Jun 022010


The Alzheimer’s Disease Neuroimaging Initiative (ADNI) continues to provide us with greater and more detailed information about AD. For quite some time, we have known that the ApoE4 genotype leads to an increased risk of developing sporadic AD. Patients with the ApoE4 gene (carriers) typically develop Alzheimer’s disease five to seven years earlier than those without the gene (non-carriers). One or more copies of the ApoE4 gene are present in 20 percent to 30 percent of the general population and in 45 percent to 60 percent of patients with Alzheimer’s disease. But some individuals with two copies of the ApoE4 gene never develop Alzheimer’s disease, and some non-carriers do. Hence, it is not currently used in routine clinical practice.

A recent study by Dr. Wolk from the University of Pennsylvania and Dr. Dickerson from Massachusetts General Hospital has shown that in addition to this influence on AD risk, ApoE4 may also affect how the disease manifests itself. They found that ApoE4 carriers had poor memory retention with greater medial temporal lobe atrophy, whereas non-carriers did worse on working memory tasks and had increased frontoparietal atrophy.

ApoE4 carriers and non-carriers showed striking differences in immediate and delayed recall in the Auditory Verbal Learning Test, which involved memorizing a list of 15 words. During the first learning trial, in which participants heard the list and repeated as many words as they could recall, the non-carriers actually did worse. Over time, though, some of the learned information gets transferred to long-term memory, and by the fifth trial, the E4 carriers and non-carriers were doing about the same, suggesting comparable overall learning. However, when asked to recall the words 30 minutes later, the E4 carriers did much worse than the non-carriers.

E4 carriers, who did comparatively worse on delayed recall, had smaller hippocampi and more cortical thinning in the medial temporal lobe, which is required for memory retention. Non-carriers, who had more trouble with immediate recall, had greater atrophy in parietal and frontal regions believed to mediate short-term memory storage. The cognitive deficits in each group correlated with atrophy in the brain regions that subserve those functions, which is a fundamental tenet of neurology.

What this means for the future of routine testing for ApoE4 remains to be seen, but such studies demonstrate that ApoE4 is likely to be mechanistically relevant to the development of AD, and its use as a diagnostic may play an important role in better characterizing patients.

Michael Rafii, MD, PhD
ADCS Associate Medical Director
This post originally appeared in Alzheimer’s Insights, an ADCS Blog.

Wolk DA, Dickerson BC, and the Alzheimer’s Disease Neuroimaging Initiative. Apolipoprotein E genotype has dissociable effects on memory and attentional-executive network function in Alzheimer’s disease. PNAS Early Edition. 17 May 2010.

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