Identification of Misdiagnosed Fronto-Temporal Dementia using APOE Genotype and Phenotype-Genotype Correlation Analyses
James T. Becker,
Oscar L. Lopez,
Objective: Postmortem and genetic studies of clinically diagnosed Frontotemporal dementia (FTD) patients
suggest that a number of clinically diagnosed FTD patients are actually "frontal variants" of Alzheimer's disease (fvAD).
The purpose of this study was to evaluate this hypothesis by combining neuropathological data, genetic association studies
of APOE, phenotype-APOE genotype correlations and discriminant analysis techniques. Methods: Neuropathological information
on 24 FTD cases, genetic association studies of APOE (168 FTD, 3083 controls and 2528 AD), phenotypegenotype
correlations and discriminant techniques (LDA, logistic regression and decision trees) were combined to identify
fvAD patients within a clinical FTD series. Results: Four of 24 FTLD patients (16.6%) met criteria for definite AD. By
comparing allele and genotype frequencies of APOE in controls, FTD and AD groups and by applying the Hardy-
Weinberg equilibrium law (HWE), we inferred a consistent (17.2%) degree of AD contamination in clinical FTD. A penetrance
analysis for APOE 4 genotype in the FTD series identified 14 features for discrimination analysis. These features
were compared between clinical AD (n=332) and clinical FTD series (n=168) and classifiers were constructed usinglinear
discriminant analysis logistic regression or decision tree techniques. The classifier had 92.8% sensitivity to FTD and
93.4% sensitivity to AD relative to neuropathology (global AUC=0.939, p<<0.001). We identified 30 potential fvAD
cases (17.85%) in the clinical FTD sample. Conclusion: The APOE locus association in clinical FTD might be entirely
explained by the existence of "hidden" fvAD cases within an FTD sample. The degree of fvAD contamination can be inferred
from APOE genotypes.
Keywords: Alzheimer's disease, apolipoprotein E4, diagnostic classification, frontotemporal lobe dementia, genetics.
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