Clinical Genetics of Alzheimer’s Disease

Zou, Zhangyu; Liu, Changyun; Che, Chunhui; Huang, Huapin

doi:https://doi.org/10.1155/2014/291862

BioMed Research International

On this page

Abstract Introduction Supplementary Materials References Copyright Related Articles

Special Issue

Advances in Alzheimer’s Disease: From Bench to Bedside

View this Special Issue

Review Article | Open Access

Volume 2014 | Article ID 291862 | https://doi.org/10.1155/2014/291862

Clinical Genetics of Alzheimer’s Disease

Zhangyu Zou,¹Changyun Liu,¹Chunhui Che,¹and Huapin Huang¹

Academic Editor: Jin-Tai Yu

Received28 Feb 2014

Accepted21 Apr 2014

Published13 May 2014

Abstract

Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease and the most common form of dementia in the elderly. It is a complex disorder with environmental and genetic components. There are two major types of AD, early onset and the more common late onset. The genetics of early-onset AD are largely understood with mutations in three different genes leading to the disease. In contrast, while susceptibility loci and alleles associated with late-onset AD have been identified using genetic 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 AD, the clinical features of EOAD according to genotypes, and the clinical implications of the genetics of AD.

1. Introduction

Alzheimer’s disease (AD), the most common progressive neurodegenerative disease and the most common form of dementia in the elderly, results from irreversible loss of neurons, particularly in the cortex and hippocampus. Clinically, AD is characterized by progressive impairments of memory, judgment, decision making, orientation to physical surroundings, and language. Pathologically, AD is characterized by the presence of extracellular neuritic plaques (NPs) containing the -amyloid peptide (A) and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein in the brain.

In 1906, Alois Alzheimer reported the case of a woman who presented with a “peculiar” dementia at the age of 51 years. Alzheimer correlated the woman’s cognitive and behavioral features with histopathological findings of extracellular “miliary foci” (senile plaques) and fibrils inside the neurons (neurofibrillary tangles) in her cerebral cortex. Emil Kraeplin subsequently named this presenile (onset <65 years) dementia “Alzheimer’s disease” (AD) [1]. Familial clustering of AD was first reported by Sjogren et al. in 1952 [2]. Since the 1980s, various families with AD exhibiting an autosomal dominant pattern of inheritance have been reported [3, 4].

With the advance of molecular genetics, in particular genetic linkage studies, positional cloning, and genome-wide association studies (GWAS), searches for the genes responsible for both autosomal dominant forms of AD and sporadic AD have been widely performed. In this review, we outline the genetic landscape for the disease. We describe what is known about the genetics of AD, the clinical features of early-onset AD (EOAD) according to genotypes, and the clinical implications of the genetics of AD.

2. Genetic Epidemiology of AD

AD is classified into two subtypes according to the age of onset. About 1–5% of AD cases present with an early-onset (before the age of 65 years, typically in the late 40s or early 50s) and are classified as having EOAD, whereas 95% of patients develop the disease after the age of 65 years and are classified as having late-onset AD (LOAD) [5]. Family aggregation in AD is more obvious among EOAD patients, who usually show a Mendelian autosomal dominant pattern of inheritance (accounting for <1% of AD cases). However, heritability of AD was estimated to be up to 79% based on twin and family studies [6]. EOAD and LOAD are associated with different patterns of genetic epidemiology.

3. Early-Onset Alzheimer’s Disease

EOAD is most often caused by rare, highly penetrant mutations in three genes encoding proteins involved in amyloid precursor protein (APP) breakdown and A generation, namely, the APP [7], presenilin 1 (PSEN1) [8], and presenilin 2 (PSEN2) [9] genes.

3.1. APP Gene

The APP gene has 18 exons and encodes a ubiquitously expressed single-pass transmembrane polypeptide of 770 amino acids. A is generated from APP by two endoproteolytic cleavage events catalyzed by -secretase and -secretase, generating a peptide of 39–43 amino acids in length; the A protein is the major component of the amyloid plaques found in AD brains. The most common form of A is 40 amino acids in length and is called A40; the longer form, A42, is less abundant than A40 but is deposited first and is more amyloidogenic.

Since Goate et al. found the first mutation (V717I) in the APP gene in one out of five EOAD families in 1991 [7], 33 different APP mutations have been identified in AD patients to date, including 23 missense mutations, nine duplications, and one deletion [10]. Most of the mutations are dominantly inherited. Most of these mutations are positioned in the vicinity of the - and -secretase cleavage sites (exons 16 and 17 of APP); therefore, they influence APP proteolytic processing and/or aggregation. A double point mutation, APP KM670/671NL, identified in two Swedish families, lies at the N-terminus of the A domain adjacent to the -secretase site [11]. Some mutations, such as the Iranian mutation (T714A) [12], Australian mutation (T714I) [13], French mutation (V715M) [14], German mutation (V715I) [15], Florida mutation (I716V) [16], and London mutation (V717I) [7], frame the other end of the A domain, located just distal to the C-terminus of the A domain adjacent to the -secretase site. Mutations such as the Flemish mutation (A692G) [17], Italian mutation (E693K) [18], Dutch mutation (E693Q) [19], Arctic mutation (E693G) [20], and Iowa mutation (D694N) [21] are located within the A coding sequence. The London mutation (V717I) [7, 22–25], the V717G [26, 27], V717F [25, 28], and V717L [25, 29–31] mutations, the Italian mutation (E693K) [18], Dutch mutation (E693Q) [19], Arctic mutation (E693G) [20], and E693del mutation [32] have been identified in APP residues V717 and E693, making both residues mutation hotspots in the APP gene.

3.2. PSEN1 and PSEN2 Gene

In 1995, mutations in the PSEN1 and PSEN2 genes, which encode the presenilin 1 and presenilin 2 proteins, respectively, required for -secretase to produce A from APP, were identified in EOAD families [8, 9, 33]. To date, approximately 200 different AD-related PSEN1 mutations and 22 AD-related PSEN2 mutations have been detected (http://www.molgen.vib-ua.be/ADMutations/) [10, 34–38]. The majority of mutations are missense mutations, but small deletions and insertions have also been reported. Mutations in PSEN1 and PSEN2 cause amino acid sequence changes throughout the protein with some clustering within the transmembrane domains and the hydrophilic loops. Mutations in exons 5, 6, 7, and 8 account for 70% of all identified mutations in PSEN1 (http://www.molgen.vib-ua.be/ADMutations/) [10]. Five different mutations of PSEN1 residue 143 (I143V/F/N/T/M, encoded by exon 5) [39–43] have been identified, making I143 residue a mutation hotspot. The presenilins act as aspartyl proteases that carry out -secretase cleavage of APP to produce A. Therefore, mutations in the PSEN1 and PSEN2 genes increase the ratio of A42 to A40.

PSEN1 mutations account for the majority (78%) of the EOFAD mutations identified, followed by APP (18%), with PSEN2 mutations found in only a few families (4%). Together, the mutations in these three genes are thought to be responsible for 30–50% of autosomal dominant AD cases and about 0.5% of AD cases in general (http://www.molgen.ua.ac.be/ADMutations) [10]. Although mutations in these genes are a rare cause of AD, the identification of these genes and mutations has been extremely important to the recent progress in the understanding of the biology of AD.

4. Pathophysiology

In 1984, Glenner first proposed that cerebral A drives all subsequent pathology [44]. This central thesis was later reinterpreted and reported as the amyloid cascade hypothesis of AD, which maintains that the accumulation of A is the primary driver of AD-related pathogenesis, including neurofibrillary tangle formation, synapse loss, and neuronal cell death [45–47]. Although the amyloid cascade is only one possible mechanism proposed for AD and amyloid alone is probably not sufficient to cause AD, the association of APP, PSEN1, and PSEN2 with amyloid synthesis and its processing indicates that the amyloid cascade theory plays an important role in EOAD. According to the amyloid cascade hypothesis, AD is a consequence of an imbalance between production and deposition of A.

The AD-linked APP mutations located near the - and -secretase cleavage sites serve to increase A42 production. The Swedish mutation, lying immediately before the beginning of the A peptide sequence, affects the efficiency of -secretase cleavage and increases the amount of A peptide produced by 2-3 fold [11]. APP mutations at the C-terminal end of A alter the activity of -secretase cleavage and shift proteolysis to produce more A42, resulting in an increased A42/A40 ratio but not an increase in the total amount of A peptides formed [48]. The Arctic mutation (E693G) is located within A dominant; therefore, rather than altering the amount of A formed or the A40/A42 ratio, it increases the rate of aggregation of mutant peptide, suggesting that APP mutations can result in A peptides with altered aggregation properties [20]. The amyloid hypothesis is further supported by the opposite situation, in which an APP mutation reducing the amount of amyloid formation in fact protects against AD [49].

Both presenilins 1 and 2 are part of the -secretase complex; therefore, they are functionally involved in the -secretase-mediated proteolytic cleavage of APP. -Secretase containing mutation-altered presenilin still catalyzes cleavage of APP, but the proteolytic site is altered; therefore, it causes either an increase in A42 levels or a decrease in A40 levels, leading to an increase in the A42/40 ratio. The relative increase in A promotes the aggregation of the peptide into oligomers and ultimately amyloid fibrils [46, 50–52].

5. Genotype-Phenotype Correlations

The clinical features of EOAD are heterogeneous, most probably due to different genetic mutations and epigenetic factors. Although the phenotypes associated with some mutations have been well characterized, significant phenotypic heterogeneity also exists both between families sharing a common mutation and within the affected individuals of a single family.

5.1. Clinical Features of EOAD with APP Mutations

Patients with APP mutations tend to present with symptoms between the ages of 40 and 65 years and have disease duration of 9–16 years. Among the APP missense mutation families reported, the phenotypes of the Flemish mutation (A692G), Dutch mutation (E693Q), Arctic mutation (E693G), Iowa mutation (D694N), and London mutation (V717I) are the most well studied and described. The phenotype is heterogeneous among these mutations. Mutations at APP residue V717, including the London mutation (APP V717I) [7, 22–25], V717G [26, 27], V717F [25, 28], and V717L [25, 29–31], demonstrate a similar phenotype with early impairment of episodic memory, dyscalculia, lack of insight, and prominent myoclonus and seizures [53]. Clinically, patients with the Flemish mutation (APP A692G) present, in their 40s, either with symptoms related to cerebrovascular events or with cognitive dysfunction; neuropathologically, massive amyloid accumulation in brain vessel walls but no neurofibrillary tangles is seen in these patients [17, 19, 54, 55]. Carriers of the Dutch mutation (APP E693Q) are characterized clinically by focal symptoms related to recurrent cerebrovascular events, usually followed by dementia, in their 40s and 50s, and pathologically by cerebral amyloid angiopathy with rare amyloid plaque pathology [19, 56, 57]. Despite the presence of marked amyloid angiopathy with abundant amyloid plaques and neurofibrillary tangles on pathological investigation, patients with the Arctic (APP E693G) mutation demonstrate a purely cognitive phenotype in their 50s [20, 58, 59]. A similar pathological feature was found in individuals with the Iowa (APP D694N) mutation: the clinical feature of the mutation carriers is progressive dementia with speech impairment without any apparent focal symptoms of cerebrovascular events [21, 60].

It is now known that duplications of the APP gene can give rise to familial AD. The characteristic features associated with APP duplication include a high frequency of seizures with early progressive impairment of episodic memory and prominent amyloid angiopathy leading to frequent intracerebral hemorrhage [61–65].

5.2. Clinical Features of EOAD with PSEN1 Mutations

EOAD patients with PSEN1 mutation typically have an early age of onset, being an average of 8.4 years earlier than the age of onset in APP mutation carriers (average 42.9 versus 51.3 years) and 14.2 years earlier than the age of onset in PSEN2 mutation carriers (average 57.1 years) [10]. Patients with very early-onset Alzheimer’s disease (VEOAD) usually have an age of onset before the age of 35 years. A study of 101 VEOAD cases from 1934 to 2007 found a PSEN1 mutation or linkage to chromosome 14 in all cases for which genetic analysis was performed, suggesting that PSEN1 mutations may be responsible for all reported cases of VEOAD [66].

PSEN1 mutation carriers predominantly showed impairment of memory and multiple cognitive domains [67, 68]. In addition to cognitive symptoms, some unusual clinical features may be present early in the course of the disease, in particular myoclonus and seizures [69]. Despite almost all of these symptoms having been reported in sporadic AD patients, extrapyramidal signs, behavioral and psychiatric symptoms (agitation, depression, delusion, and hallucinations), aphasia, and cerebellar signs are significantly more frequent in PSEN1 mutation carriers [70, 71].

The characteristic phenotype associated with a PSEN1 mutation probably represents the syndrome of “variant AD,” which is most often associated with mutations around exon 8 and characterized by early-onset familial dementia and spastic paraparesis [72, 73]. The spastic paraparesis may occur simultaneously with cognitive deficits or may predate them by several years. The patients typically present with insidiously progressive impaired gait and mild weakness in the lower limbs, with signs of hyperreflexia [73, 74]. The mean age of onset of “variant AD” ranges from 27 to the mid-50s, with the most typical age of onset being at the earlier ages in the spectrum [71, 73]. Therefore, it is not surprising that many VEOAD cases have been reported to demonstrate this syndrome [75, 76].

5.3. Clinical Features of EOAD with PSEN2 Mutations

Of the families identified with PSEN2 mutations, Volga German pedigrees with the N141I mutation are the largest and most well-studied group. Compared with PSEN1 mutation carriers, carriers of PSEN2 mutations have a later age of onset. The age of onset associated with mutations in PSEN2 is typically in the 50s, but there is a wide range from 39 to 75 years. The average disease duration is 10.6 years, longer than that in patients with PSEN1 mutations (8.4 years) but similar to that in sporadic late onset AD patients (10.6 years). Early and progressive defects in memory and executive functions are common with relative sparing of naming. Seizures (30%) are common in individuals with PSEN2 mutations. Neuropathological changes are those of typical AD with extensive neuritic plaque formation and neurofibrillary tangle accumulation. Amyloid angiopathy may be prominent and even lead to hemorrhagic stroke [77].

6. Late-Onset Alzheimer’s Disease

For most cases of LOAD, the risk of developing AD is assumed to be determined by genetic variants combined with lifestyle and environmental exposure factors. The 4-allele of the apolipoprotein E gene (APOE) on chromosome 19q13.2 is the only well-established genetic risk factor for LOAD [78]. There are three common alleles of ApoE in humans (2, 3, and 4) that differ in sequence by only one amino acid at either position 112 or 158 of the protein. One copy of the 4-allele of APOE increases AD risk by 4-fold and two copies increase the risk by 12-fold; by contrast, the 2-allele of APOE is protective against AD [79]. APOE 4-alleles are also associated with a dose-dependent decrease in age at onset (5 years/4-allele) in both sporadic and familial AD cases [80, 81]. Functionally, ApoE maintains lipoprotein metabolism and transport, but it is believed to play a role in the clearance of cerebral A in AD pathogenesis. A deposits are more abundant in 4-positive than in 4-negative cases [82]. In addition, ApoE4 is associated with other factors that may contribute to AD pathology, including low glucose usage, mitochondrial abnormalities, and cytoskeletal dysfunction [83]. Furthermore, the presence of this allele is associated with memory impairment, MCI, and progression from MCI to dementia [84]. APOE4 has been suggested to account for as much as 20–30% of AD risk.

Since the report of an association of LOAD with APOE, many hundreds of studies have been performed to look for AD susceptibility genes, but few reported genetic associations have been replicated across studies. The main reason for this is that other genetic risk factors have much smaller effect sizes than does APOE. As a result, the sample sizes used in the earlier studies were too small to have the power to detect these genes. During the last few years several technological advances have transformed the landscape regarding the genetics of common complex traits such as AD. The first of these was the development of genome-wide arrays that allowed simultaneous screening of the entire human genome in thousands of samples for novel AD loci. Since 2007, dozens of GWAS of thousands of samples from AD patients and nondemented elderly controls have been performed, resulting in the identification of a number of new genetic loci with genome-wide significance (<5 10⁻⁸) [85–109]. Some of these foci have been identified in more than two GWAS and have compelling evidence supporting an association with LOAD, including clusterin (CLU) [95, 96, 99, 107], complement component receptor 1 (CR1) [95, 104–106], and phosphatidylinositol binding clathrin assembly protein (PICALM) [96, 99, 107, 108], bridging integrator 1 (BIN1) [99, 101, 104–107], sialic acid binding Ig-like lectin (CD33) [90, 105–107], CD2-associated protein (CD2AP) [105, 106], membrane spanning 4A gene cluster (MS4A6A/MS4A4E) [105–108], ephrin receptor A1 (EPHA1) [105–107], and ATP-binding cassette transporter (ABCA7) [105–107, 109]. Recently, a rare susceptibility variant (rs75932628) in the triggering receptor expressed on myeloid cells 2 (TREM2) gene was identified to be associated with LOAD [110, 111].

The search for additional genetic risk factors requires large-scale meta-analysis of GWAS data to increase statistical power. Very recently, a large, two-stage meta-analysis of AD GWAS in individuals associated with European ancestry identified 11 novel genetic loci for LOAD in addition to the already known genes: ABCA7, APOE, BIN1, CLU, CR1, CD2AP, EPHA1, MS4A6A-MS4A4E, and PICALM genes [112]: HLA-DRB5–HLA-DRB1 (encoding major histocompatibility complex, class II, DR5 and DR1), SORL1 (encoding sortilin-related receptor, L(DLR class) 1), PTK2B (encoding protein tyrosine kinase 2), SLC24A4-RIN3 (encoding solute carrier family 24 (sodium/potassium/calcium exchanger), member 4), ZCWPW1 (encoding zinc finger, CW type with PWWP domain 1), CELF1 (encoding CUGBP, Elavlike family member 1), NME8, FERMT2 (encoding fermitin family member 2), CASS4 (encoding Cas scaffolding protein family member 4), INPP5D (encoding inositol polyphosphate-5-phosphatase, 145 kDa), and MEF2C (encoding myocyte enhancer factor 2). This brought the number of genetic loci associated with LOAD up to 22 [112].

Rare highly penetrant mutations were also reported in LOAD. Two rare mutations in the ADAM10 gene, Q170H and R181G, are identified in 7 out of 1000 LOAD families. Both mutations are located in the prodomain region and dramatically impair the ability of ADAM10 to cleave APP at the -secretase site of APP in vitro and in vivo [113]. These findings highlight the importance of the employment of whole genome or whole exome sequencing to identify rare variants causing LOAD, in addition to common variants, in future genetic studies [113].

Although the total number of AD risk genes remains elusive, there is good evidence suggesting that, in combination, they have a substantial impact on AD predisposition. The new risk alleles have a much smaller effect on AD susceptibility than does APOEε4. Estimates of the population-attributable fractions or preventive fractions for these new loci are in the range 1–8.1%. The cumulative population-attributable fraction effect and population preventive fraction effect for non-APOE candidate genes are estimated to be 31.7% and 30.4%, respectively, while the population-attributable fraction for APOEε4 is about 27.3% [112]. However, the actual effect sizes of the new loci may be much smaller because of the “winner’s curse,” a bias that arises in GWAS studies because of sampling variation and depends strongly on the power of the initial test for an association (since the new loci are only weakly associated with AD, the power to detect association is low and the odds ratios for the new loci are usually overestimated) [114].

These AD risk genes affect various pathways, roughly falling into four pathways: A metabolism, lipid metabolism, immune and complement system/inflammatory response, and cell signaling (Figure 1). Eleven loci (CLU, CR1, BIN1, ABCA7, CD33, CD2AP, EPHA1, MS4A6A-MS4A4E, TREM2, HLA-DRB5-CDRB1, INPP5D, and MEF2C) probably affect inflammatory processes; nine loci (APOE, CD33, CLU, SQRL1, CR1, PICALM, BIN1, ABCA7, and CASS4) are involved in A metabolism; eight loci (PICALM, BIN1, CD33, CD2AP, SQRL1, CLU, EPHA1, and MS4A6A-MS4A4E) are involved in processes at the cell membrane, including endocytosis; and three loci (APOE, CLU, and ABCA7) are involved in lipid biology [112, 115]. Some of these newly identified loci also suggest the existence of new pathways underlying AD, probably including hippocampal synaptic function (MEF2C and PTK2B), cytoskeletal function and axonal transport (CELF1, NME8, and CASS4), regulation of gene expression and posttranslational modification of proteins, and microglial and myeloid cell function (INPP5D) [112]. Therefore, the discoveries of these new genes open new avenues to study the pathogenesis of AD. By targeting the specific components of the pathways these gene products are involved in, novel directions for drug discovery and effective treatment may be available [114].

Although up to 80% of the AD risk is supposed to be attributable to genetic factors, all of the known LOAD genes (including APOE and new ones) account for about 60% of the total genetic variance, indicating that additional risk genes for LOAD remain to be identified.

7. Clinical Implications

7.1. Clinical Genetic Testing

Genetic testing of patients with early-onset dementia and a positive family history can be a valuable tool for identifying causative mutations, establishing the correct diagnosis, excluding some differential diagnoses, and offering at-risk relatives the option of predictive testing [76, 116]. In addition, by performing genetic testing, the physician will be able to select patients with the same underlying pathogenesis for therapeutic trials [117]. Because mutations in PSEN1 are the most frequent cause of EOFAD, it is rational to screen for PSEN1 mutations first, particularly if the patients have early age of onset, followed by APP and PSEN2 mutations [118]. If sequencing of all three genes is normal for a Mendelian family, then screening for duplication of the APP gene should also be considered [65, 117]. As discussed above, a few phenotypic clues can help prioritize mutation screening. Familial AD patients with spastic paraparesis are likely to have a PSEN1 mutation while familial AD patients with cerebral hemorrhage caused by cerebral amyloid angiopathy may have APP mutations [118]. Mutations in these genes may occasionally be identified in AD patients with no family history, especially those with an age of onset of 40 years or younger. These cases may be “true” sporadic patients withde novo mutations or “apparent” sporadic patients with no obvious family history because of a small family size, early deceased parents, incomplete penetrance, or paternity issues. Therefore, genetic testing in EOAD patients with no family history can be useful in establishing the diagnosis [117]. An algorithm for genetic testing in patients with EOAD has been proposed elsewhere [117]. It should be kept in mind that some variants might only be polymorphisms with no clinical significance rather than pathogenic mutations, especially for genetic changes that have not been reported in the past. Guerreiro et al. proposed a scale for grading mutations as not pathogenic, possibly pathogenic, probably pathogenic, and definitely pathogenic, on the basis of segregation within the family, its frequency in clinically normal individuals, and functional studies in model systems [119].

7.2. Presymptomatic Genetic Counselling

With respect to asymptomatic relatives of an EOFAD case with a pathogenic mutation, the availability of genetic testing and counselling creates both advances and dilemmas. Common reasons for testing include concerns about the early symptoms of dementia, reproductive planning, and the psychological burden of the uncertainty about their future [120, 121]. Furthermore, identified asymptomatic mutation carriers might also have the opportunity to join treatment trials for genetic at-risk groups, such as the Alzheimer’s Prevention Initiative and Dominantly Inherited Alzheimer Network initiatives [118]. On the other hand, genetic testing may trigger potential risk of emotional stress, such as depression, anxiety, or even suicide [76]. However, two independent studies have shown that, in the majority of asymptomatic individuals tested using a standardized counseling protocol, the testing was beneficial and the patients demonstrated effective coping skills without negative psychological reactions during several months of follow-up [120, 121]. Although genetic variations other than these known genes also contribute to AD risk, among which variants in ApoE and TREM2 gene have the greatest effect, genetic testing for ApoE or TREM2 genotypes is not recommended for asymptomatic individuals [118]. Guidelines and recommendations on genetic counseling procedures in asymptomatic AD have been published previously [116].

7.3. Gene Therapy

To date, no disease-modifying treatment for AD is yet available, although several disease-modifying clinical trials are ongoing. Based on the amyloid cascade hypothesis, in the majority of AD cases, the accumulation of A is a result of an imbalance between A generation and clearance. Thus, a gene therapy approach involving A-degrading enzymes would be a possible alternative strategy [122]. Gene delivery of nerve growth factor (NGF) [123], brain-derived neurotrophic factor (BDNF) [124], neprilysin [125], APOE [126], ECE [127], and cathepsin B [128] has been studied extensively in several AD animal models with promising results, and the first clinical trial using ex vivo gene delivery has been completed, with result indicating amelioration of AD pathogenesis [129]. The first human clinical trial based on rAAV-mediated NGF gene therapy has been initiated [130]. Downregulating APP [131] and -site APP cleaving enzyme 1 (BACE1) [132] levels in vivo by means of siRNA-mediated knockdown has also produced some very promising results. Therefore, gene therapy appears to have the potential to become a disease-modifying treatment for AD [122].

8. Perspectives

There have been huge advances in our understanding of the genetics of AD over the last few years. The discovery of the three EOAD-related genes, APP, PSEN1, and PSEN2, has improved our knowledge of the physiopathology of AD. Ongoing and future large-scale genome-wide association studies and next-generation whole genome or whole exome sequencing hold the promise of unraveling the complexities of the genetic architecture of this disease. This should lead to identification of novel targets for genetic testing, as well as developing preventative and curative therapies for AD.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgment

This work was supported by the National Natural Science Foundation of China (81371426).

Supplementary Materials

Overview of GWAS in AD.

Supplementary Table

References

R. E. Tanzi, “A brief history of Alzheimer's disease gene discovery,” Journal of Alzheimer's Disease, vol. 33, supplement 1, pp. S5–13, 2013.
View at: Google Scholar
T. Sjogren, H. Sjogren, and A. G. Lindgren, “Morbus Alzheimer and morbus Pick, a genetic, clinical and patho-anatomical study,” Acta Psychiatrica et Neurologica Scandinavica. Supplementum, vol. 82, pp. 1–152, 1952.
View at: Google Scholar
L. E. Nee, R. J. Polinsky, and R. Eldridge, “A family with histologically confirmed Alzheimer's disease,” Archives of Neurology, vol. 40, no. 4, pp. 203–208, 1983.
View at: Google Scholar
J. Goudsmit, B. J. White, and L. R. Weitkamp, “Familial Alzheimer's disease in two kindreds of the same geographic and ethnic origin. A clinical and genetic study,” Journal of the Neurological Sciences, vol. 49, no. 1, pp. 79–89, 1981.
View at: Publisher Site | Google Scholar
C. Reitz, C. Brayne, and R. Mayeux, “Epidemiology of Alzheimer disease,” Nature Reviews Neurology, vol. 7, no. 3, pp. 137–152, 2011.
View at: Publisher Site | Google Scholar
M. Gatz, C. A. Reynolds, L. Fratiglioni et al., “Role of genes and environments for explaining Alzheimer disease,” Archives of General Psychiatry, vol. 63, no. 2, pp. 168–174, 2006.
View at: Publisher Site | Google Scholar
A. Goate, M.-C. Chartier-Harlin, M. Mullan et al., “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.
View at: Publisher Site | Google Scholar
R. Sherrington, E. I. Rogaev, Y. Liang et al., “Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease,” Nature, vol. 375, no. 6534, pp. 754–760, 1995.
View at: Google Scholar
E. Levy-Lahad, W. Wasco, P. Poorkaj et al., “Candidate gene for the chromosome 1 familial Alzheimer's disease locus,” Science, vol. 269, no. 5226, pp. 973–977, 1995.
View at: Google Scholar
M. Cruts, J. Theuns, and C. Van Broeckhoven, “Locus-specific mutation databases for neurodegenerative brain diseases,” Human Mutation, vol. 33, no. 9, pp. 1340–1344, 2012.
View at: Google Scholar
M. Mullan, F. Crawford, K. Axelman et al., “A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of β-amyloid,” Nature Genetics, vol. 1, no. 5, pp. 345–347, 1992.
View at: Google Scholar
P. Pasalar, H. Najmabadi, A. R. Noorian et al., “An Iranian family with Alzheimer's disease caused by a novel APP mutation (THr714ALa),” Neurology, vol. 58, no. 10, pp. 1574–1575, 2002.
View at: Google Scholar
S. Kumar-Singh, C. De Jonghe, M. Cruts et al., “Nonfibrillar diffuse amyloid deposition due to a γ42-secretase site mutation points to an essential role for N-truncated Aβ42 in Alzheimer's disease,” Human Molecular Genetics, vol. 9, no. 18, pp. 2589–2598, 2000.
View at: Google Scholar
K. Ancolio, C. Dumanchin, H. Barelli et al., “Unusual phenotypic alteration of β amyloid precursor protein (βAPP) maturation by a new Val-715 → Met βAPP-770 mutation responsible for probable early-onset Alzheimer's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 7, pp. 4119–4124, 1999.
View at: Publisher Site | Google Scholar
M. Cruts, B. Dermaut, R. Rademakers, M. Van Den Broeck, F. Stögbauer, and C. Van Broeckhoven, “Novel APP mutation V715A associated with presenile Alzheimer's disease in a German family,” Journal of Neurology, vol. 250, no. 11, pp. 1374–1375, 2003.
View at: Publisher Site | Google Scholar
C. B. Eckman, N. D. Mehta, R. Crook et al., “A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43),” Human Molecular Genetics, vol. 6, no. 12, pp. 2087–2089, 1997.
View at: Google Scholar
L. Hendriks, C. M. Van Duijn, P. Cras et al., “Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the β-amyloid precursor protein gene,” Nature Genetics, vol. 1, no. 3, pp. 218–221, 1992.
View at: Google Scholar
F. Tagliavini, G. Rossi, A. Padovani et al., “A new βPP mutation related to hereditary cerebral haemorrhage,” Alzheimer's Reports, vol. 2, supplement 1, p. S28, 1999.
View at: Google Scholar
E. Levy, M. D. Carman, I. J. Fernandez-Madrid et al., “Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type,” Science, vol. 248, no. 4959, pp. 1124–1126, 1990.
View at: Google Scholar
K. Kamino, H. T. Orr, H. Payami et al., “Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region,” American Journal of Human Genetics, vol. 51, no. 5, pp. 998–1014, 1992.
View at: Google Scholar
T. J. Grabowski, H. S. Cho, J. P. G. Vonsattel, G. William Rebeck, and S. M. Greenberg, “Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy,” Annals of Neurology, vol. 49, no. 6, pp. 697–705, 2001.
View at: Publisher Site | Google Scholar
S. Naruse, S. Igarashi, K. Aoki et al., “Mis-sense mutation Val → Ile in exon 17 of amyloid precursor protein gene in Japanese familial Alzheimer's disease,” The Lancet, vol. 337, no. 8747, pp. 978–979, 1991.
View at: Google Scholar
J. Hardy, M. Mullan, M.-C. Chartier-Harlin et al., “Molecular classification of Alzheimer's disease,” The Lancet, vol. 337, no. 8753, pp. 1342–1343, 1991.
View at: Google Scholar
K. Yoshioka, T. Miki, T. Katsuya, T. Ogihara, and Y. Sakaki, “The717Val→Ile substitution in amyloid precursor protein is associated with familial Alzheimer's disease regardless of ethnic groups,” Biochemical and Biophysical Research Communications, vol. 178, no. 3, pp. 1141–1146, 1991.
View at: Publisher Site | Google Scholar
U. Finckh, C. Kuschel, M. Anagnostouli et al., “Novel mutations and repeated findings of mutations in familial Alzheimer disease,” Neurogenetics, vol. 6, no. 2, pp. 85–89, 2005.
View at: Publisher Site | Google Scholar
M.-C. Chartier-Harlin, F. Crawford, H. Houlden et al., “Early-onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene,” Nature, vol. 353, no. 6347, pp. 844–846, 1991.
View at: Publisher Site | Google Scholar
W. D. Knight, R. L. Ahsan, J. Jackson et al., “Pure progressive amnesia and the APPV717G mutation,” Alzheimer Disease and Associated Disorders, vol. 23, no. 4, pp. 410–414, 2009.
View at: Publisher Site | Google Scholar
J. Murrell, M. Farlow, B. Ghetti, and M. D. Benson, “A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease,” Science, vol. 254, no. 5028, pp. 97–99, 1991.
View at: Google Scholar
J. R. Murrell, A. M. Hake, K. A. Quaid, M. R. Farlow, and B. Ghetti, “Early-onset Alzheimer disease caused by a new mutation (V717L) in the amyloid precursor protein gene,” Archives of Neurology, vol. 57, no. 6, pp. 885–887, 2000.
View at: Google Scholar
C. De Jonghe, C. Esselens, S. Kumar-Singh et al., “Pathogenic APP mutations near the γ-secretase cleavage site differentially affect Aβ secretion and APP C-terminal fragment stability,” Human Molecular Genetics, vol. 10, no. 16, pp. 1665–1671, 2001.
View at: Google Scholar
A. K. Godbolt, J. A. Beck, J. C. Collinge, L. Cipolotti, N. C. Fox, and M. N. Rossor, “A second family with familial AD and the V717L APP mutation has a later age at onset,” Neurology, vol. 66, no. 4, pp. 611–612, 2006.
View at: Publisher Site | Google Scholar
T. Tomiyama, T. Nagata, H. Shimada et al., “A new amyloid β variant favoring oligomerization in Alzheimer's-type dementia,” Annals of Neurology, vol. 63, no. 3, pp. 377–387, 2008.
View at: Publisher Site | Google Scholar
E. I. Rogaev, R. Sherrington, E. A. Rogaeva et al., “Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene,” Nature, vol. 376, no. 6543, pp. 775–778, 1995.
View at: Google Scholar
A. Church, J. Prescott, S. Lillis et al., “A novel presenilin 1 mutation, I202F occurring at a previously predicted pathogenic site causing autosomal dominant Alzheimer's disease,” Neurobiology of Aging, vol. 32, no. 3, pp. 556.e1–556.e2, 2011.
View at: Publisher Site | Google Scholar
H. B. Nygaard, C. F. Lippa, D. Mehdi, and J. M. Baehring, “A novel presenilin 1 mutation in early-Onset Alzheimer's disease with prominent frontal features,” American Journal of Alzheimer's Disease and Other Dementias, 2014.
View at: Google Scholar
V. Dobricic, E. Stefanova, M. Jankovic et al., “Genetic testing in familial and young-onset Alzheimer's disease: mutation spectrum in a Serbian cohort,” Neurobiology of Aging, vol. 33, no. 7, pp. 1481.e7–1481.e12, 2012.
View at: Google Scholar
V. Andreoli, F. Trecroci, A. La Russa et al., “Presenilin enhancer-2 gene: Identification of a novel promoter mutation in a patient with early-onset familial Alzheimer's disease,” Alzheimer's and Dementia, vol. 7, no. 6, pp. 574–578, 2011.
View at: Publisher Site | Google Scholar
B. Jiao, B. Tang, X. Liu et al., “Mutational analysis in early-onset familial Alzheimer's disease in Mainland China,” Neurobiology of Aging, 2014.
View at: Google Scholar
M. Gallo, N. Marcello, S. A. M. Curcio et al., “A novel pathogenic PSEN1 mutation in a family with Alzheimer's disease: phenotypical and neuropathological features,” Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 425–431, 2011.
View at: Publisher Site | Google Scholar
M. N. Rossor, N. C. Fox, J. Beck, T. C. Campbell, and J. Collinge, “Incomplete penetrance of familial Alzheimer's disease in a pedigree with a novel presenilin-1 gene mutation,” The Lancet, vol. 347, no. 9014, p. 1560, 1996.
View at: Google Scholar
G. Raux, L. Guyant-Maréchal, C. Martin et al., “Molecular diagnosis of autosomal dominant early onset Alzheimer's disease:an update,” Journal of Medical Genetics, vol. 42, no. 10, pp. 793–795, 2005.
View at: Publisher Site | Google Scholar
M. Cruts, H. Backhovens, S.-Y. Wang et al., “Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3,” Human Molecular Genetics, vol. 4, no. 12, pp. 2363–2371, 1995.
View at: Google Scholar
J. M. Heckmann, W. Low, C. De Villiers et al., “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.
View at: Publisher Site | Google Scholar
G. G. Glenner and C. W. Wong, “Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein,” Biochemical and Biophysical Research Communications, vol. 122, no. 3, pp. 1131–1135, 1984.
View at: Google Scholar
J. A. Hardy and G. A. Higgins, “Alzheimer's disease: the amyloid cascade hypothesis,” Science, vol. 256, no. 5054, pp. 184–185, 1992.
View at: Google Scholar
R. E. Tanzi and L. Bertram, “Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective,” Cell, vol. 120, no. 4, pp. 545–555, 2005.
View at: Publisher Site | Google Scholar
J. Hardy and D. J. Selkoe, “The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics,” Science, vol. 297, no. 5580, pp. 353–356, 2002.
View at: Publisher Site | Google Scholar
D. Scheuner, C. Eckman, M. Jensen et al., “Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease,” Nature Medicine, vol. 2, no. 8, pp. 864–870, 1996.
View at: Publisher Site | Google Scholar
T. Jonsson, J. K. Atwal, S. Steinberg et al., “A mutation in APP protects against Alzheimer's disease and age-related cognitive decline,” Nature, vol. 488, no. 7409, pp. 96–99, 2012.
View at: Google Scholar
W. P. Esler and M. S. Wolfe, “A portrait of Alzheimer secretases—new features and familiar faces,” Science, vol. 293, no. 5534, pp. 1449–1454, 2001.
View at: Publisher Site | Google Scholar
M. Citron, T. Oltersdorf, C. Haass et al., “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.
View at: Publisher Site | Google Scholar
H. Steiner, “Uncovering gamma-secretase,” Current Alzheimer Research, vol. 1, no. 3, pp. 175–181, 2004.
View at: Google Scholar
M. N. Rossor, S. Newman, R. S. J. Frackowiak, P. Lantos, and A. M. Kennedy, “Alzheimer's disease families with amyloid precursor protein mutations,” Annals of the New York Academy of Sciences, vol. 695, pp. 198–202, 1993.
View at: Publisher Site | Google Scholar
P. Cras, F. van Harskamp, L. Hendriks et al., “Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala→Gly mutation,” Acta Neuropathologica, vol. 96, no. 3, pp. 253–260, 1998.
View at: Publisher Site | Google Scholar
G. Roks, F. Van Harskamp, I. De Koning et al., “Presentation of amyloidosis in carriers of the codon 692 mutation in the amyloid precursor protein gene (APP692),” Brain, vol. 123, no. 10, pp. 2130–2140, 2000.
View at: Google Scholar
C. Van Broeckhoven, J. Haan, E. Bakker et al., “Amyloid β protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch),” Science, vol. 248, no. 4959, pp. 1120–1122, 1990.
View at: Google Scholar
I. Fernandez-Madrid, E. Levy, K. Marder, and B. Frangione, “Codon 618 variant of Alzheimer amyloid gene associated with inherited cerebral hemorrhage,” Annals of Neurology, vol. 30, no. 5, pp. 730–733, 1991.
View at: Google Scholar
C. Nilsberth, A. Westlind-Danielsson, C. B. Eckman et al., “The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation,” Nature Neuroscience, vol. 4, no. 9, pp. 887–893, 2001.
View at: Publisher Site | Google Scholar
H. Basun, N. Bogdanovic, M. Ingelsson et al., “Clinical and neuropathological features of the arctic APP gene mutation causing early-onset Alzheimer disease,” Archives of Neurology, vol. 65, no. 4, pp. 499–505, 2008.
View at: Publisher Site | Google Scholar
S. M. Greenberg, Y. Shin, T. J. Grabowski et al., “Hemorrhagic stroke associated with the Iowa amyloid precursor protein mutation,” Neurology, vol. 60, no. 6, pp. 1020–1022, 2003.
View at: Google Scholar
K. Sleegers, N. Brouwers, I. Gijselinck et al., “APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy,” Brain, vol. 129, no. 11, pp. 2977–2983, 2006.
View at: Publisher Site | Google Scholar
I. Guyant-Marechal, E. Berger, A. Laquerrière et al., “Intrafamilial diversity of phenotype associated with app duplication,” Neurology, vol. 71, no. 23, pp. 1925–1926, 2008.
View at: Publisher Site | Google Scholar
A. Rovelet-Lecrux, T. Frebourg, H. Tuominen, K. Majamaa, D. Campion, and A. M. Remes, “APP locus duplication in a Finnish family with dementia and intracerebral haemorrhage,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 78, no. 10, pp. 1158–1159, 2007.
View at: Publisher Site | Google Scholar
H. Thonberg, M. Fallström, J. Björkström, J. Schoumans, I. Nennesmo, and C. Graff, “Mutation screening of patients with Alzheimer disease identifies APP locus duplication in a Swedish patient,” BMC Research Notes, vol. 4, p. 476, 2011.
View at: Publisher Site | Google Scholar
A. Rovelet-Lecrux, D. Hannequin, G. Raux et al., “APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy,” Nature Genetics, vol. 38, no. 1, pp. 24–26, 2006.
View at: Publisher Site | Google Scholar
C. M. Filley, Y. D. Rollins, C. Alan Anderson et al., “The genetics of very early onset Alzheimer disease,” Cognitive and Behavioral Neurology, vol. 20, no. 3, pp. 149–156, 2007.
View at: Publisher Site | Google Scholar
N. Acosta-Baena, D. Sepulveda-Falla, C. M. Lopera-Gómez et al., “Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study,” The Lancet Neurology, vol. 10, no. 3, pp. 213–220, 2011.
View at: Publisher Site | Google Scholar
A. Jimenez-Escrig, A. Rabano, C. Guerrero et al., “New V272A presenilin 1 mutation with very early onset subcortical dementia and parkinsonism,” European Journal of Neurology, vol. 11, no. 10, pp. 663–669, 2004.
View at: Publisher Site | Google Scholar
A. J. Larner, “Presenilin-1 mutation Alzheimer's disease: a genetic epilepsy syndrome?” Epilepsy and Behavior, vol. 21, no. 1, pp. 20–22, 2011.
View at: Publisher Site | Google Scholar
E. Gómez-Tortosa, S. Barquero, M. Barón et al., “Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations,” Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 873–884, 2010.
View at: Publisher Site | Google Scholar
A. J. Larner and M. Doran, “Clinical phenotypic heterogeneity of Alzheimer's disease associated with mutations of the presenilin-1 gene,” Journal of Neurology, vol. 253, no. 2, pp. 139–158, 2006.
View at: Publisher Site | Google Scholar
A. J. Larner, “Presenilin-1 mutations in Alzheimer's disease: an update on genotype-phenotype relationships,” Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 653–659, 2013.
View at: Google Scholar
H. Karlstrom, W. S. Brooks, J. B. J. Kwok et al., “Variable phenotype of Alzheimer's disease with spastic paraparesis,” Journal of Neurochemistry, vol. 104, no. 3, pp. 573–583, 2008.
View at: Publisher Site | Google Scholar
A. Verkkoniemi, H. Kalimo, A. Paetau et al., “Variant Alzheimer disease with spastic paraparesis: neuropathological phenotype,” Journal of Neuropathology and Experimental Neurology, vol. 60, no. 5, pp. 483–492, 2001.
View at: Google Scholar
N. Sodeyama, T. Iwata, K. Ishikawa et al., “Very early onset Alzheimer's disease with spastic paraparesis associated with a novel presenilin 1 mutation (Phe237I1e),” Journal of Neurology Neurosurgery and Psychiatry, vol. 71, no. 4, pp. 556–557, 2001.
View at: Publisher Site | Google Scholar
L. Wu, P. Rosa-Neto, G. Y. Hsiung et al., “Early-onset familial Alzheimer's disease (EOFAD),” Canadian Journal of Neurological Sciences, vol. 39, no. 4, pp. 436–445, 2012.
View at: Google Scholar
S. Jayadev, J. B. Leverenz, E. Steinbart et al., “Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2,” Brain, vol. 133, no. 4, pp. 1143–1154, 2010.
View at: Publisher Site | Google Scholar
W. J. Strittmatter, A. M. Saunders, D. Schmechel et al., “Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 5, pp. 1977–1981, 1993.
View at: Google Scholar
E. H. Corder, A. M. Saunders, N. J. Risch et al., “Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease,” Nature Genetics, vol. 7, no. 2, pp. 180–184, 1994.
View at: Publisher Site | Google Scholar
E. H. Corder, A. M. Saunders, W. J. Strittmatter et al., “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.
View at: Google Scholar
P. Pastor, C. M. Roe, A. Villegas et al., “Apolipoprotein Eε4 modifies Alzheimer's disease onset in an E280A PS1 kindred,” Annals of Neurology, vol. 54, no. 2, pp. 163–169, 2003.
View at: Publisher Site | Google Scholar
D. E. Schmechel, A. M. Saunders, W. J. Strittmatter et al., “Increased amyloid β-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 20, pp. 9649–9653, 1993.
View at: Publisher Site | Google Scholar
R. W. Mahley, K. H. Weisgraber, and Y. Huang, “Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 15, pp. 5644–5651, 2006.
View at: Publisher Site | Google Scholar
M. R. Farlow, Y. He, S. Tekin, J. Xu, R. Lane, and H. C. Charles, “Impact of APOE in mild cognitive impairment,” Neurology, vol. 63, no. 10, pp. 1898–1901, 2004.
View at: Google Scholar
A. Grupe, R. Abraham, Y. Li et al., “Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants,” Human Molecular Genetics, vol. 16, no. 8, pp. 865–873, 2007.
View at: Publisher Site | Google Scholar
K. D. Coon, A. J. Myers, D. W. Craig et al., “A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease,” Journal of Clinical Psychiatry, vol. 68, no. 4, pp. 613–618, 2007.
View at: Google Scholar
E. M. Reiman, J. A. Webster, A. J. Myers et al., “GAB2 Alleles Modify Alzheimer's Risk in APOE ε4 Carriers,” Neuron, vol. 54, no. 5, pp. 713–720, 2007.
View at: Publisher Site | Google Scholar
H. Li, S. Wetten, L. Li et al., “Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease,” Archives of Neurology, vol. 65, no. 1, pp. 45–53, 2008.
View at: Publisher Site | Google Scholar
R. Abraham, V. Moskvina, R. Sims et al., “A genome-wide association study for late-onset Alzheimer's disease using DNA pooling,” BMC Med Genomics, vol. 1, p. 44, 2008.
View at: Publisher Site | Google Scholar
L. Bertram, C. Lange, K. Mullin et al., “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.
View at: Publisher Site | Google Scholar
S. E. Poduslo, R. Huang, J. Huang, and S. Smith, “Genome screen of late-onset Alzheimer's extended pedigrees identifies TRPC4AP by haplotype analysis,” American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, vol. 150, no. 1, pp. 50–55, 2009.
View at: Publisher Site | Google Scholar
G. W. Beecham, E. R. Martin, Y. Li et al., “Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease,” American Journal of Human Genetics, vol. 84, no. 1, pp. 35–43, 2009.
View at: Publisher Site | Google Scholar
M. M. Carrasquillo, F. Zou, V. S. Pankratz et al., “Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease,” Nature Genetics, vol. 41, no. 2, pp. 192–198, 2009.
View at: Publisher Site | Google Scholar
S. G. Potkin, G. Guffanti, A. Lakatos et al., “Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer's Disease,” PLoS ONE, vol. 4, no. 8, Article ID e6501, 2009.
View at: Publisher Site | Google Scholar
J. C. Lambert, S. Heath, G. Even et al., “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.
View at: Publisher Site | Google Scholar
D. Harold, R. Abraham, P. Hollingworth et al., “Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease,” Nature Genetics, vol. 41, no. 10, pp. 1088–1093, 2009.
View at: Publisher Site | Google Scholar
G. Laumet, V. Chouraki, B. Grenier-Boley et al., “Systematic analysis of candidate genes for Alzheimer's disease in a French, genome-wide association study,” Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1181–1188, 2010.
View at: Publisher Site | Google Scholar
K. Bettens, N. Brouwers, H. Van Miegroet et al., “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.
View at: Publisher Site | Google Scholar
S. Seshadri, A. L. Fitzpatrick, M. A. Ikram et al., “Genome-wide analysis of genetic loci associated with Alzheimer disease,” Journal of the American Medical Association, vol. 303, no. 18, pp. 1832–1840, 2010.
View at: Publisher Site | Google Scholar
A. C. Naj, G. W. Beecham, E. R. Martin et al., “Dementia revealed: novel chromosome 6 locus for Late-onset alzheimer disease provides genetic evidence for Folate-pathway abnormalities,” PLoS Genetics, vol. 6, no. 9, Article ID e1001130, 2010.
View at: Publisher Site | Google Scholar
J. H. Lee, R. Cheng, S. Barral et al., “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.
View at: Publisher Site | Google Scholar
R. Sherva, C. T. Baldwin, R. Inzelberg et al., “Identification of novel candidate genes for Alzheimer's disease by autozygosity mapping using genome wide SNP data,” Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 349–359, 2011.
View at: Publisher Site | Google Scholar
E. M. Wijsman, N. D. Pankratz, Y. Choi et al., “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, Article ID e1001308, 2011.
View at: Publisher Site | Google Scholar
X. Hu, E. Pickering, Y. C. Liu et al., “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, Article ID e16616, 2011.
View at: Publisher Site | Google Scholar
A. C. Naj, G. Jun, G. W. Beecham et al., “Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease,” Nature Genetics, vol. 43, no. 5, pp. 436–443, 2011.
View at: Publisher Site | Google Scholar
P. Hollingworth, D. Harold, R. Sims et al., “Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease,” Nature Genetics, vol. 43, no. 5, pp. 429–436, 2011.
View at: Publisher Site | Google Scholar
M. W. Logue, M. Schu, B. N. Vardarajan et al., “A comprehensive genetic association study of Alzheimer disease in African Americans,” Archives of Neurology, vol. 68, no. 12, pp. 1569–1579, 2011.
View at: Google Scholar
M. I. Kamboh, F. Y. Demirci, X. Wang et al., “Genome-wide association study of Alzheimer's disease,” Translational Psychiatry, vol. 2, p. e117, 2012.
View at: Publisher Site | Google Scholar
C. Reitz, G. Jun, A. Naj et al., “Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E 4, and the risk of late-onset Alzheimer disease in African Americans,” Journal of the American Medical Association, vol. 309, no. 14, pp. 1483–1492, 2013.
View at: Publisher Site | Google Scholar
R. Guerreiro, A. Wojtas, J. Bras et al., “TREM2 variants in Alzheimer's disease,” The New England Journal of Medicine, vol. 368, no. 2, pp. 117–127, 2013.
View at: Publisher Site | Google Scholar
T. Jonsson, H. Stefansson, S. Steinberg et al., “Variant of TREM2 associated with the risk of Alzheimer's disease,” The New England Journal of Medicine, vol. 368, no. 2, pp. 107–116, 2013.
View at: Publisher Site | Google Scholar
J. C. Lambert, C. A. Ibrahim-Verbaas, D. Harold et al., “Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease,” Nature Genetics, vol. 45, no. 12, pp. 1452–1458, 2013.
View at: Google Scholar
M. Kim, J. Suh, D. Romano et al., “Potential late-onset Alzheimer's disease-associated mutations in the ADAM10 gene attenuate α-secretase activity,” Human Molecular Genetics, vol. 18, no. 20, pp. 3987–3996, 2009.
View at: Publisher Site | Google Scholar
D. M. Holtzman, J. C. Morris, and A. M. Goate, “Alzheimer's disease: the challenge of the second century,” Science Translational Medicine, vol. 3, no. 77, Article ID 77sr1, 2011.
View at: Publisher Site | Google Scholar
G. Tosto and C. Reitz, “Genome-wide association studies in Alzheimer's disease: a review,” Current Neurology and Neuroscience Reports, vol. 13, no. 10, p. 381, 2013.
View at: Publisher Site | Google Scholar
J. S. Goldman, S. E. Hahn, J. W. Catania et al., “Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors,” Genetics in Medicine, vol. 13, no. 6, pp. 597–605, 2011.
View at: Publisher Site | Google Scholar
P. E. Cohn-Hokke, M. W. Elting, Y. A. Pijnenburg, and J. C. van Swieten, “Genetics of dementia: update and guidelines for the clinician,” American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, vol. 159, no. 6, pp. 628–643, 2012.
View at: Publisher Site | Google Scholar
C. T. Loy, P. R. Schofield, A. M. Turner, and J. B. Kwok, “Genetics of dementia,” The Lancet, vol. 383, no. 9919, pp. 828–840, 2014.
View at: Publisher Site | Google Scholar
R. J. Guerreiro, M. Baquero, R. Blesa et al., “Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP,” Neurobiology of Aging, vol. 31, no. 5, pp. 725–731, 2010.
View at: Publisher Site | Google Scholar
E. J. Steinbart, C. O. Smith, P. Poorkaj, and T. D. Bird, “Impact of DNA testing for early-onset familial Alzheimer disease and frontotemporal dementia,” Archives of Neurology, vol. 58, no. 11, pp. 1828–1831, 2001.
View at: Google Scholar
J. Fortea, A. Lladó, J. Clarimón et al., “PICOGEN: five years experience with a genetic counselling program for dementia,” Neurologia, vol. 26, no. 3, pp. 143–149, 2011.
View at: Publisher Site | Google Scholar
P. Nilsson, N. Iwata, S. Muramatsu, L. O. Tjernberg, B. Winblad, and T. C. Saido, “Gene therapy in Alzheimer's disease-potential for disease modification,” Journal of Cellular and Molecular Medicine, vol. 14, no. 4, pp. 741–757, 2010.
View at: Publisher Site | Google Scholar
M. H. Tuszynski, D. E. Smith, J. Roberts, H. McKay, and E. Mufson, “Targeted intraparenchymal delivery of human NGF by gene transfer to the primate basal forebrain for 3 months does not accelerate β-amyloid plaque deposition,” Experimental Neurology, vol. 154, no. 2, pp. 573–582, 1998.
View at: Publisher Site | Google Scholar
A. H. Nagahara, D. A. Merrill, G. Coppola et al., “Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease,” Nature Medicine, vol. 15, no. 3, pp. 331–337, 2009.
View at: Publisher Site | Google Scholar
N. Iwata, H. Mizukami, K. Shirotani et al., “Presynaptic localization of neprilysin contributes to efficient clearance of amyloid-β peptide in mouse brain,” Journal of Neuroscience, vol. 24, no. 4, pp. 991–998, 2004.
View at: Publisher Site | Google Scholar
J. C. Dodart, R. A. Marr, M. Koistinaho et al., “Gene delivery of human apolipoprotein E alters brain Aβ burden in a mouse model of Alzheimer's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 4, pp. 1211–1216, 2005.
View at: Publisher Site | Google Scholar
N. C. Carty, K. Nash, D. Lee et al., “Adeno-associated viral (AAV) serotype 5 vector mediated gene delivery of endothelin-converting enzyme reduces Aβ deposits in APP + PS1 transgenic mice,” Molecular Therapy, vol. 16, no. 9, pp. 1580–1586, 2008.
View at: Publisher Site | Google Scholar
S. Mueller-Steiner, Y. Zhou, H. Arai et al., “Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease,” Neuron, vol. 51, no. 6, pp. 703–714, 2006.
View at: Publisher Site | Google Scholar
M. H. Tuszynski, L. Thal, M. Pay et al., “A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease,” Nature Medicine, vol. 11, no. 5, pp. 551–555, 2005.
View at: Publisher Site | Google Scholar
K. Wu, C. A. Meyers, N. K. Guerra, M. A. King, and E. M. Meyer, “The effects of rAAV2-mediated NGF gene delivery in adult and aged rats,” Molecular Therapy, vol. 9, no. 2, pp. 262–269, 2004.
View at: Publisher Site | Google Scholar
C.-S. Hong, W. F. Goins, J. R. Goss, E. A. Burton, and J. C. Glorioso, “Herpes simplex virus RNAi and neprilysin gene transfer vectors reduce accumulation of Alzheimer's disease-related amyloid-β peptide in vivo,” Gene Therapy, vol. 13, no. 14, pp. 1068–1079, 2006.
View at: Publisher Site | Google Scholar
O. Singer, R. A. Marr, E. Rockenstein et al., “Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model,” Nature Neuroscience, vol. 8, no. 10, pp. 1343–1349, 2005.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2014 Zhangyu Zou et al. 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.

PDF Download Citation

Download other formats

Order printed copies

Views

6155

Downloads

1983

Citations