title: Preclinical amyloid pathology biomarker positivity: effects on tau pathology and neurodegeneration.
abstract: Brain autopsy and biomarker studies indicate that the pathology of Alzheimer's disease (AD) is initiated at least 10-20 years before clinical symptoms. This provides a window of opportunity to initiate preventive treatment. However, this emphasizes the necessity for biomarkers that identify individuals at risk for developing AD later in life. In this cross-sectional study, originating from three epidemiologic studies in Sweden (n=1428), the objective was to examine whether amyloid pathology, as determined by low cerebrospinal fluid (CSF) concentration of the 42 amino acid form of β-amyloid (Aβ42), is associated with biomarker evidence of other pathological changes in cognitively healthy elderly. A total of 129 patients were included and CSF levels of Aβ42, total tau, tau phosphorylated at threonine 181 (p-tau), neurogranin, VILIP-1, VEGF, FABP3, Aβ40, neurofilament light, MBP, orexin A, BDNF and YKL-40 were measured. Among these healthy elderly, 35.6% (N=46) had CSF Aβ42 levels below 530 pg ml-1. These individuals displayed significantly higher CSF concentrations of t-tau (P<0.001), p-tau (181) (P<0.001), neurogranin (P=0.009) and FABP3 (P=0.044) compared with amyloid-negative individuals. Our study indicates that there is a subpopulation among healthy older individuals who have amyloid pathology along with signs of ongoing neuronal and synaptic degeneration, as well as tangle pathology. Previous studies have demonstrated that increase in CSF tau and p-tau is a specific sign of AD progression that occurs downstream of the deposition of Aβ. On the basis of this, our data suggest that these subjects are at risk for developing AD. We also confirm the association between APOE ɛ4 and amyloid pathology in healthy older individuals.
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, Centre for ageing and Health, AgeCap, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.|Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Disease Research, Neurogeriatrics Division, Karolinska Institutet, Novum, Stockholm, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Höglund
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, Centre for ageing and Health, AgeCap, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.|Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Kern
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, Centre for ageing and Health, AgeCap, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.|Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Zettergren
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, Centre for ageing and Health, AgeCap, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.|Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Börjesson-Hansson
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, Centre for ageing and Health, AgeCap, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.|Neuropsychiatric Epidemiology Unit, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, Centre for Ageing and Health, AgeCap, University of Gothenburg, Mölndal, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, Centre for ageing and Health, AgeCap, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.|Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
authors.forename: I
authors.initials: I
authors.lastname: Skoog
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, Centre for ageing and Health, AgeCap, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Blennow
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D053327:Apolipoprotein E4 / Q000235:genetics; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D019208:Brain-Derived Neurotrophic Factor / Q000134:cerebrospinal fluid; D000071451:Chitinase-3-Like Protein 1 / Q000134:cerebrospinal fluid; D003430:Cross-Sectional Studies; D000074026:Fatty Acid Binding Protein 3 / Q000134:cerebrospinal fluid; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D004676:Myelin Basic Protein / Q000134:cerebrospinal fluid; D051596:Neurocalcin / Q000134:cerebrospinal fluid; D016900:Neurofilament Proteins / Q000134:cerebrospinal fluid; D051579:Neurogranin / Q000134:cerebrospinal fluid; D000068797:Orexins / Q000134:cerebrospinal fluid; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D010750:Phosphoproteins / Q000134:cerebrospinal fluid; D013548:Sweden; D042461:Vascular Endothelial Growth Factor A / Q000134:cerebrospinal fluid; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; C493408:FABP3 protein, human; D000074026:Fatty Acid Binding Protein 3; C054369:MAPT protein, human; D004676:Myelin Basic Protein; D051596:Neurocalcin; D016900:Neurofilament Proteins; D000068797:Orexins; D010446:Peptide Fragments; D010750:Phosphoproteins; C467484:VEGFA protein, human; C496688:VSNL1 protein, human; D042461:Vascular Endothelial Growth Factor A; C075222:amyloid beta-protein (1-42); C044882:neurofilament protein L; D016875:tau Proteins; D051579:Neurogranin; C579455:BDNF protein, human