Increased levels of plasma p3-alcα35, a major fragment of Alcadeinα by γ-secretase cleavage, in Alzheimer's disease

J Alzheimers Dis. 2014;39(4):861-70. doi: 10.3233/JAD-131610.


p3-Alcα is a metabolic fragment of Alcadeinα (Alcα). Similar to the generation of the p3 fragment from amyloid-β protein precursor (AβPP) processing, Alcα is cleaved by α- and γ-secretases, leading to the secretion of p3-Alcα peptides into cerebrospinal fluid (CSF). p3-Alcα is also detected in the plasma, similar to amyloid-β (Aβ), which is a metabolic fragment of AβPP cleaved by amyloidogenic β- and γ-secretases. Because p3-Alcα is a non-aggregatable and stable peptide, unlike aggregatable Aβ and metabolically labile p3 of AβPP, the changes of p3-Alcα in quality and/or quantity in CSF and plasma are expected to be a marker for assessing alteration of substrate cleavage by γ-secretase, such as Aβ generation from AβPP. The present study describes a sandwich enzyme-linked immunosorbent assay for quantifying levels of p3-Alcα35, the major form of the p3-Alcα species, and examines levels of p3-Alcα35 in the plasma of three independent Japanese cohorts. In two of the three cohorts, the p3-Alcα35 levels were significantly increased with a concomitant decrease in the Mini-Mental State Examination score, or in clinically diagnosed Alzheimer's disease (AD) patients, when compared with age-matched non-demented subjects. The values were significantly lower in AD subjects who were administered donepezil, when compared to AD subjects without donepezil treatment. The increase in plasma p3-Alcα35 levels may indicate an endophenotype in subjects in whom AD is due to a progressing cognitive impairment in subjects with a γ-secretase malfunction, or a disorder of the clearance of peptides.

Keywords: Alzheimer's disease; alcadein; diagnosis; donepezil; p3-Alc; plasma biomarker; γ-secretase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / blood*
  • Alzheimer Disease / diagnosis*
  • Alzheimer Disease / drug therapy
  • Amyloid Precursor Protein Secretases / blood*
  • Amyloid Precursor Protein Secretases / metabolism
  • Biomarkers / blood
  • Calcium-Binding Proteins / biosynthesis
  • Calcium-Binding Proteins / blood*
  • Calcium-Binding Proteins / metabolism
  • Cognition Disorders / blood
  • Cognition Disorders / diagnosis
  • Cognition Disorders / drug therapy
  • Cohort Studies
  • Disease Progression*
  • Donepezil
  • Endophenotypes / blood
  • Female
  • Humans
  • Indans / therapeutic use
  • Male
  • Nootropic Agents / therapeutic use
  • Peptide Fragments / biosynthesis*
  • Peptide Fragments / blood*
  • Peptide Fragments / metabolism
  • Piperidines / therapeutic use


  • Biomarkers
  • CLSTN1 protein, human
  • Calcium-Binding Proteins
  • Indans
  • Nootropic Agents
  • Peptide Fragments
  • Piperidines
  • Donepezil
  • Amyloid Precursor Protein Secretases