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Apolipoprotein E e-4
Source of CHIME file: Protein Data Bank (PDB ID: 1B68).
Located on chromosome 19, ApoE is a gene that encodes for apolipoprotein E (apoE). Apolipoprotein E is a 299 amino acid polypeptide that acts as a ligand for low-density lipoprotein receptors, mediating the transport of cholesterol and other lipoproteins throughout the body (Mahley, 1988). The ApoE gene exists in 3 alleles, denoted e2, e3, and e4. e3 is the most common allele, encoding for the protein isoform apoE3. ApoE4 is encoded by the e4 allele and differs from apoE3 in that it contains arginine at positions 112 and 158, whereas apoe3 contains a cysteine at position 112 (Nathan et al., 1994). ApoE is primarily expressed in hepatic parenchymal cells in the liver (Mahley, 1988). The second largest area of ApoE expression is in the brain, with astrocytes being the major site of production. ApoE’s function in the brain and central nervous system is not completely understood, but it is thought to be involved in the mobilization and redistribution of lipids during the development of the nervous system, as well as the regeneration of peripheral nerves after injury (Nathan et al., 1994). Despite the nebulosity of the physiology of ApoE in the brain, one thing is known: the presence of one or two copies of the ApoE-e4 allele is a risk factor for late-onset Alzheimer’s disease (Parasuraman et al., 2002).
(Image Courtesy of <www.pdb.org>, Citation below.)
Alzheimer’s disease is a disorder of the brain that causes the loss of brain cells. One of its most profound symptoms is dementia, which can be defined as a decline in thinking skills, including memory loss, disorientation, and inability to reason (Alzheimer’s Assoc., 2002). Although its exact cause is unknown, there are two abnormal structures commonly found on the brains of autopsied Alzheimer’s sufferers: amyloid deposits (plaques) and neurofibrillary tangles (NFT’s). The role these structures play in the process of Alzheimer’s is unknown (Parasuraman et al., 2002). Researchers have found that these plaques and NFT’s contain accumulated amounts of apoE, and that homozygous carriers of the e4 allele exhibit more highly developed plaques. Therefore it is speculated that ApoE-e4 may contribute to the pathogenesis of Alzheimer’s disease (Nathan et al., 1994). In addition to late-onset Alzheimer’s, there are three other genes associated with rare cases of early-onset Alzheimer’s: presenilin 1, presenilin 2, and beta-amyloid precursor protein on chromosomes 14, 1, and 21, respectively. Early-onset Alzheimer’s comprises less than five percent of Alzheimer’s cases (Parasuraman et al., 2002).
Summary of Scientific Papers:
“The Apolipoprotein E Gene, Attention, and Brain Function”
by Raja Parasuraman, Pamela M. Greenwood, and Trey Sunderland.
Neuropsychology, 2002, Vol. 16, No. 2, 254-274.
In this paper, researchers from Catholic University and NIH
are looking at a connection between the ApoE- e4 allele and cognitive impairment
in adults who do not suffer from Alzheimer’s disease. The impetus behind
the study is that there is currently no way to detect AD prior to clinical
diagnosis, and therefore, the examination of brain function in at-risk individuals
might provide a possible means towards early detection. In other words, there
is no way to tell if a person is going to develop AD; one cannot be diagnosed
until symptoms have begun. Parasuraman et al., in order to find a means towards
early detection, therefore studied the spatial attentions and working memories
of healthy, middle-aged adults who have not been diagnosed with AD, but do
possess at least one copy of the ApoE- e4 allele.
In the discussion, Parasuraman et al. give a fairly detailed summary of the known (yet incomplete!) relationship between ApoE- e4 and Alzheimer’s disease, similar to that which I have provided above. They point out that past research has shown that one e4 allele confers increased risk of AD, while two copies of e4 increase the risk even further. They stress, however, that one or two copies of the allele are neither necessary nor sufficient for the development of AD, citing that only half of e4 homozygotes develop AD before age 90. The authors then go on to summarize a number of other studies regarding physiological and psychological phenomena in ApoE-e4 carriers. One of the more standout discoveries that they cite is that similar reductions in cerebral metabolism and reduced blood flow in parietal and temporal cortices occur in both AD patients and non-AD individuals who possess the ApoE-e4 gene. After describing their procedure for assessing spatial attention and working memory, the authors concluded, based on slower reaction times and less accurate responses in respective attention and memory tests, that the presence of one or two e4 alleles is connected with deficits in operations of spatial attention and working memory.
“Apolipoprotein E and Cognitive Performance” by
Jacob Raber, et al.
Nature, 2000, vol. 404, pp. 352-353.
In this brief Nature article, Raber et al. discuss spatial memory in transgenic mice that express ApoE-e4 in the brain. The researchers state that transgenic mice expressing apoE4 and mutations in human beta-amyloid precursor proteins (associated with early-onset AD in humans) are good model organisms by which to understand why human carriers of ApoE-e4 are at a greater risk of developing AD. After subjecting the mice to a water maze test, the researchers found that the hAPP/apoE4 mice exhibited impaired spatial memory retention in comparison to hAPP/apoE3 and non-transgenic controls. Furthermore, there was pronounced impairment observed in female happ/apoE4 mice. After assaying the amount of beta-amyloid in the brains of the mice, and finding no significant difference, the researchers concluded that the difference in performance was due to apoE4. They believe that their results suggest that the risk associated with ApoE-e4 is due to a weakened capacity to inhibit neuronal deficits brought upon by intracellular accumulation of beta-amyloid.
Summary of Popular Press Articles:
“Gene Tied to ‘Normal’ Age-Related Mental
Decline” by Linda Carroll
Reuters Health, August 28, 2002.
This is basically a toned-down summary of an article that appears in the August issue of Nature. It begins by saying that the gene which is ‘associated with Alzheimer’s disease’ may now be linked to age-related mental decline. The article states that mental decline in elderly people without AD is greater if they possess ApoE-e4. The researchers used an intelligence test called the Moray House Test to assess 466 study participants, who had all taken the test at age 11. The participants were then screened for the e4 allele, and it was concluded that those in possession tended to do worse on the test.
“Memory Lapse – Or Alzheimer’s?” by
The Washington Post, May 8, 2001.
This fairly long article is about the blurring of lines between what is called cognitive impairment and full-fledged AD. Beginning with a case study of Frances Goldstein, a woman who seems to have an incredible memory for things in the past but cannot remember what she was doing five minutes ago, Arthur Allen discusses the implications of lowering the threshold of Alzheimer’s diagnosis. The article states that if the bar is lowered to include individuals like Goldstein, who has been diagnosed as experiencing cognitive impairment related to old age, then the amount of people in the country with AD will double. Such a move, Allen claims, will lead toward a more pathological view of aging. In order to illustrate the reason behind this thinking, Allen cites a recent study that found many cadavers of non-AD individuals to possess the characteristic plaques and NFT's previously thought to be an exclusive feature of AD. Shifting towards the need for a concrete diagnostic test, Allen then begins to discuss ApoE-e4. Frequently, Allen quotes Trey Sunderland, co-author of the study on ApoE and attention discussed above. The final portion of the article is an overview of Sunderland’s search for the best possible marker to reveal early symptoms of AD. Rather than focusing on e4 carriers, Sunderland’s study involves a number of non-AD people who have first degree relatives who died of AD. Sunderland is striving towards this goal by subjecting this group to periodic cognitive tests, brain scans, and spinal taps to assess beta-amyloid buildup. To conclude, Allen says the best preventative measures a person can take, regardless of their ApoE allele, is proper diet and exercise.
At first, I was surprised to find that the scholarly articles
I came across did a good job at avoiding sensationalism. However, this lack
of sensation makes sense when one realizes that the connection between ApoE-
e4 and AD was established in 1993. As of 2002, the existence of a connection
has been repeatedly confirmed, and now the area of focus is explaining the
details of the relationship.
One noteworthy thing about the popular press is that both articles cited here do not refer to ApoE as the ‘Alzheimer’s Gene.’ Both are quite clear about the presence of ApoE-e4 being neither necessary nor sufficient for AD. In fact, only one article I came across, not summarized on this page, refers to ApoE as the ‘Alzheimer’s Gene’ (McKenna, 2001).
The major difference between the popular articles and scientific papers is oversimplification on the part of the popular press. In both the popular articles, ApoE-e4 is simply described as being one of 3 ApoE alleles, having a predominant role in lipid transport and an unknown role in brain physiology, and being a risk factor for AD. However, it only takes one PubMed search to realize that ApoE-e4’s role in AD is very complex, for the database pulls up studies correlating AD and ApoE-e4 with head-size, paternal occupation, caloric intake, and sex, to name a few of the more colorful ones. Basically it seems that, when describing ApoE-e4, the popular press is hung up on a risk-factor correlation established in 1993, although they reference the discoveries of papers that hint at its complexity. Perhaps this is because what is actually known about ApoE's role in AD is too confusing to mention. The articles do tend to get their point across. Admittedly, one of the stumbling blocks I came upon in researching this article was the vast amount of publications regarding the elusive role of ApoE that only lead to more questions. I finally decided upon the Parasuraman article as my main focus because I felt it provided the most comprehensive look at the known biological role of ApoE-e4, which is especially interesting because it is a psychology paper.
Allen, Arthur. "Memory Lapse - or Alzheimer's?" The Washington Post. May 8, 2001: HE01.
Alzheimer's Association. "What is Alzheimer's?" Alzheimer's Association Home. Last update: 2002. <http://www.alz.org/aboutAD/whatisAD.htm>
Carroll, Linda. “Gene Tied to ‘Normal’ Age-Related Mental Decline.” Reuters Health. August 28, 2002.
Dong, J., Peters-Libeu, C., Weisgraber, K. H., Selgelke, B. W., Rupp, B., Capila, I., Hernaiz, M. J., Lebrun, L. A., Linhardt, R. J.: "Interaction of the N-Terminal Domain of Apolipoprotein E4 with Heparin." Biochemistry 40 pp. 2826 (2001). <www.pdb.org>
Mahley, Robert W. "Apolipoprotein E: Cholesterol Transport Protein with Expanding Role in Cell Biology." Science. 240: 622- 630 (1988).
McKenna, Elizabeth. "Alzheimer's Gene Accelerates Multiple Sclerosis." Science Now. February 15, 2001. <www.sciencenow.org>
Nathan, BP, et al. "Differential Effects on Apolipoproteins E3 and E4 on Neuronal Growth in Vitro." Science. 264" 850-852 (1994).
Parasuraman, Raja, Greenwood, PM, and Sunderland, T. "The Apolipoprotein E Gene, Attention, and Brain Function." Neuropsychology. 16: 254-274 (2002).
Raber, J, et al. "Apolipoprotein E and Cognitive Performance." Nature. 404: 352-353 (2000).
© Copyright 2003 Department of Biology, Davidson College,
Davidson, NC 28035
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