Journal
ALZHEIMERS RESEARCH & THERAPY
Volume 9, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/s13195-017-0313-3
Keywords
Alzheimer's disease; APOE; Cerebrospinal fluid; Beta amyloid
Categories
Funding
- Swedish Research Council
- European Research Council
- Swedish Alzheimer Foundation
- Swedish Brain Foundation
- Knut and Alice Wallenberg Foundation
- Marianne and Marcus Wallenberg Foundation
- Torsten Soderberg Foundation
- AXA
- Fondation Universite Pierre et Marie Curie
- Fondation pour la Recherche sur Alzheimer, Paris, France
- program Investissements d'avenir [ANR-10-IAIHU-06]
- Frimurarestiftelsen
- Stiftelsen Gamla Tjanarinnor
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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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