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Apolipoprotein E  4 Is a Determinant for Alzheimer-Type Pathologic Features in Tauopathies, Synucleinopathies, and Frontotemporal Degeneration
Keith A. Josephs, MST, MD;
Yoshio Tsuboi, MD;
Natalie Cookson, BSc;
Hilary Watt, MSc;
Dennis W. Dickson, MD
Arch Neurol. 2004;61:1579-1584.
Objectives To determine if apolipoprotein E  4 influences the frequency of Alzheimer-type pathologic features in tauopathies, synucleinopathies, and frontotemporal degeneration and to determine if the frequency of Alzheimer-type pathologic features in synucleinopathies is similar to the frequency of such features in tauopathies and frontotemporal degeneration.
Methods A total of 285 patients with pathologically proven neurodegenerative disorders, including diffuse and transitional Lewy body disease, frontotemporal degeneration, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy, with a mean age of 75.1 ± 9.3 years, were suitable for genetic and pathological analysis. Disorders were grouped as tauopathies (progressive supranuclear palsy and corticobasal degeneration), synucleinopathies (Lewy body disease and multiple system atrophy), and frontotemporal degeneration. Braak neurofibrillary tangle staging and quantitative scores of senile plaques were used to determine the degree of concomitant Alzheimer-type pathologic features in each case, and apolipoprotein E genotype was determined from DNA isolated from frozen brain tissue. The relationship of apolipoprotein E 4 to Alzheimer-type pathologic features was determined.
Results Across all neurodegenerative disorders, apolipoprotein E 4 and older age independently predicted the co-occurrence of Alzheimer-type pathologic features (P<.001), whereas female sex had a lesser effect (P = .03). When divided into the 3 subgroups (tauopathies, synucleinopathies, and frontotemporal degeneration), apolipoprotein E 4 had a similar effect, whereas older age and female sex were less predictive. There was a significant difference between the frequency of Alzheimer-type pathologic features in synucleinopathies and the frequency of such features in tauopathies and frontotemporal degeneration (P<.001 for both). The frequency of apolipoprotein E 4 allele was not significantly different among the 3 groups.
Conclusions Apolipoprotein E 4, independent of older age and sex, contributes to the co-occurrence of Alzheimer-type pathologic features in tauopathies, synucleinopathies, and frontotemporal degeneration, but this does not explain why Alzheimer-type pathologic features are significantly more likely to coexist with synucleinopathies than with either tauopathies or frontotemporal degeneration.
Author Affiliations: Department of Neurology, Mayo Clinic, Rochester, Minn (Dr Josephs); Departments of Neurology (Dr Tsuboi) and Pathology/Neuropathology (Ms Cookson and Dr Dickson), Mayo Clinic, Jacksonville, Fla; Dementia Research Group, Institute of Neurology and Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London, England (Ms Watt).
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