Kaitlin B Casaletto1, Fanny M Elahi2, Brianne M Bettcher2, John Neuhaus2, Barbara B Bendlin2, Sanjay Asthana2, Sterling C Johnson2, Kristine Yaffe2, Cynthia Carlsson2, Kaj Blennow2, Henrik Zetterberg2, Joel H Kramer2. 1. From the Memory and Aging Center (K.B.C., F.M.E., J.N., K.Y., J.H.K.), Department of Neurology, University of California, San Francisco; Denver Anschutz Medical Center (B.M.B., C.C.), University of Colorado, Aurora; Wisconsin Alzheimer's Disease Research Center (B.B.B., S.C.J.) and Department of Medicine (S.A.), University of Wisconsin School of Medicine and Public Health; School of Medicine and Public Health (B.B.B., S.C.J.), Wisconsin Alzheimer's Institute; Geriatric Research Education and Clinical Center (S.C.J., C.C.), William S. Middleton Memorial Veterans Hospital, Madison, WI; San Francisco Veterans Affairs Hospital (K.Y.), CA; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology (K.B., H.Z.), and Clinical Neurochemistry Laboratory (H.Z.), University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden; and Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, Queen Square, London, UK. Kaitlin.casaletto@ucsf.edu. 2. From the Memory and Aging Center (K.B.C., F.M.E., J.N., K.Y., J.H.K.), Department of Neurology, University of California, San Francisco; Denver Anschutz Medical Center (B.M.B., C.C.), University of Colorado, Aurora; Wisconsin Alzheimer's Disease Research Center (B.B.B., S.C.J.) and Department of Medicine (S.A.), University of Wisconsin School of Medicine and Public Health; School of Medicine and Public Health (B.B.B., S.C.J.), Wisconsin Alzheimer's Institute; Geriatric Research Education and Clinical Center (S.C.J., C.C.), William S. Middleton Memorial Veterans Hospital, Madison, WI; San Francisco Veterans Affairs Hospital (K.Y.), CA; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology (K.B., H.Z.), and Clinical Neurochemistry Laboratory (H.Z.), University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden; and Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, Queen Square, London, UK.
Abstract
OBJECTIVE: To determine the association between synaptic functioning as measured via neurogranin in CSF and cognition relative to established Alzheimer disease (AD) biomarkers in neurologically healthy older adults. METHODS: We analyzed CSF concentrations of neurogranin, β-amyloid (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau) among 132 neurologically normal older adults (mean 64.5, range 55-85), along with bilateral hippocampal volumes and a measure of episodic memory (Auditory Verbal Learning Test, delayed recall). Univariable analyses examined the relationship between neurogranin and the other AD-related biomarkers. Multivariable regression models examined the relationship between neurogranin and delayed recall, adjusting for age and sex, and interaction terms (neurogranin × AD biomarkers). RESULTS: Higher neurogranin concentrations were associated with older age (ρ = 0.20, p = 0.02), lower levels of p-tau and t-tau, and smaller hippocampal volumes (p < 0.03), but not with CSF Aβ42 (p = 0.18). In addition, CSF neurogranin demonstrated a significant relationship with memory performance independent of the AD-related biomarkers; individuals with the lowest CSF neurogranin concentrations performed better on delayed recall than those with medium or high CSF neurogranin concentrations (p < 0.01). Notably, CSF p-tau, t-tau, and Aβ42 and hippocampal volumes were not significantly associated with delayed recall scores (p > 0.40), and did not interact with neurogranin to predict memory (p > 0.10). CONCLUSIONS: Synaptic dysfunction (assessed via neurogranin) may be an early pathologic process in age-related neurodegeneration, and a sensitive marker of age-related cognitive abilities, potentially preceding or even acting independently from AD pathogenesis. Synaptic functioning may be a useful early marker of cognitive aging and possibly a target for future brain aging interventions.
OBJECTIVE: To determine the association between synaptic functioning as measured via neurogranin in CSF and cognition relative to established Alzheimer disease (AD) biomarkers in neurologically healthy older adults. METHODS: We analyzed CSF concentrations of neurogranin, β-amyloid (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau) among 132 neurologically normal older adults (mean 64.5, range 55-85), along with bilateral hippocampal volumes and a measure of episodic memory (Auditory Verbal Learning Test, delayed recall). Univariable analyses examined the relationship between neurogranin and the other AD-related biomarkers. Multivariable regression models examined the relationship between neurogranin and delayed recall, adjusting for age and sex, and interaction terms (neurogranin × AD biomarkers). RESULTS: Higher neurogranin concentrations were associated with older age (ρ = 0.20, p = 0.02), lower levels of p-tau and t-tau, and smaller hippocampal volumes (p < 0.03), but not with CSF Aβ42 (p = 0.18). In addition, CSF neurogranin demonstrated a significant relationship with memory performance independent of the AD-related biomarkers; individuals with the lowest CSF neurogranin concentrations performed better on delayed recall than those with medium or high CSF neurogranin concentrations (p < 0.01). Notably, CSF p-tau, t-tau, and Aβ42 and hippocampal volumes were not significantly associated with delayed recall scores (p > 0.40), and did not interact with neurogranin to predict memory (p > 0.10). CONCLUSIONS: Synaptic dysfunction (assessed via neurogranin) may be an early pathologic process in age-related neurodegeneration, and a sensitive marker of age-related cognitive abilities, potentially preceding or even acting independently from AD pathogenesis. Synaptic functioning may be a useful early marker of cognitive aging and possibly a target for future brain aging interventions.
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