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Human Molecular Genetics, 2004, Vol. 13, Review Issue 1 R135-R141
DOI: 10.1093/hmg/ddh077

Alzheimer's disease: one disorder, too many genes?

Lars Bertram and Rudolph E. Tanzi*

Genetics and Aging Research Unit, Department of Neurology and MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

Received January 13, 2004; Accepted January 26, 2004


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 2003: A GOOD VINTAGE...
 CONCLUSION
 REFERENCES
 
The research of Alzheimer's disease (AD) genetics has been extremely prolific over the past decade, and currently more than 10 genes are reported to show either positive or negative evidence for disease association per month. Here, we review all 90 studies from 2003 reporting a total of 127 association findings between candidate genes and AD. While most positive results were largely contradictory, we identified three loci—on chromosomes 6p21, 10q24, 11q23—that yielded positive results in three or more independent studies, in addition to the well-established AD association with the gene encoding apolipoprotein E (APOE). Based on these data, we suggest that it may be prudent for investigators to pay closer attention to issues such as power, replicability and haplotype structure prior to initial publication. This should serve to greatly decrease the likelihood of false positive and false negative findings reported in future years.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
2003: A GOOD VINTAGE...
 CONCLUSION
 REFERENCES
 
Several characteristics make the search for novel Alzheimer's disease (AD) genes particularly promising. First, and most importantly, the heritability of AD is high. This has been demonstrated in various studies examining familial segregation of the disease over the past decades (1–3). Accordingly, the probability of actually finding relevant disease-causing or predisposing genes is relatively high as well, possibly even more so than for other genetically complex neuropsychiatric disorders, like Parkinson's disease, schizophrenia or affective disorders (4). Thus far, in AD this has been achieved for four genes (APP, PSEN1, PSEN2, APOE), but only variation in the latter also plays a significant role in the most common late-onset form of the disorder (see below). Fully penetrant mutations in APP, PSEN1 and PSEN2, on the other hand, lead to rare early-onset familial forms of AD via an increased generation of Aß42 and ß-amyloid deposition, a major neuropathological hallmark of the disease. Secondly, there is direct evidence, based on simulation as well as empirical data, for the presence of additional AD risk genes besides APOE. For instance, a recent simulation study predicted the existence of four to seven additional AD genes when searching for age of onset modifiers simulating a variety of different disease and inheritance models (3). This number corresponds well with empirical data obtained in full genome searches, which overlap on 11 chromosomes, six of which show ‘significant’ results in at least one study (Table 1). Finally, the progressive neurodegeneration gradually leading to cognitive decline and dementia in AD patients exhibits distinct and well-established histopathological features upon post-mortem examination, allowing for the verification of ‘clinical’ AD (5). Currently, the accuracy of a clinical AD diagnosis is near or beyond 90% in academic centers (6–8). This allows for a significant reduction of the number of phenocopies in study populations using published research criteria, and thereby increases the power of subsequent genetic or epidemiological analyses.


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  		Table 1. Overview of concordant linkage/association regions observed in full genome screens published until 2003
 
These disease-specific characteristics, together with the advent of relatively inexpensive and powerful high-throughput genotyping technologies, and the near completion of the human genome sequence have led to a steep increase in the number of laboratories studying the genetics of AD worldwide. To date, no less than 12 full-genome screens using linkage- or association-based methodologies have been published for AD, some using overlapping or identical samples, but each employing different sets of genetic markers and/or analytic strategies (8–19) (Table 1). On the other hand, the number of locus-specific, candidate gene-based AD association studies has now become nearly intractable. Over the course of 2003, more than 10 genes were reported to show either positive or negative evidence of association with different AD phenotypes per month in peer-reviewed journals as listed on NCBI's ‘PubMed’. Despite these vast efforts, no single gene has yet emerged to attain nearly the degree of replication and consistency that has been observed by literally hundreds of laboratories studying the association of APOE-{varepsilon}4 and AD. In this review, we present and discuss the findings of all genetic AD association studies published in 2003 (excluding those explicitly searching for the causes of early-onset familial AD cases, i.e. private mutations). Using these data as an example, we then attempt to pinpoint the methodological difficulties that are likely to underlie the remarkable failure to replicate genetic findings using current approaches.


   2003: A GOOD VINTAGE FOR AD GENETICS?
TOP
 ABSTRACT
 INTRODUCTION
 2003: A GOOD VINTAGE...
CONCLUSION
 REFERENCES
 
Genome screens
As outlined above, the year 2003 has been almost unprecedented in terms of the number of studies attempting to unravel the causes of AD genetics. Three full-genome screens (8,18,19), using both association and genetic linkage methods, have been added to the nine studies already reported in the literature for late-onset AD. A study-by-study comparison using a P-value of 0.01 as cut-off reveals a total of 16 regions on 11 chromosomes that yield positive signals across at least two studies with markers no further than 25 Mb apart (Table 1). Interestingly, all chromosomes with the strongest and most consistent signals, i.e. 6, 9, 10, 12, 19 and 21, had already been implicated at least 3 years earlier, but received further support in 2003. Based on these criteria the only ‘new’ AD region to emerge in 2003 is on chromosome 2p23–24, at a position between 19 and 29 Mb. Interestingly, this region was only implicated in studies using association methods and only in fairly isolated and homogeneous populations (i.e. the Finns and Wadi-Ara) (14,18). Note that inclusion and exclusion criteria applied here are arbitrary and as such may overestimate the total number of positive signals. They do, however, allow the comparison across a multitude of methodologically divergent approaches and should facilitate the interpretation of analyses based on actual candidate genes.

Candidate gene studies
Searching ‘PubMed’ (www.ncbi.nlm.nih.gov/PubMed/) with keywords ‘alzheimer* AND (association OR associated)’ for all papers published between January 1 and December 31, 2003, retrieved a total of 1037 studies (on December 28, 2003), of which 90 directly deal with genetic association between candidate polymorphisms and AD. As can be seen in Table 2, these studies examined a total of 55 genetic loci (‘locus’ being a set of markers within the same 5 Mb genomic interval) on 20 different chromosomes. A total of 55 analyzed genes within these loci were found to be ‘positive’ (as judged by the authors), while 68 tested ‘negative’. Interestingly, even 10 years after its discovery, the largest number (n=18) of reports focusing on a single gene dealt with the association between APOE and AD, using new polymorphisms, new samples/ethnic groups or new phenotypes. When these studies were not considered, a total of 38 positive and 67 negative papers remained.


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  		Table 2. Overview of chromosomal loci tested for genetic association with AD in 2003
 
If 2003 represents one of the most prolific vintages for late-onset AD genetic studies, the next most pressing question is: did the large quantity of studies also dilute the quality of the product, perhaps even making for an unpalatable quaff? The answer, in our opinion, is yes, at least in the majority of cases. There is growing consensus that the success rate and reliability of genetic association studies in complex diseases depend on the fulfillment of several criteria (20,21), three of which are discussed in more detail below. These are in addition to the ‘classic’ requirements of at least plausible biological and/or positional candidacy for any investigated locus, as well as direct proof of pathophysiological consequences of any positive disease association. While the former criterion is fulfilled for the vast majority of AD candidate genes investigated thus far, the latter condition has been more elusive. This is due to several factors that generally bedevil the study of genetic association in complex diseases, such as linkage disequilibrium with the actual (and functionally relevant) disease-modifying variant, small effect sizes (which impede the detection of significant effects using basic molecular and biochemical assays), and possibly the involvement of as yet unknown pathophysiological mechanisms. The situation of APOE-{varepsilon}4 in AD serves as a good example: while the genetic association per se has been extremely well established over the past decade, there is still no consensus as to how this association translates pathophysiologically (22,23).

Thus, before attempting to uncover the ‘functional consequences’ of any putative new disease association, we propose that more emphasis must be placed on criteria that allow for a better distinction between false-positive as well as false-negative findings prior to initial publication.

Power: does the sample size and structure enable the investigators to detect effect sizes of only moderate or small extent?
While this is an obvious concern in reports with a negative outcome, the power of a study also governs the rate of false positive findings, i.e. the probability that an observed significant association is indeed genuine and not only observed by chance (24–26). Other factors influencing the ability to detect meaningful effects include the attributable risk of the polymorphism to the overall genetic variance, degree of linkage disequilibrium (LD) between the associated allele and the actual disease predisposing variant, mode of inheritance and, to a lesser extent, disease prevalence. While these variables are, of course, difficult to estimate when the true disease gene is unknown, power for any given sample size can fairly easily be calculated for a variety of possible and plausible scenarios. In practice, however, this still remains the exception. A recent study estimated that the minimal number of cases and controls sufficient to achieve ~80% power at {alpha}=0.05 is usually far greater than 200 when the actual disease allele is not tested directly, even under the most favorable of circumstances (26). It is interesting that, regardless of these estimates, ~20% of all studies published in 2003 have still used smaller sample sizes and thus are probably not suitable for use in reaching any reliable conclusion.

Replicability: has the result been validated/replicated in an independent sample of sufficient size?
While there have been reports of ‘significant’ associations between putative candidate genes and AD on every chromosome in the human genome over the past 10 years (27), none of these findings—with the exception of APOE-{varepsilon}4—has yet been replicated consistently. Many a seemingly ‘positive’ result could (and should) have been validated in an independent dataset prior to its first publication, as several authors have long been suggesting in guidelines for the proper ‘quality control’ of genetic association findings (20,21,25,28,29). The current inflation of probable false-positive reports may have been avoided if independent replication had been sought earlier. If an independent sample cannot be found in-house, the establishment of at least temporary ‘consortia’ between collaborative laboratories to test each other's positive signals prior to publication would represent an easy and effective means to restore credibility. Upon our review of the 2003 AD genetics literature, less than 20% of all studies either referred to findings in two or more independent samples at once, or were published in tandem with independent reports investigating the same candidate genes and/or genetic variants.

Haplotype structure: have the authors made attempts to elucidate the structure of the underlying haplotype architecture?
The more current and systematic assessment of haplotype structures at various regions throughout the genome in the past 3–4 years has emphasized the importance of performing haplotype- or systematic LD-analyses when searching for novel complex disease genes (30,31), especially when effect sizes are expected to be lower than those conferred by APOE-{varepsilon}4. In addition to increasing the power of the analyses, this approach also reduces the number of statistical tests that need to be performed, which should lead to a further decrease of false-positive findings. Several very recently published complex disease associations would have been impossible to observe, without thorough assessment of the underlying haplotype architecture (32–34). Along these lines, recent studies on APOE have shown that this locus would have been easily identified by means of haplotype analysis alone, even without the prior knowledge of the {varepsilon}4 polymorphism (35,36). Yet, in 2003 only about one-third of all studies investigated more than one polymorphism per locus. Only half of these carried out a more or less ‘thorough’ assessment of haplotype structure (i.e. four or more polymorphisms per gene).

Out of all 90 papers published in 2003 on the topic of genetic association between candidate genes and the different AD phenotypes, only 21 (23%) fulfilled at least two of the above criteria. Most likely, many of the observed discrepancies across studies could be explained by a lack of methodological thoroughness. Nonetheless, there were three loci, in addition to APOE, that tested positive across at least three studies (on chromosomes 6p21, 10q24, and 11q23; Table 2). These loci are covered in the remainder of this review.

Chromosome 6p21
This chromosomal region was implicated as harboring a putative AD gene as early as 1980, based on an association finding between variants in the highly polymorphic major histocompatibility complex region (HLA-A, at ~30 Mb) and AD in a small case–control study (37). Two other potential AD candidates map within this 5 Mb interval, the genes encoding the hereditary haemochromatosis protein (HFE, at ~26 Mb) and the tumor necrosis factor alpha (TNFA, at ~31 Mb). While in 2003 two studies reported significant evidence of association with the latter two genes (38,39), two other studies did not confirm these findings (40,41). Another candidate gene located in this region, HAPA1B, has been found to be associated with certain neuropsychological variables (42), but not disease risk itself (43). Finally, one study investigated variation in onset age as a function of the HLA A2-allele in a small sample of AD patients, but did not find any significant effects (44). A literature search for association studies with any of these genes including the years before 2003 yielded at least 15 positive studies, while 10 reports found no evidence of a genetic involvement of these factors. While there has been some evidence for a direct involvement of TNFA in Aß-production and toxicity (45), direct proof for a pathogenetic relevance for any of the other genes/proteins remains to be seen. Furthermore, the full-genome screens for AD genes have consistently yielded signals on 6p21 residing between 39 and 42 Mb, whereas the associated genes map ~10 Mb further proximal. Thus, while there is increasing evidence supporting the existence of a putative AD locus on 6p21 in general, the possibility that the actual disease gene has not yet been identified cannot be excluded, despite the overlapping positive results from this year and past studies.

Chromosome 10q24
Of the six candidate loci analyzed in the region between 10q21 and 10q25 in 2003, three were reported to be associated with AD phenotypes across multiple samples (i.e. CDC2/VR22, TNFRSF6/IDE and GSTO1/2). The only locus found to be associated by more than one group of investigators is located between 90 and 94 Mb and encompasses the genes TNFRSF6 (90 Mb) and IDE/KIFF11/HHEX (46–48). Probably the best candidate on biological grounds is IDE, encoding the insulin degrading enzyme (protein: IDE). This metalloprotease has been shown to degrade monomeric Aß before it can aggregate into oligomeric forms and, ultimately, into ß-amyloid plaques (49). While several issues of the proposed mode of action still remain controversial (e.g. the precise cellular location of Aß cleavage, relevance of IDE function/dysfunction on the development of AD), there are now a number of animal models available showing the predicted effects in vivo (50–52). Before 2003, there were two papers published showing allelic association with microsatellite markers in this region (53,54), while two reports did not find association with IDE variants or nearby markers and AD (55,56). Note that the data on one of the negative studies (55) actually largely overlaps with the positive paper by Edland et al. (46), with the important exception that the authors of the first paper did not account for potential interactions between IDE and APOE {varepsilon}4-status. This may be crucial, since the latter study only found a significant effect of IDE on AD risk in individuals lacking the APOE {varepsilon}4-allele. Clearly, more studies on independent samples of sufficient size are necessary to further elucidate the potential role of IDE variants on the development of AD in the more general population.

In addition to the IDE locus, a total of four other genes on the long arm of chromosome 10 were found to be associated with AD. Two of these (CDC2 and VR22) map ~30 Mb proximal of IDE, while the other two (GSTO1/2 and PRSS11) map 10–30 Mb distal. While none of these associations has yet been confirmed in independent AD samples, it is noteworthy that two of these genes were also found to be associated in other neurodegenerative illnesses, frontotemporal dementia (CDC2) (57) and Parkinson's disease (GSTO1/2) (58), potentially suggesting a more common pathway leading to neuronal cell death across these syndromes. CDC2 encodes for the cell division cycle 2 protein which is involved in the phosphorylation of both tau and APP, and is found in neurons bearing neurofibrillary tangles. GSTO1 and 2 encode for glutathione S-transferase omega-1 and -2, which are involved in the physiological response to oxidative stress, and may in particular be responsible for regulating the expression of inflammatory cytokines like IL1-ß. Thus, while these are all plausible AD candidate genes on positional as well as biological/biochemical grounds, further studies are still necessary to elucidate their proposed roles in influencing the risk and/or age-at-onset for AD in the general population.

Chromosome 11q23
The region near the tip of the long arm of chromosome 11 has been implicated in only one of the full genome screens published to date (8) (and therefore does not appear in Table 1). Yet, there were a total of three studies showing significant association with an AD candidate gene in 2003: BACE, encoding the ß-site APP cleaving enzyme (ß-secretase) (59–61). This protein is an excellent AD candidate on biochemical grounds as it is only after the ß-secretase cleavage of APP that Aß can be liberated from its precursor via {gamma}-secretase cleavage. Most interestingly—and in contrast to all other putative AD associations discussed above—there appears to be a high degree of consistency with respect to the site and allelic nature underlying these findings: all positive studies, including the initial report by Nowotny and colleagues published in 2001 (62), observe over-representations of the G-allele of a synonymous SNP located at codon 262 (in exon 5) in AD cases as compared with healthy controls. Furthermore, in all of these studies the observed effect was most pronounced in carriers of the APOE {varepsilon}4-allele, yielding significantly elevated odds ratios ranging from 2 to 7.

In contrast to these four positive associations, there is an equal number of studies in the literature showing no apparent effects of this BACE polymorphism and AD. However, it must be pointed out that one of these only studied early-onset familial AD cases (63), and the remaining studies did not account for the potential interaction with the APOE {varepsilon}4-allele (64–66). Unless this is done, similar to the situation encountered for the variants tested in IDE (see above), no firm conclusions can be reached as to whether or not the exon 5 polymorphism in BACE is a genetic risk factor for AD in these samples. Thus, of the three known APP-cleaving enzymes and associated proteins [{alpha}- (ADAM9,10 and 17), ß- (BACE, BACE2) and {gamma}-secretase (PSEN1, APH1A, NCSTN, PEN2)], most of which have already been tested for genetic association with AD phenotypes, BACE currently shows the most promise of being a genuine and relevant risk factor for late-onset AD. As is the case for all other putative AD genes, more studies using sufficiently sized samples and appropriate analytic strategies need to be performed before more general conclusions can be reached. Note, that the first study examining the putative genetic role of BACE in late-onset AD in 2004 also reports a significant effect of the exon 5 polymorphism in a case-control sample of Chinese origin (67).


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 2003: A GOOD VINTAGE...
 CONCLUSION
REFERENCES
 
While the year 2003 has been extremely productive in terms of studies examining potential associations between candidate genes and AD phenotypes, the vast majority of results—as in previous years—remains controversial. While in some cases this could be due to factors that are disease-specific (e.g. larger than anticipated genetic heterogeneity and/or very small effect sizes of individual risk alleles), a good proportion of these controversies are probably caused by methodological issues. Based on recent empirical and simulation data regarding the genetic make-up of complex diseases and the power of association studies in general, we propose that more attention should be paid to: (i) providing power estimates based on the structure of the analyzed sample for a variety of effect sizes and allele frequencies; (ii) replicating any positive signal in at least one independent population of sufficient size and power prior to initial publication; and (iii) thoroughly assessing the haplotype structure of any investigated locus, especially before reaching any negative conclusions. Together with statistical techniques that take into account potential interactions with other genetic and non-genetic factors, and that allow for an adequate correction of multiple comparisons, adherence to these criteria should ensure the successful distinction between clinically relevant and irrelevant/false-positive findings. Eventually, as in a good vintage of wine, this strategy will elevate the quality of AD genetics research to be on par with its quantity.

ACKNOWLEDGEMENTS
This work was sponsored by grants from the NIMH, NIA (ADRC) and the Alzheimer Association. L.B. is a fellow of the Harvard Center for Neurodegeneration and Repair (HCNR), and was a fellow of the Deutsche Forschungsgemeinschaft (DFG).


   FOOTNOTES
 
* To whom correspondence should be addressed at: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA. Tel: +1 6177266845; Fax: +1 6177241823; Email: tanzi{at}helix.mgh.harvard.edu


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