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Preclinical effects of APOE ϵ4 on cerebrospinal fluid Aβ42 concentrations

Lautner, Ronald; Insel, Philip S. LU ; Skillbäck, Tobias; Olsson, Bob; Landén, Mikael; Frisoni, Giovanni B; Herukka, Sanna-Kaisa; Hampel, Harald; Wallin, Anders and Minthon, Lennart LU , et al. (2017) In Alzheimer's Research and Therapy 9(1).
Abstract

Background: From earlier studies it is known that the APOE ϵ2/ϵ3/ϵ4 polymorphism modulates the concentrations of cerebrospinal fluid (CSF) beta-amyloid1-42 (Aβ42) 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 Aβ42 varies by age, to understand the association between APOE and the onset of preclinical AD. Methods: APOE genotype and CSF Aβ42 concentration were determined in a cohort comprising 716 cognitively healthy individuals aged 17-99 from nine different clinical research centers. Results: CSF concentrations of Aβ42 were lower in... (More)

Background: From earlier studies it is known that the APOE ϵ2/ϵ3/ϵ4 polymorphism modulates the concentrations of cerebrospinal fluid (CSF) beta-amyloid1-42 (Aβ42) 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 Aβ42 varies by age, to understand the association between APOE and the onset of preclinical AD. Methods: APOE genotype and CSF Aβ42 concentration were determined in a cohort comprising 716 cognitively healthy individuals aged 17-99 from nine different clinical research centers. Results: CSF concentrations of Aβ42 were lower in APOE ϵ4 carriers than in noncarriers in a gene dose-dependent manner. The effect of APOE ϵ4 on CSF Aβ42 was age dependent. The age at which CSF Aβ42 concentrations started to decrease was estimated at 50 years in APOE ϵ4-negative individuals and 43 years in heterozygous APOE ϵ4 carriers. Homozygous APOE ϵ4 carriers showed a steady decline in CSF Aβ42 concentrations with increasing age throughout the examined age span. Conclusions: People possessing the APOE ϵ4 allele start to show a decrease in CSF Aβ42 concentration almost a decade before APOE ϵ4 noncarriers already in early middle age. Homozygous APOE ϵ4 carriers might deposit Aβ42 throughout the examined age span. These results suggest that there is an APOE ϵ4-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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published
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keywords
Alzheimer's disease, APOE, Beta amyloid, Cerebrospinal fluid
in
Alzheimer's Research and Therapy
volume
9
issue
1
publisher
BioMed Central
external identifiers
  • scopus:85032211993
  • pmid:29061195
ISSN
1758-9193
DOI
10.1186/s13195-017-0313-3
language
English
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yes
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8a1ec820-3072-4168-9ce2-4464d5dfe215
date added to LUP
2017-11-13 10:31:46
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2018-01-07 12:25:42
@article{8a1ec820-3072-4168-9ce2-4464d5dfe215,
  abstract     = {<p>Background: From earlier studies it is known that the APOE ϵ2/ϵ3/ϵ4 polymorphism modulates the concentrations of cerebrospinal fluid (CSF) beta-amyloid<sub>1-42</sub> (Aβ42) 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 Aβ42 varies by age, to understand the association between APOE and the onset of preclinical AD. Methods: APOE genotype and CSF Aβ42 concentration were determined in a cohort comprising 716 cognitively healthy individuals aged 17-99 from nine different clinical research centers. Results: CSF concentrations of Aβ42 were lower in APOE ϵ4 carriers than in noncarriers in a gene dose-dependent manner. The effect of APOE ϵ4 on CSF Aβ42 was age dependent. The age at which CSF Aβ42 concentrations started to decrease was estimated at 50 years in APOE ϵ4-negative individuals and 43 years in heterozygous APOE ϵ4 carriers. Homozygous APOE ϵ4 carriers showed a steady decline in CSF Aβ42 concentrations with increasing age throughout the examined age span. Conclusions: People possessing the APOE ϵ4 allele start to show a decrease in CSF Aβ42 concentration almost a decade before APOE ϵ4 noncarriers already in early middle age. Homozygous APOE ϵ4 carriers might deposit Aβ42 throughout the examined age span. These results suggest that there is an APOE ϵ4-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.</p>},
  articleno    = {87},
  author       = {Lautner, Ronald and Insel, Philip S. and Skillbäck, Tobias and Olsson, Bob and Landén, Mikael and Frisoni, Giovanni B and Herukka, Sanna-Kaisa and Hampel, Harald and Wallin, Anders and Minthon, Lennart and Hansson, Oskar and Blennow, Kaj and Mattsson, Niklas and Zetterberg, Henrik},
  issn         = {1758-9193},
  keyword      = {Alzheimer's disease,APOE,Beta amyloid,Cerebrospinal fluid},
  language     = {eng},
  month        = {10},
  number       = {1},
  publisher    = {BioMed Central},
  series       = {Alzheimer's Research and Therapy},
  title        = {Preclinical effects of APOE ϵ4 on cerebrospinal fluid Aβ42 concentrations},
  url          = {http://dx.doi.org/10.1186/s13195-017-0313-3},
  volume       = {9},
  year         = {2017},
}