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Preclinical effects of APOE epsilon 4 on cerebrospinal fluid A beta 42 concentrations

Journal article
Authors Ronald Lautner
P. S. Insel
Tobias Skillbäck
Bob Olsson
Mikael Landén
G. B. Frisoni
S. K. Herukka
H. Hampel
Anders Wallin
L. Minthon
O. Hansson
Kaj Blennow
N. Mattsson
Henrik Zetterberg
Published in Alzheimers Research & Therapy
Volume 9
ISSN 1758-9193
Publication year 2017
Published at Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Language en
Keywords Alzheimer's disease, APOE, Cerebrospinal fluid, Beta amyloid, apolipoprotein-e genotype, beta-amyloid pathology, alzheimers-disease, biomarkers, allele, tau, beta-amyloid((1-42)), association, stability, decline
Subject categories Neurosciences


Background: From earlier studies it is known that the APOE epsilon 2/epsilon 3/epsilon 4 polymorphism modulates the concentrations of cerebrospinal fluid (CSF) beta-amyloid(1-42) (A beta 42) in patients with cognitive decline due to Alzheimer's disease (AD), as well as in cognitively healthy controls. Here, in a large cohort consisting solely of cognitively healthy individuals, we aimed to evaluate how the effect of APOE on CSF A beta 42 varies by age, to understand the association between APOE and the onset of preclinical AD. Methods: APOE genotype and CSF A beta 42 concentration were determined in a cohort comprising 716 cognitively healthy individuals aged 17-99 from nine different clinical research centers. Results: CSF concentrations of A beta 42 were lower in APOE epsilon 4 carriers than in noncarriers in a gene dose-dependent manner. The effect of APOE epsilon 4 on CSF A beta 42 was age dependent. The age at which CSF A beta 42 concentrations started to decrease was estimated at 50 years in APOE epsilon 4-negative individuals and 43 years in heterozygous APOE epsilon 4 carriers. Homozygous APOE epsilon 4 carriers showed a steady decline in CSF A beta 42 concentrations with increasing age throughout the examined age span. Conclusions: People possessing the APOE epsilon 4 allele start to show a decrease in CSF A beta 42 concentration almost a decade before APOE epsilon 4 noncarriers already in early middle age. Homozygous APOE epsilon 4 carriers might deposit A beta 42 throughout the examined age span. These results suggest that there is an APOE epsilon 4-dependent period of early alterations in amyloid homeostasis, when amyloid slowly accumulates, that several years later, together with other downstream pathological events such as tau pathology, translates into cognitive decline.

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