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A High Throughput, Multiplexed and Targeted Proteomic CSF Assay to Quantify Neurodegenerative Biomarkers and Apolipoprotein E Isoforms Status
Published on: October 20, 2016
Preclinical effects of APOE ε4 on cerebrospinal fluid Aβ42 concentrations
Ronald Lautner1,2, Philip S Insel3,4,5, Tobias Skillbäck6,7
1Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. ronald.lautner@neuro.gu.se.
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.
Insights
The APOE ε4 allele is linked to earlier decreases in cerebrospinal fluid beta-amyloid42 in healthy individuals. This suggests an APOE ε4-driven period of altered amyloid homeostasis precedes cognitive decline in Alzheimer's disease.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- The apolipoprotein E (APOE) ε4 allele is a known risk factor for Alzheimer's disease (AD).
- APOE genotype influences cerebrospinal fluid (CSF) beta-amyloid42 (Aβ42) levels in individuals with cognitive decline and healthy controls.
- Previous research indicates a link between APOE genotype and Aβ42 concentrations, but its age-dependent effects in healthy individuals require further investigation.
Purpose of the Study:
- To investigate how the APOE genotype's effect on CSF Aβ42 concentrations varies with age in cognitively healthy individuals.
- To understand the association between APOE genotype and the early stages of preclinical Alzheimer's disease.
Main Methods:
- Analysis of APOE genotype and CSF Aβ42 concentration in 716 cognitively healthy individuals.
- Cohort age range: 17-99 years.
- Data collected from nine different clinical research centers.
Main Results:
- CSF Aβ42 concentrations were lower in APOE ε4 carriers compared to noncarriers, in a gene dose-dependent manner.
- The impact of APOE ε4 on CSF Aβ42 levels was found to be age-dependent.
- CSF Aβ42 began decreasing around age 50 in APOE ε4-negative individuals, age 43 in heterozygous carriers, and showed a steady decline in homozygous carriers.
Conclusions:
- Individuals with the APOE ε4 allele exhibit decreased CSF Aβ42 levels nearly a decade earlier than noncarriers, starting in early middle age.
- Homozygous APOE ε4 carriers may experience Aβ42 deposition throughout the studied age range.
- These findings suggest an APOE ε4-dependent window for early amyloid homeostasis alterations, potentially preceding downstream pathologies and cognitive decline in Alzheimer's disease.
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