Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease

INTRODUCTION Identifying CSF-based biomarkers for the β-amyloidosis that initiates Alzheimer's disease (AD) could provide inexpensive and dynamic tests to distinguish AD from normal aging and predict future cognitive decline. METHODS We developed immunoassays specifically detecting all C-terminal variants of secreted amyloid β-protein and identified a novel biomarker, the Aβ 37/42 ratio, that outperforms the canonical Aβ42/40 ratio as a means to evaluate the γ-secretase activity and brain Aβ accumulation. RESULTS We show that Aβ 37/42 can distinguish physiological and pathological status in (1) presenilin-1 mutant vs wild-type cultured cells, (2) AD vs control brain tissue, and (3) AD versus cognitively normal (CN) subjects in CSF, where 37/42 (AUC 0.9622) outperformed 42/40 (AUC 0.8651) in distinguishing CN from AD. DISCUSSION We conclude that the Aβ 37/42 ratio sensitively detects presenilin/γ-secretase dysfunction and better distinguishes CN from AD than Aβ42/40 in CSF. Measuring this novel ratio alongside promising phospho-tau analytes may provide highly discriminatory fluid biomarkers for AD.

[1]  V. Menon,et al.  Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors , 2021, Neuron.

[2]  D. Selkoe,et al.  Discovery of aryl aminothiazole γ-secretase modulators with novel effects on amyloid β-peptide production , 2021, bioRxiv.

[3]  D. Holtzman,et al.  A blood-based diagnostic test incorporating plasma Aβ42/40 ratio, ApoE proteotype, and age accurately identifies brain amyloid status: findings from a multi cohort validity analysis , 2021, Molecular Neurodegeneration.

[4]  D. Selkoe,et al.  Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides , 2021, The Journal of biological chemistry.

[5]  Toshiharu Suzuki,et al.  γ-Secretase activity is associated with Braak Senile Plaque stages. , 2020, The American journal of pathology.

[6]  M. Verbeek,et al.  Aβ43 in human Alzheimer’s disease: effects of active Aβ42 immunization , 2019, Acta Neuropathologica Communications.

[7]  K. Blennow,et al.  Performance of Fully Automated Plasma Assays as Screening Tests for Alzheimer Disease–Related β-Amyloid Status , 2019, JAMA neurology.

[8]  Yigong Shi,et al.  Recognition of the amyloid precursor protein by human γ-secretase , 2019, Science.

[9]  D. Selkoe,et al.  A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor , 2019, The Journal of cell biology.

[10]  John X. Morris,et al.  Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network , 2018, Alzheimer's Research & Therapy.

[11]  D. Borchelt,et al.  Short Aβ peptides attenuate Aβ42 toxicity in vivo , 2018, The Journal of experimental medicine.

[12]  K. Blennow,et al.  Low-dose γ-secretase inhibition increases secretion of Aβ peptides and intracellular oligomeric Aβ , 2017, Molecular and Cellular Neuroscience.

[13]  K. Blennow,et al.  Concordance Between Different Amyloid Immunoassays and Visual Amyloid Positron Emission Tomographic Assessment , 2017, JAMA neurology.

[14]  Y. Ihara,et al.  Distinct deposition of amyloid-β species in brains with Alzheimer’s disease pathology visualized with MALDI imaging mass spectrometry , 2017, Acta Neuropathologica Communications.

[15]  J. C. Love,et al.  Cell-type Dependent Alzheimer's Disease Phenotypes: Probing the Biology of Selective Neuronal Vulnerability , 2017, Alzheimer's & Dementia.

[16]  Yigong Shi,et al.  Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase , 2016, Proceedings of the National Academy of Sciences.

[17]  A. Paetau,et al.  Deposition of C-terminally truncated Aβ species Aβ37 and Aβ39 in Alzheimer’s disease and transgenic mouse models , 2016, Acta Neuropathologica Communications.

[18]  O. Hansson,et al.  Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography , 2016, Brain : a journal of neurology.

[19]  K. Blennow,et al.  CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios: better diagnostic markers of Alzheimer disease , 2016, Annals of clinical and translational neurology.

[20]  D. Selkoe,et al.  Physical and functional interaction between the α- and γ-secretases: A new model of regulated intramembrane proteolysis , 2015, The Journal of cell biology.

[21]  Nick C Fox,et al.  Qualitative changes in human γ-secretase underlie familial Alzheimer’s disease , 2015, The Journal of experimental medicine.

[22]  Sjors H. W. Scheres,et al.  An atomic structure of human γ-secretase , 2015, Nature.

[23]  K. Blennow,et al.  The amyloid-β degradation pattern in plasma—A possible tool for clinical trials in Alzheimer's disease , 2014, Neuroscience Letters.

[24]  T. Südhof,et al.  Rapid Single-Step Induction of Functional Neurons from Human Pluripotent Stem Cells , 2013, Neuron.

[25]  M. Takeda,et al.  γ-secretase modulators and presenilin 1 mutants act differently on presenilin/γ-secretase function to cleave Aβ42 and Aβ43. , 2013, Cell reports.

[26]  Scott M. Brue,et al.  Data resource profile: the Rochester Epidemiology Project (REP) medical records-linkage system. , 2012, International journal of epidemiology.

[27]  I. Tooyama,et al.  Age‐related modulation of γ‐secretase activity in non‐human primate brains , 2012, Journal of neurochemistry.

[28]  B. de Strooper,et al.  The mechanism of γ-Secretase dysfunction in familial Alzheimer disease , 2012, The EMBO journal.

[29]  M. Miyajima,et al.  Altered γ-secretase activity in mild cognitive impairment and Alzheimer's disease , 2012, EMBO molecular medicine.

[30]  Xulun Zhang,et al.  Modulation of γ-Secretase Reduces β-Amyloid Deposition in a Transgenic Mouse Model of Alzheimer's Disease , 2010, Neuron.

[31]  K. Blennow,et al.  Distinct cerebrospinal fluid amyloid β peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease , 2010, Molecular Neurodegeneration.

[32]  K. Blennow,et al.  Prediction of Alzheimer’s Disease Using a Cerebrospinal Fluid Pattern of C-Terminally Truncated β-Amyloid Peptides , 2008, Neurodegenerative Diseases.

[33]  V. Pankratz,et al.  The Mayo Clinic Study of Aging: Design and Sampling, Participation, Baseline Measures and Sample Characteristics , 2008, Neuroepidemiology.

[34]  Johannes Kornhuber,et al.  Blood‐based neurochemical diagnosis of vascular dementia: a pilot study , 2007, Journal of neurochemistry.

[35]  P. Lewczuk,et al.  Electrophoretic separation of amyloid β peptides in plasma , 2004 .

[36]  Michael S. Wolfe,et al.  γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[37]  J. Regula,et al.  Reconstitution of γ-secretase activity , 2003, Nature Cell Biology.

[38]  T. Iwatsubo,et al.  The role of presenilin cofactors in the γ-secretase complex , 2003, Nature.

[39]  J. Kornhuber,et al.  Highly conserved and disease‐specific patterns of carboxyterminally truncated Aβ peptides 1–37/38/39 in addition to 1–40/42 in Alzheimer's disease and in patients with chronic neuroinflammation , 2002, Journal of neurochemistry.

[40]  D. Selkoe,et al.  Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity , 1999, Nature.

[41]  D. Selkoe,et al.  Additive Effects of PS1 and APP Mutations on Secretion of the 42-Residue Amyloid β-Protein , 1998, Neurobiology of Disease.

[42]  Weiming Xia,et al.  Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice , 1997, Nature Medicine.

[43]  G. Schellenberg,et al.  Secreted amyloid β–protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease , 1996, Nature Medicine.

[44]  S. Prusiner,et al.  Formic acid pretreatment enhances immunostaining of cerebral and systemic amyloids. , 1987, Laboratory investigation; a journal of technical methods and pathology.