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Li Y, Tacey K, Doil L, van Luchene R, Garcia V, Rowland C, Schrodi S, Leong D, Lau K, Catanese J, Sninsky J, Nowotny P, Holmans P, Hardy J, Powell J, Lovestone S, Thal L, Owen M, Williams J, Goate A, Grupe A. Association of ABCA1 with late-onset Alzheimer's disease is not observed in a case-control study. Neurosci Lett. 2004 Aug 19;366(3):268-71. PubMed.
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Massachusetts General Hospital
After ApoE, which has an unusually large effect size as a
View all comments by Rudy Tanzilate-onset AD gene, the remaining AD genes would be expected to have
more modest to moderate effect sizes. Thus, one really needs to
routinely use at least a thousand or so uniformly ascertained
subjects in a case-control study to have a chance of replicating a
given AD candidate gene. In this case, the collaboration between Li
and colleagues and Celera tested 796 individuals (which is pretty
sizeable) and could not replicate the original findings. In addition,
at the recent AD meeting in Philadelphia, we could not replicate the
association with ABCA1 using family-based association on the large
NIMH AD sample. So, the possibilities are 1) the original result was
a false positive which often plagues case control studies, 2) the
original association was real but was due to linkage disequilibrium
with a nearby gene and thus not readily able to be confirmed in all
populations studied, or 3) the association was real, but the ABCA1
has a very small effect size in AD, and is, thus, difficult to
replicate across various populations. I should note that in our
presentation in Philadelphia of negative findings for ABCA1, which
sits in the chromosome 9 AD linkage peak region, in contrast, we
presented evidence for strong association with the gene encoding
ubiquilin 1 within that same peak in two independent family samples.
Washington University
ABCA1 has been shown to be critical outside the brain for effluxing phospholipid and cholesterol from cells onto HDL. In the periphery, ApoAI is the main apolipoprotein in HDL. The absence of ABCA1 function results in Tangier's disease in which plasma HDL is very poorly lipidated and is rapidly metabolized resulting in very low plasma HDL levels. The two new papers by Wahrle et al. and Hirsch-Reinshagen et al. show, using ABCA1 knockout mice, that ABCA1 is also critical for effluxing phospholipid and cholesterol from glial cells onto ApoE-containing HDL in the brain. Since ApoE is the most abundant apolipoprotein produced in the brain, this results in the production of very cholesterol- and phospholipid-poor CNS HDL. There are also very low levels of ApoE in the CNS of these mice, probably because the poorly lipidated ApoE is metabolized more rapidly. These results have important implications for any effect that ApoE may have in the normal brain, but perhaps more importantly, in the physiological setting of CNS diseases such as Alzheimer's disease. As one example, it is clear from animal studies that the amount of ApoE regulates the onset, amount, conformation, and toxicity of the amyloid-β peptide. These studies suggest that by altering ABCA1 function, the amount and lipidation state of ApoE will change in the brain. This is likely to impact the onset of amyloid-β-related pathology.
In regard to the genetics paper from the groups of Grupe and Goate, there was no association with certain SNPs in ABCA1 and LOAD.
View all comments by David HoltzmanIf the main effect that ABCA1 might have on AD is related to altering ApoE levels and lipidation (or altering Aβ levels as suggested by some other recent papers), unless the SNPs actually alter the function of ABCA1 enough to alter ApoE or Aβ levels in the CNS, one might not expect to see them alter risk for AD. The SNPs in this paper will need to be examined to determine if they actually alter ABCA1 function or not.
Cholesterol
and Alzheimer's
I would like to point Alzforum readers to see the key
note by Cheryl Wellington, senior author of one of the discussed articles
entitled "Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain".
It is freely available at Neurobiology of Lipids noteworthy articles' collection.
Also, please see NoL
collections index on different aspects of the role of fats in brain
function and Alzheimer's disease.
I would like also to point readers to our 2001 FASEB Journal
View all comments by Alexei Koudinovarticle "Essential
role for cholesterol in synaptic function and neuronal degeneration",
and our last year's ARF
hypothesis submission setting the pathogenic primacy of cholesterol
metabolism dysfunction in Alzheimer's, and explaining why Abeta and TAU changes
are secondary neurodegeneration features.
Karolinska Institute
The field of complex disease genetics is in a rapid developmental mode. However, we still know frighteningly little about how gene sequence variation can affect gene function, and most genetic association studies are not designed with this in mind. Exploratory studies (a category under which the vast majority of association studies must be said to fall) merely highlight genomic regions for further analysis. Engaging in debate around genetic association data can be futile if the effect sizes we are dealing with on an epidemiological level are small. This is also true if the number of pathogenic alleles in a genomic region, their impact upon a gene, and their potential interactions are not yet known. Efforts to find genes that influence disease might be better seen as a community undertaking where the accumulating bulk of data from many independent groups can eventually lead to a strong case for (or against) a particular gene. Very few groups have available clinical materials which can capture small genetic effects and demonstrate association conclusively (if one chooses to ever regard high probability as conclusive). The ABCA1 story is in its infancy and ultimately may turn out not to be relevant to AD at all, but a number of additional hypotheses are being tested in our laboratory (at present a major focus is upon CSF Aβ42 levels). The recent publications describing the relationship between ABCA1 and ApoE are extremely encouraging from a biological viewpoint, but the ultimate genetic question is whether different "versions" of the ABCA1 gene exist in human populations that differentially affect AD risk or severity.
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