diagnosis and p-tau/β-amyloid42 (Aβ42): those with low p-tau/Aβ42 and unimpaired cognition were classified as controls (n = 25); those with high p-tau/Aβ42 diagnosed with AD-dementia or AD-mild cognitive impairment were classified as AD-Dementia (n = 40); and those with high p-tau/Aβ42 but unimpaired cognition were classified as mismatches (n = 14). A similar, secondary analysis was performed with no age exclusion criteria (n = 411). RESULTS: In both the primary and secondary analyses, biomarker levels between groups were compared with the use of analysis of covariance while controlling for age and demographic variables. Despite p-tau/Aβ42 and Aβ42/Aβ40 levels comparable to those of the AD-Dementia group, mismatches had significantly lower levels of NFL and total tau. While not significantly lower than the AD-Dementia group on YKL-40 and neurogranin, mismatches were also not significantly different from controls. CONCLUSIONS: These results provide evidence that, in the absence of significant neurodegenerative processes, individuals who harbor AD neuropathology may remain cognitively unimpaired. This finding provides insight into the biological processes phenotypic of dementia and supports monitoring multiple biomarkers in individuals positive for AD neuropathology.
OBJECTIVE: To test the hypothesis that cognitively unimpaired individuals with Alzheimer disease (AD) neuropathology differ from individuals with AD dementia on biomarkers of neurodegeneration, synaptic dysfunction, and glial activation. METHODS: In a cross-sectional study, adult participants >70 years old (n = 79, age 77.1 ± 5.3 years) underwent comprehensive cognitive evaluation and CSF collection, which was assayed for markers of amyloid, phosphorylated tau (p-tau), neurodegeneration (neurofilament light protein [NFL] and total tau), synaptic dysfunction (neurogranin), and glial activation (chitinase-3-like protein 1 [YKL-40]). Participants were divided into 3 groups based on diagnosis and p-tau/β-amyloid42 (Aβ42): those with low p-tau/Aβ42 and unimpaired cognition were classified as controls (n = 25); those with high p-tau/Aβ42 diagnosed with AD-dementia or AD-mild cognitive impairment were classified as AD-Dementia (n = 40); and those with high p-tau/Aβ42 but unimpaired cognition were classified as mismatches (n = 14). A similar, secondary analysis was performed with no age exclusion criteria (n = 411). RESULTS: In both the primary and secondary analyses, biomarker levels between groups were compared with the use of analysis of covariance while controlling for age and demographic variables. Despite p-tau/Aβ42 and Aβ42/Aβ40 levels comparable to those of the AD-Dementia group, mismatches had significantly lower levels of NFL and total tau. While not significantly lower than the AD-Dementia group on YKL-40 and neurogranin, mismatches were also not significantly different from controls. CONCLUSIONS: These results provide evidence that, in the absence of significant neurodegenerative processes, individuals who harbor AD neuropathology may remain cognitively unimpaired. This finding provides insight into the biological processes phenotypic of dementia and supports monitoring multiple biomarkers in individuals positive for AD neuropathology.
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