Alzheimer's disease (AD) is a neurodegenerative disorder resulting in memory loss and other cognitive impairments, such as deficits in language, judgment, and perception. Behavioral and psychiatric abnormalities may occur during the course of disease as well. Several risk factors have been attributed to AD including age, Down's syndrome, family history, and Apolipoprotein E (ApoE) genotype. In demented individuals, the most prevalent known genetic risk factor for late-onset AD is the ApoE genotype. It is one of the most widely researched topics in neurology - over 5,000 articles researching aspects of this gene have appeared in the last twenty years.
Three alleles, or isoforms, of ApoE exist: e2, e3, and e4. These alleles combine to form six different genotypes: e2/2, e3/2, e4/2, e3/3, e4/3, e4/4. It is believed that ApoE plays an important role in regulating plasma lipids and lipoproteins.1 A recent study by Frikke-Schmidt et al. in Neurology suggested that the e4 allele increases the risk for ischemic heart disease (IHD) by elevating cholesterol and triglycerides while decreasing high-density lipoprotein (HDL) cholesterol.1
Frikke-Schmidt et al. tested the hypothesis that ApoE was a risk factor for AD, other dementia (OD), as well ischemic cerebrovascular disease (ICVD). Over 9000 individuals were genotyped for this study. Of this group, almost 800 individuals were diagnosed with either ICVD, AD, or OD.
After examining these individuals several observations were made in relation to the ApoE genotype.1
- ApoE genotype was NOT a risk factor for ICVD.
- ApoE genotypes e4/3 and e4/4 vs. e3/3 were significant risk factors for AD; and
- e4/3 was a risk factor for other dementia (OD).
- The effects on risk for AD and OD were independent of lipid and lipoprotein levels.
- "...if all e4/3 or e4/4 individuals carried the e3/3 genotype instead, the total burden of AD in this study would decrease by 37% and 20%."
The gene dosage hypothesis (that the more e4 alleles an individual harbors the greater the risk for developing AD) of the e4 allele was confirmed. It was determined that e4/3 and e4/4 genotypes had 3- and 10- fold risks for AD, respectively.1 The authors suggest "cognitive impairment is due to a direct effect of the ApoE protein in the brain, although other unknown peripheral mechanisms may also play a role."1 The researchers conclude that ApoE is a risk factor for AD and OD, but not for ICVD.
Artiss Powell, MD is a behavioral neurologist with a focus on the evaluation and care of demented individuals, as well as on aphasia, memory disorder, and attention disorder. An Associate Professor of Neurology at the University of Medicine and Dentistry of New Jersey (UMDNJ) Robert Wood Johnson (RWJ) School of Medicine, he is also the Director of the Behavioral Neurology Program. In addition to being author and co-author of numerous articles published in leading scientific journals, Dr. Powell has also given many presentations on dementia and Alzheimer's disease. In this interview, Dr. Powell shares his view on the breaking news about AD and ICVD, as well as on the importance of ApoE in the clinical setting.
| Athena: | How does the information in this article by Frikke-Schmidt, et al. relate to the use of ApoE for AD diagnosis? | |
| Dr. Powell: | Frikke-Schmidt, et al. provide data for the value of ApoE to predict risks of AD in the Netherlands. The study considered whether ApoE, through effects on lipoprotein, serves as a risk factor for ischemic cerebrovascular disease (ICVD), AD, and other dementias (OD). In their study, ApoE was not a risk factor for ICVD in this population. ApoE e4 was associated, however, with increased risk of AD. Individuals with a 3/4 genotype had a 3-fold risk of having AD, while those with a 4/4 genotype were 10-times more likely to have the disease. It is also interesting that ApoE e3/4 was associated with a 2.5-fold risk of OD, one-third of which were thought to have vascular dementia. In their study, if all individuals carried a 3/3 genotype instead, there would have been one-third fewer AD patients from the 3/4 genotype and one-fifth fewer AD patients from the homozygous 4/4 genotype. Similarly, if all individuals with OD had a 3/3 genotype instead of a 3/4 one, there would be twenty-five percent fewer patients with this disorder. Through their study, Frikke-Schmidt, et al. determined the risks provided by ApoE for AD, ICVD, and OD. |
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| Athena: | Since up to one-third of patients with vascular dementia may also meet the criteria for AD according to the study, would you recommend ApoE to differentiate between them? | |
| Dr. Powell: | Frikke-Schmidt et al. show that the prevalence of ICVD was unaffected by the ApoE genotype, but an individual's genotype is important as a risk factor for OD, a third of whom are estimated to have vascular dementia. Their data suggests that ApoE does not play a role in determining the risk for ICVD. However, the study does suggest that an ApoE e4 genotype favors a diagnosis of AD. |
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| Athena: | What other current studies are underway which are looking at the predictive value of ApoE in the general population? | |
| Dr. Powell: |  The role of ApoE in AD pathogenesis is under intense, active study. It is thought to be at the very heart of the pathology that underlies Alzheimer's disease. Microtubules are essential for axon transport and ApoE is important to microtubule stability. The form of ApoE possessed by an individual appears to determine whether the microtubule proteins are hyperphosphorylated. This process is an important determinant of stability and the affected system is critical to neuronal health, since cell products must be transported from the cell body to the synapse, and back, by way of this system. There is also a suggestion that ApoE potentiates toxicity of ß-Amyloid. In this manner, it may actively contribute to the disease process; its exact role is yet to be fully determined.In my view, ApoE appears to contribute 5-10% additional confidence towards an AD diagnosis. |
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| Athena: | How do you think ApoE should be used in clinical practice? | |
| Dr. Powell: | In demented patients over age 60, the likelihood of Alzheimer's disease is increased by an ApoE e4 genotype; there is a dose effect: the increased probability of having AD with two e4 alleles is greater than the risk from having one e4 gene. A diagnosis of AD should be entertained if there is an appropriate clinical presentation. |
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| Athena: | How do you use ApoE? | |
| Dr. Powell: | I obtain ApoE genotypes in all patients presenting with intellectual decline. I use the results as an aide to help me decide who to follow more closely and longer. For example, I follow-up with e4 positive patients more often than e4 negative patients for whom I have a more positive outlook. I use ApoE as a prognostic indicator: Who can I be more optimistic about? Who is more likely to decline? In brief, it helps me triage patients so that I can more appropriately help with socioeconomic advice. |
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| Athena: | Thank you, Dr. Powell. | |
