Genetics of Alzheimer's Disease

Abstract

Alzheimer's disease is the most common form of dementia and is the only top 10 cause of death in the United States that lacks disease-altering treatments. It is a complex disorder with environmental and genetic components. There are two major types of Alzheimer's disease, early onset and the more common late onset. The genetics of early-onset Alzheimer's disease are largely understood with variants in three different genes leading to disease. In contrast, while several common alleles associated with late-onset Alzheimer's disease, including APOE, have been identified using association studies, the genetics of late-onset Alzheimer's disease are not fully understood. Here we review the known genetics of early- and late-onset Alzheimer's disease.

Perry G. Ridge 1 and Mark T. W. Ebbert 1, 2 and John S. K. Kauwe 1

Recommended by Mikko Hiltunen

1, 401 WIDB, Department of Biology, Brigham Young University, Provo, UT 84602, USA
2, 500 W. Chipeta Way, ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT 84108, USA

Received 16 April 2013; Revised 8 July 2013; Accepted 8 July 2013

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Introduction

Alzheimer's disease (AD) is a devastating disease characterized by decreased cognition and is also the most common form of dementia affecting an estimated 24 to 35 million people worldwide [1-3]. Incidence is further expected to increase to 1 in 85 people by 2050 because of an aging population [2]. Persons diagnosed with AD typically survive 3 to 9 years after diagnosis [1]. Full-time care is often required as AD progresses, further impacting patients and their loved ones. With the anticipated increase in AD incidence, it is essential to achieve early diagnosis, effective treatments, and a better understanding of the underlying etiology.

Effective AD diagnostics remain elusive given the disease's similarity to other dementias and poorly understood etiology. The National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's disease and Related Disorders Association have jointly established criteria for AD diagnosis [4]. A diagnosis of probable AD is made based on meeting criteria in two areas: (1) core diagnostic criteria; and (2) supportive features. To receive a diagnosis of probable AD, a person must meet all criteria for core diagnostic criteria and one of four possible supportive features. Certain exclusion criteria exist, which if present, prevent diagnosis of probable AD. Diagnosis based on the core criteria is challenging because the criteria rely primarily on clinical observations and history. A full description of AD diagnosis can be found in Dubois et al. [4]. These are new criteria and are still used primarily for research in some countries.

Understanding AD etiology will be critical to effectively diagnose and treat the disease; however, while a number of hypotheses exist, the exact cause of AD is unknown. The most widely accepted hypothesis is the amyloid cascade hypothesis [5]. Amyloid precursor protein (APP) is cleaved by two pathways. In the nonamyloidogenic pathway, full length APP is cleaved by α and γ -secretases to produce a secreted C-terminal fragment of 83 residues. Cleavage via the β and γ -secretases can be promiscuous and produces several species of amyloid beta ( A β ) fragments. The most common fragment consists of 40 residues ( A _{β 40} ) and is known to inhibit amyloid deposition [6]. A fragment consisting of 42 residues ( A _{β 42} ) is also commonly produced. A _{β 42} self-aggregates and can grow into extracellular fibrils arranged into β -pleated sheets which are the insoluble fibers of neuritic and diffuse plaques (NPs) [1]. This is thought to be the first step in AD development [7]. Subsequently, intracellular neurofibrillary tangles (NFTs) are formed, which are largely composed of hyperphosphorylated tau proteins. The formation of NFTs is largely thought to be driven by the accumulation of NPs [1]. The presence of NPs and NFTs is the hallmark pathologies of AD [8].

Another hypothesis of AD involves the mitochondria. It is widely accepted that mitochondrial function is disrupted in the brains of AD patients [1, 9-13] and that NPs aggregate within mitochondria [14, 15]. It is not known, however, whether mitochondrial dysfunction is a cause or effect of NP aggregation [11]. These questions led to the proposal of the mitochondrial cascade hypothesis [10]. Briefly, mitochondrial function and morphology change and decline with age [13, 16]. As function begins to decline, mitochondria try to compensate. During this phase, the compensation causes alterations in the mitochondria. Finally, as the mitochondria begin to fail, there are additional compensatory changes. Changes such as A β aggregation and tau phosphorylation are some of the transformations that occur as a result of compensating and failing mitochondria; however, the mitochondrial cascade, if correct, likely only explains a subset of AD cases. In contrast to the mitochondrial cascade hypothesis, in the amyloid cascade hypothesis, changes such as A β aggregation and tau phosphorylation happen first and lead to the dysfunction of mitochondria [10, 13, 17]. Each of these hypotheses is likely to be affected by both genetic and nongenetic factors.

Various nongenetic factors impact both risk for and protection from AD--the greatest of which is age [1, 18]. Other risk factors include hypertension, estrogen supplements [19], smoking [20, 21], stroke, heart disease, depression, arthritis, and diabetes [22], although some of these may be early signs of disease rather than risk factors. On the other hand, certain lifestyle choices appear to decrease the risk of AD: exercise [23], intellectual stimulation [24], and maintaining a Mediterranean diet (including fish) [25, 26]. While these nongenetic factors may affect AD risk, genetics play a critical role. The genetics of AD are complicated, however, as it is a highly heterogeneous disorder.

Several genes are known to harbor either causative or risk variants for AD. There are two primary types of AD as defined by age. The first is early-onset AD (EOAD), and the second type is late-onset AD (LOAD). Each has a unique set of causative or risk modifying genetic factors. EOAD genes are known to harbor mutations that cause AD. In contrast, LOAD genes are associated with risk for AD, but known alleles are insufficient to cause AD. In this review, we will discuss the genetics of AD, including a discussion of causative genes as well as genes with replicable association with AD.

2. Genetics

2.1. Early-Onset Alzheimer's Disease

Early-onset AD begins before age 65, and incidence estimates range from 0-1% [27] to 6%-7% [19] of total AD cases. While EOAD is believed to be dominantly inherited, it is not fully penetrant. In fact, fewer than 13% of EOAD cases demonstrate a fully penetrant autosomal dominant inheritance for multiple generations [19]. Mutations in three different genes are known to cause EOAD: amyloid beta (A4) precursor protein (APP) [28], presenilin 1 (PSEN1) [29], and presenilin 2 (PSEN2) [30]. The majority of these mutations appear to be dominantly inherited; however, not all are completely penetrant. Clinical features and pathology vary depending on the mutation's locus and position within each gene.

2.1.1. APP

APP is located on chromosome 21 (21q21.2-21q21.3) and was one of the first causal genes identified for AD. There are at least 10 different APP isoforms. The primary transcript (NM_000484, NP_000475) is also the longest transcript with 18 exons. The exact function of APP is not certain, but several possible functions have been suggested such as synaptic development [31], neuronal migration [32], or as a receptor, although there have been arguments against this [33]. It is clear, however, that APP is cleaved into A β molecules, including A _{β 42} , which are secreted and can then accumulate in the brain forming NPs [1]. At least 25 pathogenic mutations have been identified in APP with the majority located in or adjacent to the A β domain (http://www.molgen.ua.ac.be/ADMutations) [33, 34]. Duplications of APP, including in Down's syndrome patients [35], are sufficient in many cases to cause EOAD due to increased A _{β 42} production and deposition [36, 37]. Mutations in APP account for 13-16% of all EOAD cases [38, 39].

There is substantial phenotypic heterogeneity in individuals with EOAD resulting from sequence variation in APP depending on exactly where the variant is located in the gene. Mutations are typically grouped into before, in, and after the A β domain [40]. Depending on the mutation, A _{β 42} levels may increase, A _{β 42} and A _{β 40} levels may increase (as in the case of the Swedish mutation), or total A β production may decrease [41-44]. The Swedish, Arctic, and London mutations are three prominent APP variants [28, 44-48]. These mutations are located in different domains of APP and lead to EOAD by different mechanisms. The Arctic mutation (E693G, inside the A β domain) appears to be dominantly inherited and fully penetrant with an average age of onset of 57 years and results in lower total A _{β 42} and A _{β 40} levels with ratios similar to wild type and leads to protofibril formation [44, 47]. In contrast to the Arctic mutation, the Swedish and London mutations flank the A β domain. The Swedish mutation is actually a double mutation before the A β domain (K670 M and N671 K) resulting in increased total A β production and changes inintercellular A β localization [45]. Finally, the London mutation (V717I) is located after the A β domain and results in higher A _{β 42} [28].

2.1.2. PSEN1

PSEN1 is located on chromosome 14 (14q24.3) and has at least two isoforms. Of the three genes known to cause EOAD, mutations in PSEN1 account for a greater percentage of EOAD cases (18-50%) than either of the other genes [49-51]. To date, there are at least 185 known AD causing mutations in PSEN1 (http://www.molgen.ua.ac.be/ADMutations) [34, 52]. PSEN1 EOAD is autosomal dominant; however it is incompletely penetrant. Furthermore, there can be substantial variation in age at onset (mean 45.5 years old), rate of progression, and severity of disease (average survival after diagnosis 8.4 years) [53]. Some of the variation is attributed to specific mutations in PSEN1 [54-56]. PSEN1 is a component of γ -secretase, which is one of the secretases responsible for APP cleavage [57]. Mutations in PSEN1 can change the secretase activity of γ -secretase and increase the ratio of A _{β 42} to A _{β 40} -and A _{β 42} more readily forms NPs [58, 59]. In general, PSEN1 mutations can be grouped into two groups: before protein position 200 and after. Pathology resulting from mutations before position 200 resembles the pathology found in sporadic AD cases, whereas mutations at subsequent positions in the protein result in more severe amyloid angiopathy [60].

2.1.3. PSEN2

PSEN2 is located on chromosome 1 (1q31-q42) and has two known isoforms. EOAD causing mutations in PSEN2 are relatively rare compared to PSEN1, have higher age of onset (53.7 years old), live longer after diagnosis (10.6), appear to have a more variable penetrance, and have not been as extensively studied [53, 61]. To date, there are 12 known pathogenic mutations in PSEN2 [34, 52]. While the exact function of PSEN2 is unknown, it is believed to have a similar function to PSEN1 (as described before) [62] and to cause AD pathology by increasing A _{β 42} levels [57].

2.2. Late-Onset Alzheimer's Disease

The second type of AD is late-onset AD (LOAD) or sporadic AD. Even though numerous genetic risk factors and biomarkers have been identified for LOAD, no causative gene has been identified. While there are many genes associated with LOAD, ten different loci (Table 1) meet all the criteria to be included in the "Top Results" list of the Alzheimer Research Forum or ALZGENE (accessed October 2011, for details about construction of the list see http://www.alzgene.org/) for associations with AD [63]. In this section we briefly introduce each of these loci in the following groups (grouped by common function, pathway, or family): apolipoproteins and lipid homeostasis, genes involved in endocytosis, MS4 family proteins, and other loci. We also review recently identified rare AD variants.

Table 1: Late-onset Alzheimer's disease associated genes/variants.

Variant	Gene	Abbreviation	Risk/protective
rs7412	Apolipoprotein E	APOE	Risk
rs429358	Apolipoprotein E	APOE	Protective
rs744373	Bridging integrator 1	BIN1	Risk
rs11136000	Clusterin	CLU	Protective
rs3764650	ATP-binding cassette, subfamily A (ABC1), member 7	ABCA7	Risk
rs3818361	Complement component (3b/4b) receptor 1 (Knops blood group)	CR1	Risk
rs3851179	Phosphatidylinositol binding clathrin assembly protein	PICALM	Protective
rs610932	Membrane-spanning 4 domains, subfamily A, member 6A	MS4A6A	Protective
rs3865444	CD33 molecule	CD33	Protective
rs670139	Membrane-spanning 4 domains, subfamily A, member 4E	MS4A4E	Risk
rs9349407	CD2-associated protein	CD2AP	Risk

Each of the top variants associated with late-onset Alzheimer's disease from meta-analysis done by the Alzheimer Research Forum is listed here, together with the specific associated variant, and whether the variant increases risk or provides protection.

2.2.1. Apolipoproteins and Lipid Homeostasis

Apolipoproteins are a family of proteins involved in lipid homeostasis. These proteins bind and transport lipids through the lymphatic and circulatory systems. Two different apolipoproteins and an ABC transporter have been shown to associate with AD. The first is apolipoprotein E (APOE), which is located on chromosome 19 (19q13.2) and consists of four total exons (three coding). There is only one major isoform (NM_000041, NP_000032), which encodes protein 317 amino acids in length. APOE is a component of the chylomicron and plays a pivotal role in very low density lipoprotein clearance from circulation [64]. Impaired function of APOE results in increased plasma levels of cholesterol and triglycerides [64].

There are three primary APOE alleles: [straight epsilon] 2 (rs429358), [straight epsilon] 3 (wild type), and [straight epsilon] 4 (rs7412). These alleles differ by substitutions at positions 112 and 158 (protein positions correspond to the processed protein) where the wild type allele [straight epsilon] 3 is Cys112 and Arg158, [straight epsilon] 2 is Cys112 and Arg158Cys, and [straight epsilon] 4 is Cys112Arg and Arg158. [straight epsilon] 3 has an estimated population frequency of 78.3% (8.5%-98%), whereas [straight epsilon] 2 has a population frequency of 6.4% (0%-37.5%) and [straight epsilon] 4 14.5% (0%-49%) [65]. The [straight epsilon] 4 allele is the risk allele and is the most significant known genetic risk factor for LOAD. This allele was first identified as a genetic risk factor for LOAD in 1993 by Corder et al. [66]. The association for this allele has been replicated numerous times in various ethnic groups including Caucasians [66], African Americans [67, 68], Asians [69, 70], and Hispanics [68]. The [straight epsilon] 4 allele is the only widely accepted genetic risk factor for LOAD [71] and increases risk with increasing [straight epsilon] 4 dosage. In contrast, [straight epsilon] 2 decreases AD risk [72]. Possible APOE genotypes, listed in order of AD risk, are [straight epsilon] 2/[straight epsilon] 2, [straight epsilon] 2/[straight epsilon] 3, [straight epsilon] 3/[straight epsilon] 3 or [straight epsilon] 2/[straight epsilon] 4, [straight epsilon] 3/[straight epsilon] 4, and [straight epsilon] 4/[straight epsilon] 4 [72]. Although AD risk is much higher in persons with one or more [straight epsilon] 4 alleles, [straight epsilon] 4 is not causative and some individuals homozygous for [straight epsilon] 4 never develop AD [66].

Despite APOE's importance in AD genetics, its exact role in AD is unknown. Levels of A _{β 42} deposition in the brain are, however, correlated with the number of [straight epsilon] 4 alleles [73], and APOE is hypothesized to be involved in the clearance of A _{β 42} from the brain, proteolytic degradation of A _{β 42} , and astrocyte mediated degradation of A _{β 42} [74-76].

The second apolipoprotein associated with AD is clusterin (CLU). A single variant, rs11136000, in CLU has been associated with AD in multiple different ethnic groups as a protective allele [71, 77-90] and has been associated with lower levels of A _{β 42} [91]. CLU, also known as apolipoprotein J, is located on chromosome 8 (8p21-p12). It has been suggested that CLU may increase the toxicity of A _{β 42} [92] and that it is involved in A _{β 42} clearance [93, 94]. Additionally, AD affected people have increased CLU in circulation, and CLU levels are correlated with a higher rate of cognitive decline [95-97]. Lastly, A β increases CLU expression [98], and there may be a direct interaction between A _{β 40} and CLU [99-101].

Another gene, ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7), was recently identified as an AD susceptibility locus based on a significant association between rs3764650 and AD [86, 102], where rs3764650 is located in intron 13 of ABCA7. ABCA7 is an ATP-binding cassette transporter used to move numerous molecules across membranes, and interference of ABCA7 decreases phagocytosis [103]. ABCA7 helps maintain lipid homeostasis through its role in lipid transport across the cellular membrane [104, 105]. Additionally, ABCA7 expression is responsive to lipoprotein levels and type [106]. Lipid dysfunction, changes in lipid homeostasis, and modifications of neuronal membrane homeostasis can all cause numerous diseases, including AD [107-109]. This provides a basis for how ABCA7 can lead to AD. rs3764560 is associated with increased risk for AD and, given ABCA7's role in lipid transport and phagocytosis, likely disrupts, or is in linkage disequilibrium (LD) with a variant that disrupts lipid homeostasis and/or membrane homeostasis.

2.2.2. Genes Involved in Endocytosis

Other important groups of genes are genes involved in endocytosis. Endocytosis is the process a cell uses to transport molecules across the cell membrane into the cell. Previous studies have demonstrated a role for endocytosis in AD generally, and clathrin-mediated endocytosis specifically [110]. Generally, APP is processed in endosomes; therefore endocytosis of APP from the cell surface is necessary for A _{β 42} production, while specifically inhibiting clathrin-mediated endocytosis decreases levels of A _{β 42} [110]. As such, endocytosis is a primary interest in AD etiology, and several genes involved in endocytosis such as BIN1, PICALM, CR1, and CD2AP are, unsurprisingly, associated with AD.

The first of these, bridging integrator 1 (BIN1), is located immediately downstream of rs744373, an SNP associated with AD [71, 77, 82, 86, 87, 90, 102, 111]. BIN1 is located on chromosome 2 (2q14) and has at least 10 different isoforms. BIN1 has multiple functions. First, BIN1 is involved in synaptic vesicle endocytosis [87, 112]. Like clathrin-mediated endocytosis, although to a lesser extent, synaptic activity endocytosis has a role in APP processing [110]. Second, BIN1 decreases the formation of clathrin-coated vesicles--a necessary step in clathrin-mediated endocytosis [113]. Mutations in BIN1 could, hypothetically, have different effects on the risk for AD. Variants that adversely affect BIN1's role in synaptic vesicle endocytosis would likely be protective since they would decrease APP processing efficiency. In contrast, variants that prevent BIN1 from inhibiting clathrin-coated vesicle formation would increase clathrin-mediated endocytosis and APP processing, resulting in increased A _{β 42} production. These variants would increase risk for AD. A single variant could conceivably have both effects; however, since clathrin-mediated endocytosis has a larger role in APP processing, the net effect would increase AD risk. rs744373 in BIN1 is one potential example and is associated with increased AD risk.

Another gene associated with AD and endocytosis is phosphatidylinositol binding clathrin assembly protein (PICALM) located on chromosome 11 (11q14) and has at least four known isoforms. Harold et al. [71] identified a single variant, rs3851179, associated with increased AD risk. This same association has been replicated several times [78, 82, 83, 86, 87, 114]. PICALM is involved in protein trafficking and synaptic vesicle endocytosis and may control levels of GluR2 and VAMP2 [112, 115, 116]. Its main function, however, is as a clathrin assembly protein, where it increases clathrin-coated vesicle assembly and helps regulate the amount of membrane recycling and clathrin-mediated endocytosis [115, 117]. The finding that rs3851179 is a protective allele against AD is consistent with a hypothesis that this variant decreases formation of clathrin-coated vesicles by disrupting PICALM function.

Another gene in the endocytic set associated with AD is complement component (3b/4b) receptor 1 (CR1). CR1 was first identified as a risk locus for AD in 2009 (rs3818361) [71, 85, 114], with replication in several ethnic groups [78, 79, 83, 87, 118]. CR1 is located on chromosome 1 (1q32) and has at least two known isoforms. Although an exact function for CR1 is not known, it has been suggested that CR1, working with C3b (a complement fragment in the complement cascade), plays a role in A β clearance [85, 118, 119]. Additionally, CR1 appears to facilitate endocytosis [120]. rs3818361 is associated with increased risk for AD. Variants in CR1 could potentially cause AD by disrupting its A β clearing function or by a gain-of-function mutation resulting in increased endocytosis.

Lastly, rs9349407 in a new AD susceptibility gene named CD2-associated protein (CD2AP) was recently reported [86, 102]. CD2AP is located on chromosome 6 (6p12) and is responsible for regulation of the actin cytoskeleton [121, 122]. CD2AP is additionally involved in receptor-mediated endocytosis [123]. Changing endocytosis can modify lipid homeostasis and APP processing, among other things, and is a plausible explanation for how rs9349407, or a variant in LD with rs9349407, could cause AD.

2.2.3. MS4A6A and MS4A4E

MS4 family proteins are another essential gene set in AD. Membrane-spanning 4 domains, subfamily A, member 6A (MS4A6A) and membrane-spanning 4 domains, subfamily A, member 4E (MS4A4E) were recently identified as AD risk loci with rs610932 (MS4A6A) and rs670139 (MS4A4E) showing association with AD [71, 86, 102]. rs610932 is located in the 3[variant prime]-UTR of MS4A6A, and rs670139 is in the intergenic region between MS4A6A and MS4A4E. Each has a different association with AD where rs610932 is protective and rs670139 increases AD risk. MS4A6A and MS4A4E are located together on chromosome 11 (11q12.1 and 11q12.2, resp.) with at least four and one known isoform(s), respectively, and are located in a cluster with other MS4A (membrane-spanning 4 domains subfamily A) subfamily genes [124, 125]. Very little is known about the function of either of these genes.

2.2.4. Other

Another locus associated with AD, which did not fit in any of the previous categories is rs3865444 in CD33 molecule (CD33). An association for rs3865444 was initially identified in 2008 [126] and was subsequently replicated several times [71, 86, 102, 127]. CD33 is a myeloid antigen located on chromosome 19q13.3 with at least three known isoforms and is expressed in a variety of tissues and cell types. Interestingly, CD33 plays a major role in leukemia [128], but no widely accepted hypotheses currently exist for its involvement in AD.

2.2.5. Rare Variants (TREM2 and APP)

In addition to loci reported on the Alzheimer Research Forum and ALZGENE, several groups recently identified two rare variants using novel study designs by combining next-generation sequencing and AD genetics. The first, rs63750847, is located in APP [129]. This missense variant is extremely rare (estimated frequency of 0.038%) and observed almost exclusively in people of Icelandic descent. This variant seems to confer protection against AD (odds ratio of 5 to 7 depending on the control group). In contrast, APOE [straight epsilon] 4, the largest known risk variant, has an odds ratio of 3.7. This variant is located close to the BACE1 cleavage site and results in reduced A _{β 42} production [129]. Interestingly, elderly controls bearing rs63750847 also experienced less cognitive decline than noncarrier controls suggesting shared physiology for both normal and AD-related cognitive decline.

A second rare variant, rs75932628, was recently identified in TREM2 [130, 131]. rs75932628 is a missense risk variant with a population frequency of 0.3% and odds ratio of ~3. This variant is hypothesized to increase risk for AD by disrupting the role of TREM2 in the regulation of phagocytosis and/or the inflammatory response [130]. We believe that these rare variants and others yet to be identified explain a large portion of genetic risk for AD. As such, a greater effort to identify any remaining variants must be a priority in AD research.

2.2.6. Mitochondrial Genetics and Alzheimer's Disease

As previously explained, mitochondria malfunction in AD is well known, but it is unclear whether these changes are a cause or effect of AD. Similarly, what role, if any, the mitochondrial genome has in AD risk is unknown even though numerous studies have been performed analyzing mitochondrial variation and/or haplotypes to identify sequence features in the mitochondrial genome associated with AD. While a number of these studies have identified significant associations, there is no consensus and some of these studies offer conflicting results. In Table 2, we list a summary of studies looking at variation in the mitochondrial genome and its role in AD.

Table 2: Mitochondrial variation/haplogroups associated with AD.

Haplogroup	Dataset	Effect	Ethnicity	No. cases/controls
B4C1 [132]	Selected SNPs	Risk	Japanese	96/384
G2A [132]	Selected SNPs	Risk	Japanese	96/384
HV [133]	Haplogroups, SNPs	Risk	Polish	222/252
H [134]	HVS-I sequence	Risk	Iranian	30/100
H5/H5A [135]	D-loop sequence, restriction analysis	Risk	Italian	936/776
H6A1A/H6A1B [136]	Full mtDNA sequences	Protective	Caucasian	101/632
K [137]	Haplogroups	Protective	Italian	N/A*
N9B1 [132]	Selected SNPs	Risk	Japanese	96/384
U [134, 138]	HVS-I sequence, 10 SNPs	Risk	Iranian, Caucasian	30/100, 989/328**
U [137, 138]	Haplogroups, 10 SNPs	Protective	Italian, Caucasian	N/A*, 989/328**
UK [139]	138 SNPs	Risk	Caucasian	170/188
None [140]	4 SNPs	None	Unknown	70/80
None [141]	European haplogroups	None	Unknown	185/179
None [142]	U, K, J, and T haplogroups	None	English	185/447
None [143]	European haplogroups	None	Tuscan	209/191
None [144]	Haplogroups	None	Finnish	128/99***
None [145]	138 SNPs	None	Caucasian	3250/1221

^* The authors showed that haplogroups U and K neutralized the risk of the APOE e4 allele.

^{* *} The authors demonstrated an increased risk for AD for males with haplogroup U and decreased risk for females with haplogroup U.

^{* * *} These were early onset AD cases.

3. Endophenotypes of Alzheimer's Disease

The use of endophenotypes of Alzheimer's disease to understand the genetic basis for AD risk is becoming more common. Cerebrospinal fluid levels of A _{β 42} and tau are perhaps the most accepted biomarkers for AD and have recently been used both to characterize the biological effects of known risk factors and to identify novel AD risk markers. Using quantitative endophenotypes instead of qualitative case/control status as the phenotype for a genetic study may reduce heterogeneity in clinical diagnosis, thus increasing power to detect genetic associations [146]. In addition, this approach can provide more specific hypotheses for the biological mechanism by which associated variants alter risk. Large-scale association studies of cerebrospinal fluid levels of A _{β 42} and tau/p-tau have successfully identified variants in several genes that alter risk or rate of progression of Alzheimer's disease [147-149]. Genetic variants in PPP3R1 and MAPT have been shown to be associated with cerebrospinal fluid p-tau levels and rate of decline in Alzheimer's disease patients in three independent samples [147, 149]. The largest genome-wide association study of cerebrospinal fluid tau levels to date identified three loci that show significant association. Two of these loci do not show evidence for association with AD risk or other AD related traits. The third locus (rs9877502) is on chromosome 3 between GEMC1 and OSTN. This locus shows significant association with several Alzheimer's disease phenotypes including AD risk, neurofibrillary tangle counts, and cognitive decline.

Cerebrospinal fluid levels of A _{β 42} and tau/p-tau have also been used to characterize the biological effects of reported Alzheimer's disease risk markers. The APOE [straight epsilon] 4 allele shows strong and replicable association with cerebrospinal fluid A _{β 42} and tau levels in several studies. Significant associations between variants in CLU, MS4A4A, and SORL1 and cerebrospinal A _{β 42} levels [91, 150] and between variants in CLU, PICALM, and CR1 and cerebrospinal tau levels have been reported [148, 151, 152]. The recent success of these approaches to both characterize newly discovered AD risk variants and identify novel risk variants suggests that the use of endophenotypes is an important part of the ongoing effort to solve the genetic architecture of AD.

4. Conclusions

Here we reviewed known genetic risk and protective factors of AD. Research findings thus far are substantial; however, we still know relatively little about the genetics of AD. 11 nuclear markers have been identified by association studies, and all but one of these have a small effect on risk (the two APOE alleles have larger effect). Additionally, these are not causative variants, even the APOE alleles, but are only associated with disease status. Functional variants have not been identified for any of the known AD markers. Many of the limitations that restricted our ability to find causative and additional AD biomarkers in the past no longer exist, and it is clear that many AD variants remain unidentified [153]. These unidentified variants, like the APP and TREM2 variants, will likely be rare, have large effect on risk, and require innovative study designs to discover. The application of next-generation sequencing to AD genetics will provide the necessary information to identify additional disease variants. The sequencing of large numbers of AD cases and controls (as in the case of APP and TREM2) will reveal additional, large effect AD variants, and the sequencing of large families will reveal rare, highly penetrant AD variants.

The study of epistasis is another area likely to add to our understanding of the genetics of AD, and recently, many researchers have called for an increased focus and developing more robust approaches to study gene-by-gene interactions [154-161]. Preliminary research has yielded a number of discoveries across diseases such as cancer, rheumatoid arthritis, and AD [162-187] and improved analytical methods [188-192]. Discovered interactions that affect AD risk include (1) IL-6 and IL-10 discovered by Infante et al. [193] and replicated by Combarros et al. [184]; (2) GSTM3 and the HHEX/IDE/KIF11 locus discovered by Bullock et al. [185]; (3) HMGCR and ABCA1 discovered by Rodríguez-Rodríguez et al. [186]; and TF and HFE first reported by Robson et al. [194] and replicated by Kauwe et al. [187].

There are, however, many challenges remaining. For instance, in 2009 Combarros et al. attempted to replicate more than 100 epistatic findings and were only able to replicate 27 [188], suggesting that many epistatic interactions may be false positives. Clearly current approaches need to be improved before we can efficiently study epistasis.

There have been huge advances in our understanding of the genetics of AD over the last few years. These advances are promising and illustrate the power and utility of modern approaches. As we begin to leverage datasets with increasing number of individuals and complete genomic coverage, we will have the opportunity to unravel the complexities of the genetic architecture of this disease, including the effects of rare variants and epistasis. This information provides the foundation for the development of preventative and curative therapies.

Conflict of Interests

The authors declare no conflict of interests.

Acknowledgments

Resources for this work were provided by Grants from NIH (R01AG042611), the Alzheimer's Association (MNIRG-11-205368), and the Brigham Young University Gerontology Program.

References

[1] H. W. Querfurth, F. M. LaFerla, "Alzheimer's disease," The New England Journal of Medicine , vol. 362, no. 4, pp. 329-344, 2010.

[2] R. Brookmeyer, E. Johnson, K. Ziegler-Graham, H. M. Arrighi, "Forecasting the global burden of Alzheimer's disease," Alzheimer's and Dementia , vol. 3, no. 3, pp. 186-191, 2007.

[3] C. Ballard, S. Gauthier, A. Corbett, C. Brayne, D. Aarsland, E. Jones, "Alzheimer's disease," The Lancet , vol. 377, no. 9770, pp. 1019-1031, 2011.

[4] B. Dubois, H. H. Feldman, C. Jacova, S. T. DeKosky, P. Barberger-Gateau, J. Cummings, A. Delacourte, D. Galasko, S. Gauthier, G. Jicha, K. Meguro, J. O'Brien, F. Pasquier, P. Robert, M. Rossor, S. Salloway, Y. Stern, P. J. Visser, P. Scheltens, "Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria," Lancet Neurology , vol. 6, no. 8, pp. 734-746, 2007.

[5] J. A. Hardy, G. A. Higgins, "Alzheimer's disease: the amyloid cascade hypothesis," Science , vol. 256, no. 5054, pp. 184-185, 1992.

[6] J. Kim, L. Onstead, S. Randle, R. Price, L. Smithson, C. Zwizinski, D. W. Dickson, T. Golde, E. McGowan, "Aβ 40 inhibits amyloid deposition in vivo," The Journal of Neuroscience , vol. 27, no. 3, pp. 627-633, 2007.

[7] R. A. Armstrong, "The pathogenesis of alzheimer's disease: a reevaluation of the 'amyloid cascade hypothesis'," International Journal of Alzheimer's Disease , vol. 2011, 2011.

[8] K. L. Newell, B. T. Hyman, J. H. Growdon, E. T. Hedley-Whyte, "Application of the National Institute on Aging (NIA)-Reagan Institute criteria for the neuropathological diagnosis of Alzheimer disease," Journal of Neuropathology and Experimental Neurology , vol. 58, no. 11, pp. 1147-1155, 1999.

[9] M. Ankarcrona, F. Mangialasche, B. Winblad, "Rethinking Alzheimer's disease therapy: are mitochondria the key?,", supplement 2 Journal of Alzheimer's Disease , vol. 20, pp. S579-S590, 2010.

[10] R. H. Swerdlow, S. M. Khan, "A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease," Medical Hypotheses , vol. 63, no. 1, pp. 8-20, 2004.

[11] M. Mancuso, D. Orsucci, G. Siciliano, L. Murri, "Mitochondria, mitochondrial DNA and Alzheimer's disease. What comes first?," Current Alzheimer Research , vol. 5, no. 5, pp. 457-468, 2008.

[12] I. Onyango, S. Khan, B. Miller, R. Swerdlow, P. Trimmer, J. Bennett Jr., "Mitochondrial genomic contribution to mitochondrial dysfunction in Alzheimer's disease," Journal of Alzheimer's Disease , vol. 9, no. 2, pp. 183-193, 2006.

[13] R. H. Swerdlow, J. M. Burns, S. M. Khan, "The Alzheimer's disease mitochondrial cascade hypothesis,", supplement 2 Journal of Alzheimer's Disease , vol. 20, pp. S265-S279, 2010.

[14] L. Devi, B. M. Prabhu, D. F. Galati, N. G. Avadhani, H. K. Anandatheerthavarada, "Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction," The Journal of Neuroscience , vol. 26, no. 35, pp. 9057-9068, 2006.

[15] H. K. Anandatheerthavarada, L. Devi, "Amyloid precursor protein and mitochondrial dysfunction in Alzheimer's disease," Neuroscientist , vol. 13, no. 6, pp. 626-638, 2007.

[16] D. C. Chan, "Mitochondria: dynamic organelles in disease, aging, and development," Cell , vol. 125, no. 7, pp. 1241-1252, 2006.

[17] R. H. Swerdlow, S. M. Khan, "The Alzheimer's disease mitochondrial cascade hypothesis: an update," Experimental Neurology , vol. 218, no. 2, pp. 308-315, 2009.

[18] K. Herrup, "Reimagining Alzheimer's disease--an age-based hypothesis," The Journal of Neuroscience , vol. 30, no. 50, pp. 16755-16762, 2010.

[19] C. Patterson, J. W. Feightner, A. Garcia, G.-Y. R. Hsiung, C. MacKnight, A. D. Sadovnick, "Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease," Canadian Medical Association Journal , vol. 178, no. 5, pp. 548-556, 2008.

[20] J. K. Cataldo, J. J. Prochaska, S. A. Glantz, "Cigarette smoking is a risk factor for Alzheimer's disease: an analysis controlling for tobacco industry affiliation," Journal of Alzheimer's Disease , vol. 19, no. 2, pp. 465-480, 2010.

[21] O. P. Almeida, G. K. Hulse, D. Lawrence, L. Flicker, "Smoking as a risk factor for Alzheimer's disease: contrasting evidence from a systematic review of case-control and cohort studies," Addiction , vol. 97, no. 1, pp. 15-28, 2002.

[22] J. Lindsay, D. Laurin, R. Verreault, R. Hébert, B. Helliwell, G. B. Hill, I. McDowell, "Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging," American Journal of Epidemiology , vol. 156, no. 5, pp. 445-453, 2002.

[23] L. J. Podewils, E. Guallar, L. H. Kuller, L. P. Fried, O. L. Lopez, M. Carlson, C. G. Lyketsos, "Physical activity, APOE genotype, and dementia risk: findings from the Cardiovascular Health Cognition Study," American Journal of Epidemiology , vol. 161, no. 7, pp. 639-651, 2005.

[24] H.-X. Wang, A. Karp, B. Winblad, L. Fratiglioni, "Late-life engagement in social and leisure activities is associated with a decreased risk of dementia: a longitudinal study from the Kungsholmen Project," American Journal of Epidemiology , vol. 155, no. 12, pp. 1081-1087, 2002.

[25] N. Scarmeas, Y. Stern, R. Mayeux, J. A. Luchsinger, "Mediterranean diet, alzheimer disease, and vascular mediation," Archives of Neurology , vol. 63, no. 12, pp. 1709-1717, 2006.

[26] C. Patterson, J. Feightner, A. Garcia, C. MacKnight, "General risk factors for dementia: a systematic evidence review," Alzheimer's and Dementia , vol. 3, no. 4, pp. 341-347, 2007.

[27] K. Blennow, M. J. de Leon, H. Zetterberg, "Alzheimer's disease," The Lancet , vol. 368, no. 9533, pp. 387-403, 2006.

[28] A. Goate, M.-C. Chartier-Harlin, M. Mullan, J. Brown, F. Crawford, L. Fidani, L. Giuffra, A. Haynes, N. Irving, L. James, R. Mant, P. Newton, K. Rooke, P. Roques, C. Talbot, M. Pericak-Vance, A. Roses, R. Williamson, J. Hardy, "Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease," Nature , vol. 349, no. 6311, pp. 704-706, 1991.

[29] R. Sherrington, E. I. Rogaev, Y. Liang, E. A. Rogaeva, G. Levesque, M. Ikeda, H. Chi, C. Lin, K. Holman, T. Tsuda, L. Mar, J.-F. Foncin, A. C. Bruni, M. P. Montesi, S. Sorbi, I. Rainero, L. Pinessi, L. Nee, I. Chumakov, P. H. St George-Hyslop, "Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease," Nature , vol. 375, no. 6534, pp. 754-760, 1995.

[30] E. Levy-Lahad, W. Wasco, P. Poorkaj, D. M. Romano, J. Oshima, W. H. Pettingell, C.-E. Yu, P. D. Jondro, S. D. Schmidt, K. Wang, A. C. Crowley, Y.-H. Fu, S. Y. Guenette, D. Galas, E. Nemens, E. M. Wijsman, T. D. Bird, G. D. Schellenberg, R. E. Tanzi, "Candidate gene for the chromosome 1 familial Alzheimer's disease locus," Science , vol. 269, no. 5226, pp. 973-977, 1995.

[31] C. Priller, T. Bauer, G. Mitteregger, B. Krebs, H. A. Kretzschmar, J. Herms, "Synapse formation and function is modulated by the amyloid precursor protein," The Journal of Neuroscience , vol. 26, no. 27, pp. 7212-7221, 2006.

[32] T. L. Young-Pearse, J. Bai, R. Chang, J. B. Zheng, J. J. Loturco, D. J. Selkoe, "A critical function for β -amyloid precursor protein in neuronal migration revealed by in utero RNA interference," The Journal of Neuroscience , vol. 27, no. 52, pp. 14459-14469, 2007.

[33] G. Thinakaran, E. H. Koo, "Amyloid precursor protein trafficking, processing, and function," The Journal of Biological Chemistry , vol. 283, no. 44, pp. 29615-29619, 2008.

[34] M. Cruts, C. Van Broeckhoven, "Molecular genetics of Alzheimer's disease," Annals of Medicine , vol. 30, no. 6, pp. 560-565, 1998.

[35] L. N. Geller, H. Potter, "Chromosome missegregation and trisomy 21 mosaicism in Alzheimer's disease," Neurobiology of Disease , vol. 6, no. 3, pp. 167-179, 1999.

[36] K. Sleegers, N. Brouwers, I. Gijselinck, J. Theuns, D. Goossens, J. Wauters, J. Del-Favero, M. Cruts, C. M. Van Duijn, C. Van Broeckhoven, "APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy," Brain , vol. 129, no. 11, pp. 2977-2983, 2006.

[37] B. V. Hooli, G. Mohapatra, M. Mattheisen, "Role of common and rare APP DNA sequence variants in Alzheimer disease," Neurology , vol. 78, pp. 1250-1257, 2012.

[38] J. C. Janssen, J. A. Beck, T. A. Campbell, A. Dickinson, N. C. Fox, R. J. Harvey, H. Houlden, M. N. Rossor, J. Collinge, "Early onset familial Alzheimer's disease: mutation frequency in 31 families," Neurology , vol. 60, no. 2, pp. 235-239, 2003.

[39] G. Raux, L. Guyant-Maréchal, C. Martin, J. Bou, C. Penet, A. Brice, D. Hannequin, T. Frebourg, D. Campion, "Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update," Journal of Medical Genetics , vol. 42, no. 10, pp. 793-795, 2005.

[40] E. Rogaeva, "The solved and unsolved mysteries of the genetics of early-onset Alzheimer's disease," NeuroMolecular Medicine , vol. 2, no. 1, pp. 1-10, 2002.

[41] M. Citron, T. Oltersdorf, C. Haass, L. McConlogue, A. Y. Hung, P. Seubert, C. Vigo-Pelfrey, I. Lieberburg, D. J. Selkoe, "Mutation of the β -amyloid precursor protein in familial Alzheimer's disease increases β -protein production," Nature , vol. 360, no. 6405, pp. 672-674, 1992.

[42] M. Citron, C. Vigo-Pelfrey, D. B. Teplow, C. Miller, D. Schenk, J. Johnston, B. Winblad, N. Venizelos, L. Lannfelt, D. J. Selkoe, "Excessive production of amyloid β -protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation," Proceedings of the National Academy of Sciences of the United States of America , vol. 91, no. 25, pp. 11993-11997, 1994.

[43] C. Haass, A. Y. Hung, D. J. Selkoe, D. B. Teplow, "Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid β -protein precursor," The Journal of Biological Chemistry , vol. 269, no. 26, pp. 17741-17748, 1994.

[44] C. Nilsberth, A. Westlind-Danielsson, C. B. Eckman, M. M. Condron, K. Axelman, C. Forsell, C. Stenh, J. Luthman, D. B. Teplow, S. G. Younkin, J. Näslund, L. Lannfelt, "The "Arctic" APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation," Nature Neuroscience , vol. 4, no. 9, pp. 887-893, 2001.

[45] C. Haass, C. A. Lemere, A. Capell, M. Citron, P. Seubert, D. Schenk, L. Lannfelt, D. J. Selkoe, "The Swedish mutation causes early-onset Alzheimer's disease by β -secretase cleavage within the secretory pathway," Nature Medicine , vol. 1, no. 12, pp. 1291-1296, 1995.

[46] J. V. Dorpe, L. Smeijers, I. Dewachter, D. Nuyens, K. Spittaels, C. Van den Haute, M. Mercken, D. Moechars, I. Laenen, C. Kuiperi, K. Bruynseels, I. Tesseur, R. Loos, H. Vanderstichele, F. Checler, R. Sciot, F. Van Leuven, "Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the London mutant of human APP in neurons," American Journal of Pathology , vol. 157, no. 4, pp. 1283-1298, 2000.

[47] C. Sahlin, A. Lord, K. Magnusson, H. Englund, C. G. Almeida, P. Greengard, F. Nyberg, G. K. Gouras, L. Lannfelt, L. N. G. Nilsson, "The Arctic Alzheimer mutation favors intracellular amyloid-β production by making amyloid precursor protein less available to α -secretase," Journal of Neurochemistry , vol. 101, no. 3, pp. 854-862, 2007.

[48] D. Moechars, I. Dewachter, K. Lorent, D. Reversé, V. Baekelandt, A. Naidu, I. Tesseur, K. Spittaels, C. Van Den Haute, F. Checler, E. Godaux, B. Cordell, F. Van Leuven, "Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain," The Journal of Biological Chemistry , vol. 274, no. 10, pp. 6483-6492, 1999.

[49] M. Cruts, C. M. van Duijn, H. Backhovens, M. Van Den Broeck, A. Wehnert, S. Serneels, R. Sherrington, M. Hutton, J. Hardy, P. H. St George-Hyslop, A. Hofman, C. Van Broeckhoven, "Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease," Human Molecular Genetics , vol. 7, no. 1, pp. 43-51, 1998.

[50] D. Campion, J.-M. Flaman, A. Brice, D. Hannequin, B. Dubois, C. Martin, V. Moreau, F. Charbonnier, O. Didierjean, S. Tardieu, C. Penet, M. Puel, F. Pasquier, F. Le Doze, G. Bellis, A. Calenda, R. Heilig, M. Martinez, T. Frebourg, "Mutations of the presenilin I gene in families with early-onset Alzheimer's disease," Human Molecular Genetics , vol. 4, no. 12, pp. 2373-2377, 1995.

[51] M. Hutton, F. Busfield, M. Wragg, R. Crook, J. Perez-Tur, R. F. Clark, G. Prihar, C. Talbot, H. Phillips, K. Wright, M. Baker, C. Lendon, K. Duff, A. Martinez, H. Houlden, A. Nichols, E. Karran, G. Roberts, P. Roques, M. Rossor, J. Craig Venter, M. D. Adams, R. T. Cline, C. A. Phillips, R. A. Fuldner, J. Hardy, A. Goate, "Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease," NeuroReport , vol. 7, no. 3, pp. 801-805, 1996.

[52] M. Cruts, C. Van Broeckhoven, "Presenilin mutations in Alzheimer's disease," Human Mutation , vol. 11, pp. 183-190, 1998.

[53] S. Jayadev, J. B. Leverenz, E. Steinbart, J. Stahl, W. Klunk, C.-E. Yu, T. D. Bird, "Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2," Brain , vol. 133, no. 4, pp. 1143-1154, 2010.

[54] T. Moehlmann, E. Winkler, X. Xia, D. Edbauer, J. Murrell, A. Capell, C. Kaether, H. Zheng, B. Ghetti, C. Haass, H. Steiner, "Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ 42 production," Proceedings of the National Academy of Sciences of the United States of America , vol. 99, no. 12, pp. 8025-8030, 2002.

[55] L. A. Rudzinski, R. M. Fletcher, D. W. Dickson, R. Crook, M. L. Hutton, J. Adamson, N. R. Graff-Radford, "Early onset familial alzheimer disease with spastic paraparesis, dysarthria, and seizures and N135S mutation in PSEN1," Alzheimer Disease and Associated Disorders , vol. 22, no. 3, pp. 299-307, 2008.

[56] J. M. Heckmann, W.-C. Low, C. de Villiers, S. Rutherfoord, A. Vorster, H. Rao, C. M. Morris, R. S. Ramesar, R. N. Kalaria, "Novel presenilin 1 mutation with profound neurofibrillary pathology in an indigenous Southern African family with early-onset Alzheimer's disease," Brain , vol. 127, no. 1, pp. 133-142, 2004.

[57] H. Steiner, E. Winkler, D. Edbauer, S. Prokop, G. Basset, A. Yamasaki, M. Kostka, C. Haass, "PEN-2 is an integral component of the γ -secretase complex required for coordinated expression of presenilin and nicastrin," The Journal of Biological Chemistry , vol. 277, no. 42, pp. 39062-39065, 2002.

[58] M. Citron, D. Westaway, W. Xia, G. Carlson, T. Diehl, G. Levesque, K. Johnson-Wood, M. Lee, P. Seubert, A. Davis, D. Kholodenko, R. Motter, R. Sherrington, B. Perry, H. Yao, R. Strome, I. Lieberburg, J. Rommens, S. Kim, D. Schenk, P. Fraser, P. St. George Hyslop, D. J. Selkoe, "Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β -protein in both transfected cells and transgenic mice," Nature Medicine , vol. 3, no. 1, pp. 67-72, 1997.

[59] G. D. Schellenberg, T. D. Bird, E. M. Wijsman, H. T. Orr, L. Anderson, E. Nemens, J. A. White, L. Bonnycastle, J. L. Weber, M. E. Alonso, H. Potter, L. L. Heston, G. M. Martin, "Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14," Science , vol. 258, no. 5082, pp. 668-671, 1992.

[60] N. S. Ryan, M. N. Rossor, "Correlating familial Alzheimers disease gene mutations with clinical phenotype," Biomarkers in Medicine , vol. 4, no. 1, pp. 99-112, 2010.

[61] R. Sherrington, S. Froelich, S. Sorbi, D. Campion, H. Chi, E. A. Rogaeva, G. Levesque, E. I. Rogaev, C. Lin, Y. Liang, M. Ikeda, L. Mar, A. Brice, Y. Agid, M. E. Percy, F. Clerget-Darpoux, S. Piacentini, G. Marcon, B. Nacmias, L. Amaducci, T. Frebourg, L. Lannfelt, J. M. Rommens, P. H. St George-Hyslop, "Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant," Human Molecular Genetics , vol. 5, no. 7, pp. 985-988, 1996.

[62] D. M. Kovacs, H. J. Fausett, K. J. Page, T.-W. Kim, R. D. Moir, D. E. Merriam, R. D. Hollister, O. G. Hallmark', R. Mancini, K. M. Felsenstein, B. T. Hyman, R. E. Tanzi, W. Wasco, "Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells," Nature Medicine , vol. 2, no. 2, pp. 224-229, 1996.

[63] L. Bertram, M. B. McQueen, K. Mullin, D. Blacker, R. E. Tanzi, "Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database," Nature Genetics , vol. 39, no. 1, pp. 17-23, 2007.

[64] R. W. Mahley, "Apolipoprotein E: cholesterol transport protein with expanding role in cell biology," Science , vol. 240, no. 4852, pp. 622-630, 1988.

[65] D. T. A. Eisenberg, C. W. Kuzawa, M. G. Hayes, "Worldwide allele frequencies of the human apolipoprotein E gene: climate, local adaptations, and evolutionary history," American Journal of Physical Anthropology , vol. 143, no. 1, pp. 100-111, 2010.

[66] E. H. Corder, A. M. Saunders, W. J. Strittmatter, D. E. Schmechel, P. C. Gaskell, G. W. Small, A. D. Roses, J. L. Haines, M. A. Pericak-Vance, "Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families," Science , vol. 261, no. 5123, pp. 921-923, 1993.

[67] H. C. Hendrie, K. S. Hall, S. Hui, F. W. Unverzagt, C. E. Yu, D. K. Lahiri, A. Sahota, M. Farlow, B. Musick, C. A. Class, A. Brashear, V. E. Burdine, B. O. Osuntokun, A. O. Ogunniyi, O. Gureje, O. Baiyewu, G. D. Schellenberg, "Apolipoprotein E genotypes and Alzheimer's disease in a community study of elderly African Americans," Annals of Neurology , vol. 37, no. 1, pp. 118-120, 1995.

[68] G. Maestre, R. Ottman, Y. Stern, B. Gurland, M. Chun, M.-X. Tang, M. Shelanski, B. Tycko, R. Mayeux, "Apolipoprotein E and Alzheimer's disease: ethnic variation in genotypic risks," Annals of Neurology , vol. 37, no. 2, pp. 254-259, 1995.

[69] S. Noguchi, K. Murakami, N. Yamada, H. Payami, J. Kaye, L. L. Heston, T. D. Bird, G. D. Schellenberg, "Apolipoprotein E genotype and Alzheimer's disease," The Lancet , vol. 342, no. 8873, pp. 737-738, 1993.

[70] A. Ueki, M. Kawano, Y. Namba, M. Kawakami, K. Ikeda, "A high frequency of apolipoprotein E4 isoprotein in Japanese patients with late-onset nonfamilial Alzheimer's disease," Neuroscience Letters , vol. 163, no. 2, pp. 166-168, 1993.

[71] D. Harold, R. Abraham, P. Hollingworth, "Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease," Nature Genetics , vol. 41, pp. 1088-1093, 2009.

[72] E. H. Corder, A. M. Saunders, N. J. Risch, W. J. Strittmatter, D. E. Schmechel, P. C. Gaskell Jr., J. B. Rimmler, P. A. Locke, P. M. Conneally, K. E. Schmader, G. W. Small, A. D. Roses, J. L. Haines, M. A. Pericak-Vance, "Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease," Nature Genetics , vol. 7, no. 2, pp. 180-184, 1994.

[73] E. M. Reiman, K. Chen, X. Liu, D. Bandy, M. Yu, W. Lee, N. Ayutyanont, J. Keppler, S. A. Reeder, J. B. S. Langbaum, G. E. Alexander, W. E. Klunk, C. A. Mathis, J. C. Price, H. J. Aizensteini, S. T. DeKosky, R. J. Caselli, "Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease," Proceedings of the National Academy of Sciences of the United States of America , vol. 106, no. 16, pp. 6820-6825, 2009.

[74] K. R. Bales, J. C. Dodart, R. B. DeMattos, D. M. Holtzman, S. M. Paul, "Apolipoprotein E, amyloid, and Alzheimer disease," Molecular Interventions , vol. 2, no. 6, pp. 363-375, 2002.

[75] M. Koistinaho, S. Lin, X. Wu, M. Esterman, D. Koger, J. Hanson, R. Higgs, F. Liu, S. Malkani, K. R. Bales, S. M. Paul, "Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides," Nature Medicine , vol. 10, no. 7, pp. 719-726, 2004.

[76] Q. Jiang, C. Y. D. Lee, S. Mandrekar, B. Wilkinson, P. Cramer, N. Zelcer, K. Mann, B. Lamb, T. M. Willson, J. L. Collins, J. C. Richardson, J. D. Smith, T. A. Comery, D. Riddell, D. M. Holtzman, P. Tontonoz, G. E. Landreth, "ApoE promotes the proteolytic degradation of Aβ ," Neuron , vol. 58, no. 5, pp. 681-693, 2008.

[77] A. Biffi, C. D. Anderson, R. S. Desikan, M. Sabuncu, L. Cortellini, N. Schmansky, D. Salat, J. Rosand, "Genetic variation and neuroimaging measures in Alzheimer disease," Archives of Neurology , vol. 67, no. 6, pp. 677-685, 2010.

[78] M. M. Carrasquillo, O. Belbin, T. A. Hunter, L. Ma, G. D. Bisceglio, F. Zou, J. E. Crook, V. S. Pankratz, D. W. Dickson, N. R. Graff-Radford, R. C. Petersen, K. Morgan, S. G. Younkin, "Replication of CLU, CR1, and PICALM associations with Alzheimer disease," Archives of Neurology , vol. 67, no. 8, pp. 961-964, 2010.

[79] J. J. Corneveaux, A. J. Myers, A. N. Allen, J. J. Pruzin, M. Ramirez, A. Engel, M. A. Nalls, K. Chen, W. Lee, K. Chewning, S. E. Villa, H. B. Meechoovet, J. D. Gerber, D. Frost, H. L. Benson, S. O'Reilly, L. B. Chibnik, J. M. Shulman, A. B. Singleton, D. W. Craig, K. R. Van Keuren-Jensen, T. Dunckley, D. A. Bennett, P. L. de Jager, C. Heward, J. Hardy, E. M. Reiman, M. J. Huentelman, "Association of CR1, CLU and PICALM with Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals," Human Molecular Genetics , vol. 19, no. 16, pp. 3295-3301, 2010.

[80] V. Giedraitis, L. Kilander, M. Degerman-Gunnarsson, J. Sundelöf, T. Axelsson, A.-C. Syvänen, L. Lannfelt, A. Glaser, "Genetic analysis of Alzheimer's disease in the Uppsala Longitudinal Study of Adult Men," Dementia and Geriatric Cognitive Disorders , vol. 27, no. 1, pp. 59-68, 2009.

[81] R. J. Guerreiro, J. Beck, J. R. Gibbs, I. Santana, M. N. Rossor, J. M. Schott, M. A. Nalls, H. Ribeiro, B. Santiago, N. C. Fox, C. Oliveira, J. Collinge, S. Mead, A. Singleton, J. Hardy, "Genetic variability in CLU and its association with Alzheimer's disease," PLoS ONE , vol. 5, no. 3, 2010.

[82] X. Hu, E. Pickering, Y. C. Liu, S. Hall, H. Fournier, E. Katz, B. Dechairo, S. John, P. van Eerdewegh, H. Soares, "Meta-analysis for genome-wide association study identifies multiple variants at the BIN1 locus associated with late-onset Alzheimer's disease," PLoS ONE , vol. 6, no. 2, 2011.

[83] G. Jun, A. C. Naj, G. W. Beecham, "Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes," Archives of Neurology , vol. 67, pp. 1473-1484, 2010.

[84] M. I. Kamboh, R. L. Minster, F. Y. Demirci, M. Ganguli, S. T. DeKosky, O. L. Lopez, M. M. Barmada, "Association of CLU and PICALM variants with Alzheimer's disease," Neurobiology of Aging , vol. 33, no. 3, pp. 518-521, 2012.

[85] J.-C. Lambert, S. Heath, G. Even, D. Campion, K. Sleegers, M. Hiltunen, O. Combarros, D. Zelenika, M. J. Bullido, B. Tavernier, L. Letenneur, K. Bettens, C. Berr, F. Pasquier, N. Fiévet, P. Barberger-Gateau, S. Engelborghs, P. De Deyn, I. Mateo, A. Franck, S. Helisalmi, E. Porcellini, O. Hanon, M. M. De Pancorbo, C. Lendon, C. Dufouil, C. Jaillard, T. Leveillard, V. Alvarez, P. Bosco, M. Mancuso, F. Panza, B. Nacmias, P. Boss, P. Piccardi, G. Annoni, D. Seripa, D. Galimberti, D. Hannequin, F. Licastro, H. Soininen, K. Ritchie, H. Blanché, J.-F. Dartigues, C. Tzourio, I. Gut, C. Van Broeckhoven, A. Alpérovitch, M. Lathrop, P. Amouyel, B. Arosio, E. Coto, M. D. Zompo, V. Deramecourt, J. Epelbaum, P. Forti, A. Brice, R. Ferri, E. Scarpini, G. Siciliano, V. Solfrizzi, S. Sorbi, G. Spalletta, G. Ravaglia, J. Sahel, F. Valdivieso, S. Vepsäläinen, A. Pilotto, "Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease," Nature Genetics , vol. 41, no. 10, pp. 1094-1099, 2009.

[86] A. C. Naj, G. Jun, G. W. Beecham, "Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease," Nature Genetics , vol. 43, pp. 436-441, 2011.

[87] S. Seshadri, A. L. Fitzpatrick, M. A. Ikram, "Genome-wide analysis of genetic loci associated with Alzheimer disease," Journal of the American Medical Association , vol. 303, no. 18, pp. 1832-1840, 2010.

[88] B. Tycko, L. Feng, L. Nguyen, "Polymorphisms in the human apolipoprotein-J/clusterin gene: ethnic variation and distribution in Alzheimer's disease," Human Genetics , vol. 98, pp. 430-436, 1996.

[89] J.-T. Yu, L. Li, Q.-X. Zhu, Q. Zhang, W. Zhang, Z.-C. Wu, J. Guan, L. Tan, "Implication of CLU gene polymorphisms in Chinese patients with Alzheimer's disease," Clinica Chimica Acta , vol. 411, no. 19-20, pp. 1516-1519, 2010.

[90] E. M. Wijsman, N. D. Pankratz, Y. Choi, J. H. Rothstein, K. M. Faber, R. Cheng, J. H. Lee, T. D. Bird, D. A. Bennett, R. Diaz-Arrastia, A. M. Goate, M. Farlow, B. Ghetti, R. A. Sweet, T. M. Foroud, R. Mayeux, "Genome-wide association of familial late-onset alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE," PLoS Genetics , vol. 7, no. 2, 2011.

[91] L. S. Elias-Sonnenschein, S. Helisalmi, T. Natunen, "Genetic loci associated with Alzheimer's disease and cerebrospinal fluid biomarkers in a Finnish case-control cohort," PLoS One , vol. 8, 2013.

[92] R. B. DeMattos, M. A. O'dell, M. Parsadanian, J. W. Taylor, J. A. K. Harmony, K. R. Bales, S. M. Paul, B. J. Aronow, D. M. Holtzman, "Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease," Proceedings of the National Academy of Sciences of the United States of America , vol. 99, no. 16, pp. 10843-10848, 2002.

[93] R. B. DeMattos, J. R. Cirrito, M. Parsadanian, P. C. May, M. A. O'Dell, J. W. Taylor, J. A. K. Harmony, B. J. Aronow, K. R. Bales, S. M. Paul, D. M. Holtzman, "ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo," Neuron , vol. 41, no. 2, pp. 193-202, 2004.

[94] R. D. Bell, A. P. Sagare, A. E. Friedman, G. S. Bedi, D. M. Holtzman, R. Deane, B. V. Zlokovic, "Transport pathways for clearance of human Alzheimer's amyloid β -peptide and apolipoproteins E and J in the mouse central nervous system," Journal of Cerebral Blood Flow and Metabolism , vol. 27, no. 5, pp. 909-918, 2007.

[95] E. M. C. Schrijvers, P. J. Koudstaal, A. Hofman, M. M. B. Breteler, "Plasma clusterin and the risk of Alzheimer disease," Journal of the American Medical Association , vol. 305, no. 13, pp. 1322-1326, 2011.

[96] M. Thambisetty, Y. An, A. Kinsey, D. Koka, M. Saleem, A. Guntert, M. Kraut, L. Ferrucci, C. Davatzikos, S. Lovestone, S. M. Resnick, "Plasma clusterin concentration is associated with longitudinal brain atrophy in mild cognitive impairment," NeuroImage , vol. 59, no. 1, pp. 212-217, 2012.

[97] M. Thambisetty, A. Simmons, L. Velayudhan, A. Hye, J. Campbell, Y. Zhang, L.-O. Wahlund, E. Westman, A. Kinsey, A. Güntert, P. Proitsi, J. Powell, M. Causevic, R. Killick, K. Lunnon, S. Lynham, M. Broadstock, F. Choudhry, D. R. Howlett, R. J. Williams, S. I. Sharp, C. Mitchelmore, C. Tunnard, R. Leung, C. Foy, D. O'Brien, G. Breen, S. J. Furney, M. Ward, I. Kloszewska, P. Mecocci, H. Soininen, M. Tsolaki, B. Vellas, A. Hodges, D. G. M. Murphy, S. Parkins, J. C. Richardson, S. M. Resnick, L. Ferrucci, D. F. Wong, Y. Zhou, S. Muehlboeck, A. Evans, P. T. Francis, C. Spenger, S. Lovestone, "Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease," Archives of General Psychiatry , vol. 67, no. 7, pp. 739-748, 2010.

[98] M. J. Ladu, J. A. Shah, C. A. Reardon, G. S. Getz, G. Bu, J. Hu, L. Guo, L. J. Van Eldik, "Apolipoprotein E receptors mediate the effects of β -amyloid on astrocyte cultures," The Journal of Biological Chemistry , vol. 275, no. 43, pp. 33974-33980, 2000.

[99] I. P. Trougakos, E. S. Gonos, "Regulation of clusterin/apolipoprotein J, a functional homologue to the small heat shock proteins, by oxidative stress in ageing and age-related diseases," Free Radical Research , vol. 40, no. 12, pp. 1324-1334, 2006.

[100] B. V. Zlokovic, C. L. Martel, E. Matsubara, J. G. Mccomb, G. Zheng, R. T. Mccluskey, B. Frangione, J. Ghiso, "Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid β at the blood-brain and blood-cerebrospinal fluid barriers," Proceedings of the National Academy of Sciences of the United States of America , vol. 93, no. 9, pp. 4229-4234, 1996.

[101] E. Matsubara, C. Soto, S. Governale, B. Frangione, J. Ghiso, "Apolipoprotein J and Alzheimer's amyloid β solubility," Biochemical Journal , vol. 316, no. 2, pp. 671-679, 1996.

[102] P. Hollingworth, D. Harold, R. Sims, A. Gerrish, J.-C. Lambert, M. M. Carrasquillo, R. Abraham, M. L. Hamshere, J. S. Pahwa, V. Moskvina, K. Dowzell, N. Jones, A. Stretton, C. Thomas, A. Richards, D. Ivanov, C. Widdowson, J. Chapman, S. Lovestone, J. Powell, P. Proitsi, M. K. Lupton, C. Brayne, D. C. Rubinsztein, M. Gill, B. Lawlor, A. Lynch, K. S. Brown, P. A. Passmore, D. Craig, B. McGuinness, S. Todd, C. Holmes, D. Mann, A. D. Smith, H. Beaumont, D. Warden, G. Wilcock, S. Love, P. G. Kehoe, N. M. Hooper, E. R. L. C. Vardy, J. Hardy, S. Mead, N. C. Fox, M. Rossor, J. Collinge, W. Maier, F. Jessen, E. Rüther, B. Schürmann, R. Heun, H. Kölsch, H. Van Den Bussche, I. Heuser, J. Kornhuber, J. Wiltfang, M. Dichgans, L. Frölich, H. Hampel, J. Gallacher, M. Hüll, D. Rujescu, I. Giegling, A. M. Goate, J. S. K. Kauwe, C. Cruchaga, P. Nowotny, J. C. Morris, K. Mayo, K. Sleegers, K. Bettens, S. Engelborghs, P. P. De Deyn, C. Van Broeckhoven, G. Livingston, N. J. Bass, H. Gurling, A. McQuillin, R. Gwilliam, P. Deloukas, A. Al-Chalabi, C. E. Shaw, M. Tsolaki, A. B. Singleton, R. Guerreiro, T. W. Mühleisen, M. M. Nöthen, S. Moebus, K.-H. Jöckel, N. Klopp, H.-E. Wichmann, V. S. Pankratz, S. B. Sando, J. O. Aasly, M. Barcikowska, Z. K. Wszolek, D. W. Dickson, N. R. Graff-Radford, R. C. Petersen, C. M. Van Duijn, M. M. B. Breteler, M. A. Ikram, A. L. Destefano, A. L. Fitzpatrick, O. Lopez, L. J. Launer, S. Seshadri, C. Berr, D. Campion, J. Epelbaum, J.-F. Dartigues, C. Tzourio, A. Alpérovitch, M. Lathrop, T. M. Feulner, P. Friedrich, C. Riehle, M. Krawczak, S. Schreiber, M. Mayhaus, S. Nicolhaus, S. Wagenpfeil, S. Steinberg, H. Stefansson, K. Stefansson, J. SnÆdal, S. Björnsson, P. V. Jonsson, V. Chouraki, B. Genier-Boley, M. Hiltunen, H. Soininen, O. Combarros, D. Zelenika, M. Delepine, M. J. Bullido, F. Pasquier, I. Mateo, A. Frank-Garcia, E. Porcellini, O. Hanon, E. Coto, V. Alvarez, P. Bosco, G. Siciliano, M. Mancuso, F. Panza, V. Solfrizzi, B. Nacmias, S. Sorbi, P. Bossù, P. Piccardi, B. Arosio, G. Annoni, D. Seripa, A. Pilotto, E. Scarpini, D. Galimberti, A. Brice, D. Hannequin, F. Licastro, L. Jones, P. A. Holmans, T. Jonsson, M. Riemenschneider, K. Morgan, S. G. Younkin, M. J. Owen, M. O'Donovan, P. Amouyel, J. Williams, "Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease," Nature Genetics , vol. 43, no. 5, pp. 429-435, 2011.

[103] N. Tanaka, S. Abe-Dohmae, N. Iwamoto, M. L. Fitzgerald, S. Yokoyama, "Helical apolipoproteins of high-density lipoprotein enhance phagocytosis by stabilizing ATP-binding cassette transporter A7," Journal of Lipid Research , vol. 51, no. 9, pp. 2591-2599, 2010.

[104] M. Hayashi, S. Abe-Dohmae, M. Okazaki, K. Ueda, S. Yokoyama, "Heterogeneity of high density lipoprotein generated by ABCA1 and ABCA7," Journal of Lipid Research , vol. 46, no. 8, pp. 1703-1711, 2005.

[105] N. Tanaka, S. Abe-Dohmae, N. Iwamoto, S. Yokoyama, "Roles of ATP-binding cassette transporter A7 in cholesterol homeostasis and host defense system," Journal of Atherosclerosis and Thrombosis , vol. 18, no. 4, pp. 274-281, 2011.

[106] W. E. Kaminski, E. Orsó, W. Diederich, J. Klucken, W. Drobnik, G. Schmitz, "Identification of a novel human sterol-sensitive ATP-binding cassette transporter (ABCA7)," Biochemical and Biophysical Research Communications , vol. 273, no. 2, pp. 532-538, 2000.

[107] K. R. Bales, "Brain lipid metabolism, apolipoprotein E and the pathophysiology of Alzheimer's disease," Neuropharmacology , vol. 59, no. 4-5, pp. 295-302, 2010.

[108] G. Di Paolo, T.-W. Kim, "Linking lipids to Alzheimer's disease: cholesterol and beyond," Nature Reviews Neuroscience , vol. 12, no. 5, pp. 284-296, 2011.

[109] T. Matsuzaki, K. Sasaki, J. Hata, Y. Hirakawa, K. Fujimi, T. Ninomiya, S. O. Suzuki, S. Kanba, Y. Kiyohara, T. Iwaki, "Association of Alzheimer disease pathology with abnormal lipid metabolism: the hisayama study," Neurology , vol. 77, no. 11, pp. 1068-1075, 2011.

[110] F. Wu, P. J. Yao, "Clathrin-mediated endocytosis and Alzheimer's disease: an update," Ageing Research Reviews , vol. 8, no. 3, pp. 147-149, 2009.

[111] J. H. Lee, R. Cheng, S. Barral, C. Reitz, M. Medrano, R. Lantigua, I. Z. Jiménez-Velazquez, E. Rogaeva, P. H. St. George-Hyslop, R. Mayeux, "Identification of novel loci for Alzheimer disease and replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals," Archives of Neurology , vol. 68, no. 3, pp. 320-328, 2011.

[112] M. A. Cousin, P. J. Robinson, "The dephosphins: dephosphorylation by calcineurin triggers synaptic vesicle endocytosis," Trends in Neurosciences , vol. 24, no. 11, pp. 659-665, 2001.

[113] F. Simpson, N. K. Hussain, B. Qualmann, R. B. Kelly, K. Brian K, P. S. McPherson, S. L. Schmid, "SH3-domain-containing proteins function at distinct steps in clathrin-coated vesicle formation," Nature Cell Biology , vol. 1, no. 2, pp. 119-124, 1999.

[114] E. M. Reiman, J. A. Webster, A. J. Myers, J. Hardy, T. Dunckley, V. L. Zismann, K. D. Joshipura, J. V. Pearson, D. Hu-Lince, M. Huentelman, D. W. Craig, K. D. Coon, W. S. Liang, R. H. Herbert, T. Beach, K. C. Rohrer, A. S. Zhao, D. Leung, L. Bryden, L. Marlowe, M. Kaleem, D. Mastroeni, A. Grover, C. B. Heward, R. Ravid, J. Rogers, M. L. Hutton, S. Melquist, R. C. Petersen, G. E. Alexander, R. Caselli, W. Kukull, A. Papassotiropoulos, D. A. Stephan, "GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers," Neuron , vol. 54, no. 5, pp. 713-720, 2007.

[115] A. Harel, M. P. Mattson, P. J. Yao, "CALM, a clathrin assembly protein, influences cell surface GluR2 abundance," NeuroMolecular Medicine , vol. 13, no. 1, pp. 88-90, 2011.

[116] A. Harel, F. Wu, M. P. Mattson, C. M. Morris, P. J. Yao, "Evidence for CALM in directing VAMP2 trafficking," Traffic , vol. 9, no. 3, pp. 417-429, 2008.

[117] M. H. Dreyling, J. A. Martinez-Climent, M. Zheng, J. Mao, J. D. Rowley, S. K. Bohlander, "The t(10;11)(p13;q14) in the U937 cell line results in the fusion of the AF10 gene and CALM, encoding a new member of the AP-3 clathrin assembly protein family," Proceedings of the National Academy of Sciences of the United States of America , vol. 93, no. 10, pp. 4804-4809, 1996.

[118] Q. Zhang, J.-T. Yu, Q.-X. Zhu, W. Zhang, Z.-C. Wu, D. Miao, L. Tan, "Complement receptor 1 polymorphisms and risk of late-onset Alzheimer's disease," Brain Research , vol. 1348, pp. 216-221, 2010.

[119] J. Rogers, R. Li, D. Mastroeni, A. Grover, B. Leonard, G. Ahern, P. Cao, H. Kolody, L. Vedders, W. P. Kolb, M. Sabbagh, "Peripheral clearance of amyloid β peptide by complement C3-dependent adherence to erythrocytes," Neurobiology of Aging , vol. 27, no. 12, pp. 1733-1739, 2006.

[120] T. V. Arumugam, T. Magnus, T. M. Woodruff, L. M. Proctor, I. A. Shiels, S. M. Taylor, "Complement mediators in ischemia-reperfusion injury," Clinica Chimica Acta , vol. 374, no. 1-2, pp. 33-45, 2006.

[121] S. Yaddanapudi, M. M. Altintas, A. D. Kistler, "CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival," The Journal of Clinical Investigation , vol. 121, pp. 3965-3980, 2011.

[122] Y. Ma, H. Yang, J. Qi, D. Liu, P. Xiong, Y. Xu, W. Feng, G. Zheng, P. Li, M. Fang, Z. Tan, F. Zheng, F. Gong, "CD2AP is indispensable to multistep cytotoxic process by NK cells," Molecular Immunology , vol. 47, no. 5, pp. 1074-1082, 2010.

[123] S. Kobayashi, A. Sawano, Y. Nojima, M. Shibuya, Y. Maru, "The c-Cbl/CD2AP complex regulates VEGF-induced endocytosis and degradation of Flt-1 (VEGFR-1)," The FASEB Journal , vol. 18, no. 7, pp. 929-931, 2004.

[124] K. Ishibashi, M. Suzuki, S. Sasaki, M. Imai, "Identification of a new multigene four-transmembrane family (MS4A) related to CD20, HTm4 and β subunit of the high-affinity IgE receptor," Gene , vol. 264, no. 1, pp. 87-93, 2001.

[125] Y. Liang, T. R. Buckley, L. Tu, S. D. Langdon, T. F. Tedder, "Structural organization of the human MS4A gene cluster on Chromosome 11q12," Immunogenetics , vol. 53, no. 5, pp. 357-368, 2001.

[126] L. Bertram, C. Lange, K. Mullin, M. Parkinson, M. Hsiao, M. F. Hogan, B. M. M. Schjeide, B. Hooli, J. DiVito, I. Ionita, H. Jiang, N. Laird, T. Moscarillo, K. L. Ohlsen, K. Elliott, X. Wang, D. Hu-Lince, M. Ryder, A. Murphy, S. L. Wagner, D. Blacker, K. D. Becker, R. E. Tanzi, "Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE," American Journal of Human Genetics , vol. 83, no. 5, pp. 623-632, 2008.

[127] K. Bettens, N. Brouwers, H. Van Miegroet, A. Gil, S. Engelborghs, P. P. De Deyn, R. Vandenberghe, C. Van Broeckhoven, K. Sleegers, "Follow-up study of susceptibility loci for Alzheimer's disease and onset age identified by genome-wide association," Journal of Alzheimer's Disease , vol. 19, no. 4, pp. 1169-1175, 2010.

[128] E. C. M. Brinkman-Van der Linden, T. Angata, S. A. Reynolds, L. D. Powell, S. M. Hedrick, A. Varki, "CD33/Siglec-3 binding specificity, expression pattern, and consequences of gene deletion in mice," Molecular and Cellular Biology , vol. 23, no. 12, pp. 4199-4206, 2003.

[129] T. Jonsson, J. K. Atwal, S. Steinberg, "A mutation in APP protects against Alzheimer's disease and age-related cognitive decline," Nature , vol. 488, pp. 96-99, 2012.

[130] R. Guerreiro, A. Wojtas, J. Bras, "TREM2 variants in Alzheimer's disease," The New England Journal of Medicine , vol. 368, pp. 117-127, 2013.

[131] T. Jonsson, H. Stefansson, S. Steinberg, "Variant of TREM2 associated with the risk of Alzheimer's disease," The New England Journal of Medicine , vol. 368, pp. 107-116, 2013.

[132] S. Takasaki, "Mitochondrial haplogroups associated with Japanese Alzheimer's patients," Journal of Bioenergetics and Biomembranes , vol. 41, no. 5, pp. 407-410, 2009.

[133] A. Maruszak, J. A. Canter, M. Styczynska, C. Zekanowski, M. Barcikowska, "Mitochondrial haplogroup H and Alzheimer's disease-is there a connection?," Neurobiology of Aging , vol. 30, no. 11, pp. 1749-1755, 2009.

[134] F. Fesahat, M. Houshmand, M. S. S. Panahi, K. Gharagozli, F. Mirzajani, "Do haplogroups H and U act to increase the penetrance of Alzheimer's disease?," Cellular and Molecular Neurobiology , vol. 27, no. 3, pp. 329-334, 2007.

[135] A. Santoro, V. Balbi, E. Balducci, C. Pirazzini, F. Rosini, F. Tavano, A. Achilli, P. Siviero, N. Minicuci, E. Bellavista, M. Mishto, S. Salvioli, F. Marchegiani, M. Cardelli, F. Olivieri, B. Nacmias, A. M. Chiamenti, L. Benussi, R. Ghidoni, G. Rose, C. Gabelli, G. Binetti, S. Sorbi, G. Crepaldi, G. Passarino, A. Torroni, C. Franceschi, "Evidence for sub-haplogroup H5 of mitochondrial DNA as a risk factor for late onset alzheimer's disease," PLoS ONE , vol. 5, no. 8, 2010.

[136] P. Ridge, T. Maxwell, C. Corcoran, "Mitochondrial genomic analysis of late onset Alzheimer's disease reveals protective haplogroups H6A1A/H6A1B: the Cache County Study on Memory in Aging," PLoS One , vol. 7, 2012.

[137] G. Carrieri, M. Bonafè, M. De Luca, G. Rose, O. Varcasia, A. Bruni, R. Maletta, B. Nacmias, S. Sorbi, F. Corsonello, E. Feraco, K. F. Andreev, A. I. Yashin, C. Franceschi, G. De Benedictis, "Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease," Human Genetics , vol. 108, no. 3, pp. 194-198, 2001.

[138] J. M. van der Walt, Y. A. Dementieva, E. R. Martin, W. K. Scott, K. K. Nicodemus, C. C. Kroner, K. A. Welsh-Bohmer, A. M. Saunders, A. D. Roses, G. W. Small, D. E. Schmechel, P. Murali Doraiswamy, J. R. Gilbert, J. L. Haines, J. M. Vance, M. A. Pericak-Vance, "Analysis of European mitochondrial haplogroups with Alzheimer disease risk," Neuroscience Letters , vol. 365, no. 1, pp. 28-32, 2004.

[139] A. Lakatos, O. Derbeneva, D. Younes, D. Keator, T. Bakken, M. Lvova, M. Brandon, G. Guffanti, D. Reglodi, A. Saykin, M. Weiner, F. Macciardi, N. Schork, D. C. Wallace, S. G. Potkin, "Association between mitochondrial DNA variations and Alzheimer's disease in the ADNI cohort," Neurobiology of Aging , vol. 31, no. 8, pp. 1355-1363, 2010.

[140] G. Zsurka, J. Kálmán, A. Juhász, A. Császár, I. Raskó, Z. Janka, P. Venetianer, "No mitochondrial haplotype was found to increase risk for Alzheimer's disease," Biological Psychiatry , vol. 44, no. 5, pp. 371-373, 1998.

[141] P. F. Chinnery, G. A. Taylor, N. Howell, R. M. Andrews, C. M. Morris, R. W. Taylor, I. G. McKeith, R. H. Perry, J. A. Edwardson, D. M. Turnbull, "Mitochondrial DNA haplogroups and susceptibility to AD and dementia with Lewy bodies," Neurology , vol. 55, no. 2, pp. 302-304, 2000.

[142] A. Pyle, T. Foltynie, W. Tiangyou, C. Lambert, S. M. Keers, L. M. Allcock, J. Davison, S. J. Lewis, R. H. Perry, R. Barker, D. J. Burn, P. F. Chinnery, "Mitochondrial DNA haplogroup cluster UKJT reduces the risk of PD," Annals of Neurology , vol. 57, no. 4, pp. 564-567, 2005.

[143] M. Mancuso, M. Nardini, D. Micheli, A. Rocchi, C. Nesti, N. J. Giglioli, L. Petrozzi, C. Rossi, R. Ceravolo, A. Bacci, A. Choub, G. Ricci, G. Tognoni, M. L. Manca, G. Siciliano, L. Murri, "Lack of association between mtDNA haplogroups and Alzheimer's disease in Tuscany," Neurological Sciences , vol. 28, no. 3, pp. 142-147, 2007.

[144] J. Krüger, R. Hinttala, K. Majamaa, A. M. Remes, "Mitochondrial DNA haplogroups in early-onset Alzheimer's disease and frontotemporal lobar degeneration," Molecular Neurodegeneration , vol. 5, article 8, 2010.

[145] G. Hudson, R. Sims, D. Harold, "No consistent evidence for association between mtDNA variants and Alzheimer disease," Neurology , vol. 78, no. 14, pp. 1038-1042, 2012.

[146] J. M. Schott, ADNI Investigators, "Using CSF biomarkers to replicate genetic associations in Alzheimer's disease," Neurobiology of Aging , vol. 33, no. 7, pp. 1486.e9-1486.e15, 2011.

[147] D. Peterson, C. Munger, J. Crowley, "Variants in PPP3R1 and MAPT are associated with more rapid functional decline in Alzheimer's disease: The Cache County Dementia Progression Study," Alzheimer's & Dementia , 2013.

[148] C. Cruchaga, J. S. Kauwe, O. Harari, "GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease," Neuron , vol. 78, pp. 256-268, 2013.

[149] C. Cruchaga, J. S. K. Kauwe, K. Mayo, N. Spiegel, C. Cruchaga, J. S. K. Kauwe, K. Mayo, N. Spiegel, S. Bertelsen, P. Nowotny, A. R. Shah, R. Abraham, P. Hollingworth, D. Harold, M. M. Owen, J. Williams, S. Lovestone, E. R. Peskind, G. Li, J. B. Leverenz, D. Galasko, J. C. Morris, A. M. Fagan, D. M. Holtzman, A. M. Goate, "SNPs associated with cerebrospinal fluid Phospho-tau levels influence rate of decline in alzheimer's disease," PLoS Genetics , vol. 6, no. 9, 2010.

[150] P. Alexopoulos, L.-H. Guo, M. Kratzer, C. Westerteicher, A. Kurz, R. Perneczky, "Impact of SORL1 single nucleotide polymorphisms on Alzheimer's disease cerebrospinal fluid markers Alzheimer's Disease Neuroimaging Initiative," Dementia and Geriatric Cognitive Disorders , vol. 32, no. 3, pp. 164-170, 2011.

[151] J. S. K. Kauwe, C. Cruchaga, C. M. Karch, B. Sadler, M. Lee, K. Mayo, W. Latu, M. Su'a, A. M. Fagan, D. M. Holtzman, J. C. Morris, A. M. Goate, "Fine mapping of genetic variants in BIN1, CLU, CR1 and PICALM for association with cerebrospinal fluid biomarkers for Alzheimer's disease," PLoS ONE , vol. 6, no. 2, 2011.

[152] B.-M. M. Schjeide, C. Schnack, J.-C. Lambert, C. M. Lill, J. Kirchheiner, H. Tumani, M. Otto, R. E. Tanzi, H. Lehrach, P. Amouyel, C. A. F. Von Arnim, L. Bertram, "The role of clusterin, complement receptor 1, and phosphatidylinositol binding clathrin assembly protein in Alzheimer disease risk and cerebrospinal fluid biomarker levels," Archives of General Psychiatry , vol. 68, no. 2, pp. 207-213, 2011.

[153] S. H. Lee, D. Harold, D. R. Nyholt, "Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer's disease, multiple sclerosis and endometriosis," Human Molecular Genetics , vol. 22, pp. 832-841, 2013.

[154] J. H. Moore, "The ubiquitous nature of epistasis in determining susceptibility to common human diseases," Human Heredity , vol. 56, no. 1-3, pp. 73-82, 2003.

[155] J. H. Moore, S. M. Williams, "Traversing the conceptual divide between biological and statistical epistasis: systems biology and a more modern synthesis," BioEssays , vol. 27, no. 6, pp. 637-646, 2005.

[156] J. H. Moore, S. M. Williams, "Epistasis and its implications for personal genetics," American Journal of Human Genetics , vol. 85, no. 3, pp. 309-320, 2009.

[157] H. J. Cordell, "Epistasis: what it means, what it doesn't mean, and statistical methods to detect it in humans," Human Molecular Genetics , vol. 11, no. 20, pp. 2463-2468, 2002.

[158] R. Culverhouse, B. K. Suarez, J. Lin, T. Reich, "A perspective on epistasis: limits of models displaying no main effect," American Journal of Human Genetics , vol. 70, no. 2, pp. 461-471, 2002.

[159] Ö. Carlborg, C. S. Haley, "Epistasis: too often neglected in complex trait studies?," Nature Reviews Genetics , vol. 5, no. 8, pp. 618-625, 2004.

[160] T. A. Thornton-Wells, J. H. Moore, J. L. Haines, "Genetics, statistics and human disease: analytical retooling for complexity," Trends in Genetics , vol. 20, no. 12, pp. 640-647, 2004.

[161] P. C. Phillips, "Epistasis--the essential role of gene interactions in the structure and evolution of genetic systems," Nature Reviews Genetics , vol. 9, no. 11, pp. 855-867, 2008.

[162] M. D. Ritchie, L. W. Hahn, N. Roodi, L. R. Bailey, W. D. Dupont, F. F. Parl, J. H. Moore, "Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer," American Journal of Human Genetics , vol. 69, no. 1, pp. 138-147, 2001.

[163] A. S. Andrew, H. H. Nelson, K. T. Kelsey, J. H. Moore, A. C. Meng, D. P. Casella, T. D. Tosteson, A. R. Schned, M. R. Karagas, "Concordance of multiple analytical approaches demonstrates a complex relationship between DNA repair gene SNPs, smoking and bladder cancer susceptibility," Carcinogenesis , vol. 27, no. 5, pp. 1030-1037, 2006.

[164] L. Briollais, Y. Wang, I. Rajendram, V. Onay, E. Shi, J. Knight, H. Ozcelik, "Methodological issues in detecting gene-gene interactions in breast cancer susceptibility: a population-based study in Ontario," BMC Medicine , vol. 5, article 22, 2007.

[165] M. Chen, A. M. Kamat, M. Huang, H. B. Grossman, C. P. Dinney, S. P. Lerner, X. Wu, J. Gu, "High-order interactions among genetic polymorphisms in nucleotide excision repair pathway genes and smoking in modulating bladder cancer risk," Carcinogenesis , vol. 28, no. 10, pp. 2160-2165, 2007.

[166] C.-T. Tsai, J.-J. Hwang, M. D. Ritchie, J. H. Moore, F.-T. Chiang, L.-P. Lai, K.-L. Hsu, C.-D. Tseng, J.-L. Lin, Y.-Z. Tseng, "Renin-angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort: detection of high order gene-gene interaction," Atherosclerosis , vol. 195, no. 1, pp. 172-180, 2007.

[167] I. H. S. Chan, T. F. Leung, N. L. S. Tang, C. Y. Li, Y. M. Sung, G. W. K. Wong, C. K. Wong, C. W. K. Lam, "Gene-gene interactions for asthma and plasma total IgE concentration in Chinese children," Journal of Allergy and Clinical Immunology , vol. 117, no. 1, pp. 127-133, 2006.

[168] J.-Y. Lee, J.-C. Kwon, J.-J. Kim, "Multifactor dimensionality reduction (MDR) analysis to detect single nucleotide polymorphisms associated with a carcass trait in a Hanwoo population," Asian-Australasian Journal of Animal Sciences , vol. 21, no. 6, pp. 784-788, 2008.

[169] M. D. Ritchie, D. W. Haas, A. A. Motsinger, J. P. Donahue, H. Erdem, S. Raffanti, P. Rebeiro, A. L. George, R. B. Kim, J. L. Haines, T. R. Sterling, "Drug transporter and metabolizing enzyme gene variants and nonnucleoside reverse-transcriptase inhibitor hepatotoxicity," Clinical Infectious Diseases , vol. 43, no. 6, pp. 779-782, 2006.

[170] H.-W. Park, E.-S. Shin, J.-E. Lee, H.-S. Kwon, E. Chun, S.-S. Kim, Y.-S. Chang, Y.-K. Kim, K.-U. Min, Y.-Y. Kim, S.-H. Cho, "Multilocus analysis of atopy in Korean children using multifactor- dimensionality reduction," Thorax , vol. 62, no. 3, pp. 265-269, 2007.

[171] M. Manuguerra, G. Matullo, F. Veglia, H. Autrup, A. M. Dunning, S. Garte, E. Gormally, C. Malaveille, S. Guarrera, S. Polidoro, F. Saletta, M. Peluso, L. Airoldi, K. Overvad, O. Raaschou-Nielsen, F. Clavel-Chapelon, J. Linseisen, H. Boeing, D. Trichopoulos, A. Kalandidi, D. Palli, V. Krogh, R. Tumino, S. Panico, H. B. Bueno-De-Mesquita, P. H. Peeters, E. Lund, G. Pera, C. Martinez, P. Amiano, A. Barricarte, M. J. Tormo, J. R. Quiros, G. Berglund, L. Janzon, B. Jarvholm, N. E. Day, N. E. Allen, R. Saracci, R. Kaaks, P. Ferrari, E. Riboli, P. Vineis, "Multi-factor dimensionality reduction applied to a large prospective investigation on gene-gene and gene-environment interactions," Carcinogenesis , vol. 28, no. 2, pp. 414-422, 2006.

[172] A. Julià, J. Moore, L. Miquel, C. Alegre, P. Barceló, M. Ritchie, S. Marsal, "Identification of a two-loci epistatic interaction associated with susceptibility to rheumatoid arthritis through reverse engineering and multifactor dimensionality reduction," Genomics , vol. 90, no. 1, pp. 6-13, 2007.

[173] T. L. Edwards, K. Lewis, D. R. Velez, S. Dudek, M. D. Ritchie, "Exploring the performance of multifactor dimensionality reduction in large scale SNP studies and in the presence of genetic heterogeneity among epistatic disease models," Human Heredity , vol. 67, no. 3, pp. 183-192, 2009.

[174] Y. M. Cho, M. D. Ritchie, J. H. Moore, J. Y. Park, K.-U. Lee, H. D. Shin, H. K. Lee, K. S. Park, "Multifactor-dimensionality reduction shows a two-locus interaction associated with type 2 diabetes mellitus," Diabetologia , vol. 47, no. 3, pp. 549-554, 2004.

[175] K. J. H. Robson, D. J. Lehmann, V. L. C. Wimhurst, K. J. Livesey, M. Combrinck, A. T. Merryweather-Clarke, D. R. Warden, A. D. Smith, "Synergy between the C2 allele of transferrin and the C282Y allele of the haemochromatosis gene (HFE) as risk factors for developing Alzheimer's disease," Journal of Medical Genetics , vol. 41, no. 4, pp. 261-265, 2004.

[176] A. Muendlein, C. H. Saely, T. Marte, F. Schmid, L. Koch, P. Rein, P. Langer, S. Aczel, H. Drexel, "Synergistic effects of the apolipoprotein E [straight epsilon] 3/[straight epsilon] 2/[straight epsilon] 4, the cholesteryl ester transfer protein TaqIB, and the apolipoprotein C3 -482 C > T polymorphisms on their association with coronary artery disease," Atherosclerosis , vol. 199, no. 1, pp. 179-186, 2008.

[177] L. Polito, P. G. Kehoe, A. Davin, "The SIRT2 polymorphism rs10410544 and risk of Alzheimer's disease in two Caucasian case-control cohorts," Alzheimer's & Dementia , vol. 9, no. 4, pp. 392-399, 2013.

[178] M. Hiltunen, A. Mannermaa, S. Helisalmi, A. Koivisto, M. Lehtovirta, M. Ryynänen, P. Riekkinen Sr., H. Soininen, "Butyrylcholinesterase K variant and apolipoprotein E4 genes do not act in synergy in Finnish late-onset Alzheimer's disease patients," Neuroscience Letters , vol. 250, no. 1, pp. 69-71, 1998.

[179] F. Licastro, M. Chiappelli, L. M. E. Grimaldi, K. Morgan, N. Kalsheker, E. Calabrese, A. Ritchie, E. Porcellini, G. Salani, M. Franceschi, N. Canal, "A new promoter polymorphism in the alpha-1-antichymotrypsin gene is a disease modifier of Alzheimer's disease," Neurobiology of Aging , vol. 26, no. 4, pp. 449-453, 2005.

[180] C. Talbot, H. Houlden, N. Craddock, R. Crook, M. Hutton, C. Lendon, G. Prihar, J. C. Morris, J. Hardy, A. Goate, "Polymorphism in AACT gene may lower age of onset of Alzheimer's disease," NeuroReport , vol. 7, no. 2, pp. 534-536, 1996.

[181] O. Combarros, M. García-Román, A. Fontalba, J. L. Fernández-Luna, J. Llorca, J. Infante, J. Berciano, "Interaction of the H63D mutation in the hemochromatosis gene with the apolipoprotein E epsilon 4 allele modulates age at onset of Alzheimer's disease," Dementia and Geriatric Cognitive Disorders , vol. 15, no. 3, pp. 151-154, 2003.

[182] K. Kamino, K. Nagasaka, M. Imagawa, H. Yamamoto, H. Yoneda, A. Ueki, S. Kitamura, K. Namekata, T. Miki, S. Ohta, "Deficiency in mitochondrial aldehyde dehydrogenase increases the risk for late-onset Alzheimer's disease in the Japanese population," Biochemical and Biophysical Research Communications , vol. 273, no. 1, pp. 192-196, 2000.

[183] J.-M. Kim, R. Stewart, I.-S. Shin, J.-S. Jung, J.-S. Yoon, "Assessment of association between mitochondrial aldehyde dehydrogenase polymorphism and Alzheimer's disease in an older Korean population," Neurobiology of Aging , vol. 25, no. 3, pp. 295-301, 2004.

[184] O. Combarros, C. M. van Duijn, N. Hammond, O. Belbin, A. Arias-Vásquez, M. Cortina-Borja, M. G. Lehmann, Y. S. Aulchenko, M. Schuur, H. Kölsch, R. Heun, G. K. Wilcock, K. Brown, P. G. Kehoe, R. Harrison, E. Coto, V. Alvarez, P. Deloukas, I. Mateo, R. Gwilliam, K. Morgan, D. R. Warden, A. D. Smith, D. J. Lehmann, "Replication by the Epistasis Project of the interaction between the genes for IL-6 and IL-10 in the risk of Alzheimer's disease," Journal of Neuroinflammation , vol. 6, article 22, 2009.

[185] J. M. Bullock, C. Medway, M. Cortina-Borja, "Discovery by the Epistasis project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimer's disease," Neurobiology of Aging , vol. 34, no. 4, pp. 1309.e1-1309.e7, 2013.

[186] E. Rodríguez-Rodríguez, I. Mateo, J. Infante, J. Llorca, I. García-Gorostiaga, J. L. Vázquez-Higuera, P. Sánchez-Juan, J. Berciano, O. Combarros, "Interaction between HMGCR and ABCA1 cholesterol-related genes modulates Alzheimer's disease risk," Brain Research , vol. 1280, pp. 166-171, 2009.

[187] J. S. K. Kauwe, S. Bertelsen, K. Mayo, C. Cruchaga, R. Abraham, P. Hollingworth, D. Harold, M. J. Owen, J. Williams, S. Lovestone, J. C. Morris, A. M. Goate, "Suggestive synergy between genetic variants in TF and HFE as risk factors for Alzheimer's disease," American Journal of Medical Genetics B , vol. 153, no. 4, pp. 955-959, 2010.

[188] O. Combarros, M. Cortina-Borja, A. D. Smith, D. J. Lehmann, "Epistasis in sporadic Alzheimer's disease," Neurobiology of Aging , vol. 30, no. 9, pp. 1333-1349, 2009.

[189] M. Cortina-Borja, A. D. Smith, O. Combarros, D. J. Lehmann, "The synergy factor: a statistic to measure interactions in complex diseases," BMC Research Notes , vol. 2, article 105, 2009.

[190] M. D. Ritchie, L. W. Hahn, J. H. Moore, "Power of multifactor dimensionality reduction for detecting gene-gene interactions in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity," Genetic Epidemiology , vol. 24, no. 2, pp. 150-157, 2003.

[191] L. W. Hahn, M. D. Ritchie, J. H. Moore, "Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions," Bioinformatics , vol. 19, no. 3, pp. 376-382, 2003.

[192] C. S. Coffey, P. R. Hebert, M. D. Ritchie, H. M. Krumholz, J. M. Gaziano, P. M. Ridker, N. J. Brown, D. E. Vaughan, J. H. Moore, "An application of conditional logistic regression and multifactor dimensionality reduction for detecting gene-gene interactions on risk of myocardial infarction: the importance of model validation," BMC Bioinformatics , vol. 5, article 49, 2004.

[193] J. Infante, C. Sanz, J. L. Fernández-Luna, J. Llorca, J. Berciano, O. Combarros, "Gene-gene interaction between interleukin-6 and interleukin-10 reduces AD risk," Neurology , vol. 63, no. 6, pp. 1135-1136, 2004.

[194] K. J. H. Robson, D. J. Lehmann, V. L. C. Wimhurst, K. J. Livesey, M. Combrinck, A. T. Merryweather-Clarke, D. R. Warden, A. D. Smith, "Synergy between the C2 allele of transferrin and the C282Y allele of the haemochromatosis gene (HFE) as risk factors for developing Alzheimer's disease," Journal of Medical Genetics , vol. 41, no. 4, pp. 261-265, 2004.