High Frequency of Apolipoprotein E ϵ4 Allele in Young Individuals with Very Mild Alzheimer's Disease-Related Neurofibrillary Changes

doi:10.1006/exnr.1998.6860

Experimental Neurology

Volume 153, Issue 1, September 1998, Pages 152-155

https://doi.org/10.1006/exnr.1998.6860 Get rights and content

Abstract

The pathological process of initial neurofibrillary (NF) changes underlying Alzheimer‘s disease (AD) represents the early preclinical phase of the disease. In a small percentage of individuals, these initial NF changes (Braaks’ stage I of six stages) may develop at a surprisingly young age. The aim of this study was to determine the impact of apolipoprotein E (ApoE) on the development of such initial NF changes in young individuals. To this end, the ApoE genotypes were determined using a seminested polymerase chain reaction assay followed by restriction isotyping in young individuals (n= 44; mean age of 38 years) with initial NF changes (stage I). The results were compared with ApoE genotypes of age-matched controls (n= 70) devoid of such changes (stage 0). Stage I cases exhibited a significantly higher ϵ4 allele frequency compared to controls (0.18 vs 0.09,P= 0.039). Thus, the present study reveals an association of ϵ4 allele with the early onset of AD-related NF changes in young individuals. This finding underlines the relevance of the asymptomatic phase in the course of AD.

References (20)

H. Braak et al.
Frequency of stages of Alzheimer-related lesions in different age categories
Neurobiol. Aging
(1997)
E. Ghebremedhin et al.
Improved method facilitates reliable APOE genotyping of genomic DNA extracted from formaldehyde-fixed pathology specimens
J. Neurosci. Methods
(1998)
Zs. Nagy et al.
Influence of the apolipoprotein E genotype on amyloid deposition and neurofibrillary tangle formation in Alzheimer's disease
Neuroscience
(1995)
T.G. Ohm et al.
Close-meshed prevalence rates of different stages as a tool to uncover the rate of Alzheimer‘s disease-related neurofibrillary changes
Neuroscience
(1995)
T.G. Ohm et al.
Apolipoprotein E polymorphism influences not only cerebral senile plaque load but also Alzheimer-type neurofibrillary tangle formation
Neuroscience
(1995)
J. Poirier et al.
Apolipoprotein E polymorphism and Alzheimer’s disease
Lancet
(1993)
J. Poirier
Apolipoprotein E in animal models of CNS injury and in Alzheimer‘s disease
Trends Neurosci.
(1994)
A.M. Saunders et al.
Specificity, sensitivity, and predictive value of apolipoprotein-E genotyping for sporadic Alzheimer‘s disease
Lancet
(1996)
W.J. Strittmatter et al.
Hypothesis: Microtuble instability and paired helical filament formation in the Alzheimer disease brain are related to apolipoprotein E genotype
Exp. Neurol.
(1994)

There are more references available in the full text version of this article.

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Regular ArticleHigh Frequency of Apolipoprotein E ϵ4 Allele in Young Individuals with Very Mild Alzheimer's Disease-Related Neurofibrillary Changes☆

Abstract

Neurobiol. Aging

J. Neurosci. Methods

Neuroscience

Neuroscience

Neuroscience

Lancet

Trends Neurosci.

Lancet

Exp. Neurol.

Regular Article
High Frequency of Apolipoprotein E ϵ4 Allele in Young Individuals with Very Mild Alzheimer's Disease-Related Neurofibrillary Changes☆