APOE Genotype Modulates Alzheimer's Disease Phenotype

Megan Brooks

May 19, 2010

May 19, 2010 — The ε4 allele of the apolipoprotein E (APOE) gene, which is the major genetic risk factor for Alzheimer's disease (AD), may also influence the actual expression of the disease, even in its mildest stages, and account for some of the heterogeneity in the types of cognitive problems seen in patients with AD, a new study suggests.

"This work provides proof of concept that genetics may not only impact the risk for dementia but also the nature of a dementia syndrome," first study author David A. Wolk, MD, assistant professor in the Department of Neurology at the University of Pennsylvania, Philadelphia, and assistant director of the Penn Memory Center told Medscape Neurology.

Their findings were published online May 17 in an early edition of the Proceedings of the National Academy of Sciences United States of America.

Phenotypic Variability

Dr. Wolk and coauthor Bradford C. Dickerson, MD, associate professor of neurology at Massachusetts General Hospital and Harvard Medical School, Boston, investigated cognitive and neuroanatomical phenotypic variability in 67 APOE ε4 carriers and 24 noncarriers with mild AD. To allay concerns about misdiagnosis, only patients with a cerebrospinal fluid (CSF) molecular profile consistent with pathological AD were included, they note.

The researchers found that APOE ε4 allele carriers displayed significantly greater impairment on measures of memory retention, whereas noncarriers displayed greater impairment on tests of working memory, executive control, and word retrieval.

The 2 groups also demonstrated anatomical dissociations consistent with these cognitive differences: APOE ε4 allele carriers exhibited greater medial temporal lobe atrophy, whereas noncarriers had greater frontoparietal atrophy, including areas thought to subserve these cognitive processes.

"What was particularly remarkable about this study was the high correspondence between the differential effect of APOE status on cognitive symptoms and on evidence of brain atrophy," Dr. Wolk said.

"Threads of the current findings have been reported previously," Dr. Wolk noted, "but the current study brought together this set of findings in a relatively large cohort with CSF molecular support for diagnostic accuracy — a confound in prior studies."

On the basis of prior work, "we expected memory and the hippocampus to be most vulnerable in carriers of the APOE ε4 allele," Dr. Wolk said. "This finding was corroborated. Additionally, limited work had suggested some evidence that there were cognitive areas and brain atrophy that were more affected in the noncarriers. Again, our results supported this notion."

The current findings, he concluded, suggest that more "global measures" of cognitive functioning may be less sensitive to the specific cognitive issues in APOE ε4 allele carriers and noncarriers. 

Selective Vulnerability

Steven E. Arnold, MD, director of the Penn Memory Center, who was not directly involved in the study, told Medscape Neurology that this research is not only "fascinating from a clinical prediction standpoint," but it also highlights "how little we yet know about the mechanisms by which APOE genotype promotes neurodegeneration in AD as well as why there is such selective vulnerability of distinct neural systems in the disease."

Continued studies in transgenic animals examining selective vulnerability may shed some light here, he added. "In addition, longitudinal studies with structural and molecular imaging that map progression of disease will also be very instructive," Dr. Arnold said.  

Dr. Wolk and Dr. Arnold have disclosed no relevant financial relationships.

Proc Natl Acad Sci U S A. Published online May 17, 2010.


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