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Structural Genomics of Alzheimer’s Disease\nThe genetic defects identified in AD can be classified into three main categories: (a) Mendelian mutations in AD primary genes; (b) multiple susceptibility SNPs in many different genes distributed across the human genome; and (c) mitochondrial DNA (mtDNA) mutations. \n(a) Mendelian or mutational defects in genes directly linked to AD, including (i) \u003e30 mutations in the amyloid beta (Aβ) precursor protein (APP) gene (21q21) (AD1); (ii) \u003e160 mutations in the presenilin 1 (PSEN1) gene (14q24.3) (AD3); and (iii) \u003e10 mutations in the presenilin 2 (PSEN2) gene (1q31–q42) (AD4) [8,20,21]. PSEN1 and PSEN2 are important determinants of γ-secretase activity responsible for proteolytic cleavage of APP and NOTCH receptor proteins. Mendelian mutations are very rare in AD (1:1000). Mutations in exons 16 and 17 of the APP gene appear with a frequency of 0.30% and 0.78%, respectively, in AD patients. Likewise, PSEN1, PSEN2, and microtubule-associated protein Tau (MAPT) (17q21.1) mutations are present in less than 2% of the cases. Mutations in these genes confer specific phenotypic profiles to patients with dementia: amyloidogenic pathology associated with APP, PSEN1 and PSEN2 mutations; and tauopathy associated with MATP mutations, representing the two major pathogenic hypotheses for AD [8,23,24,25]. \n(b) Multiple polymorphic risk variants characterized in over 200 different genes can increase neuronal vulnerability to premature death (Table 1) [8]. Among susceptibility genes, the apolipoprotein E (APOE) gene (19q13.2)(AD2) is the most prevalent as a risk factor for AD, especially in those subjects harboring the APOE-4 allele, whereas carriers of the APOE-2 allele might be protected against dementia [8]. APOE-related pathogenic mechanisms are also associated with brain aging and with the neuropathological hallmarks of AD. \nIn 1993 Allen Roses and co-workers found a clear association between APOE genotypes and AD, demonstrating that the frequency of the APOE-4 allele was significantly higher in LOAD [26,27,28]. Since then, many other studies have confirmed the early findings of Saunders et al. [27,28] and Corder et al. [29] reporting an increased frequency of the APOE-4 allele in AD and the association of the APOE-4 allele with LOAD and sporadic forms of AD [26,27,28,29,30,31]. APOE-4 may influence AD pathology interacting with APP metabolism and Aβ accumulation, enhancing hyperphosphorylation of tau protein and NFT formation, reducing choline acetyltransferase activity, increasing oxidative processes, modifying inflammation-related neuroimmunotrophic activity and glial activation, altering lipid metabolism, lipid transport and membrane biosynthesis in sprouting and synaptic remodeling, and inducing neuronal apoptosis [8,17,26,27,28,29,30,31,32,33]. Age-related changes in brain structure and function have been reported as potential indicators of premature neurodegeneration [34].\nOther genes of this category are included in Table 1. One of the newest members of the AD-gene family is SORL1, a gene which encodes a mosaic protein with a domain structure which suggests it is a member of both the vacuolar protein sorting-10 (Vps10) domain-containing receptor family and the low density lipoprotein receptor (LDLR). Inherited variants of the SORL1 neuronal sorting receptor are associated with late-onset AD. Polymorphisms in two different clusters of intronic sequences within the SORL1 gene may regulate tissue-specific expression of SORL1, which directs trafficking of APP into recycling pathways. When SORL1 is underexpressed, APP is sorted into Aß-generating compartments leading to amyloid accumulation in neuronal tissues [35]. As with many other potential AD-related genes, the association of SORL1 with AD [35,36] could not be replicated in other studies [37]. \nSorting protein-related receptor with A-type repeats (SORLA) is a major risk factor in cellular processes leading to AD. It acts as a sorting receptor for the APP that regulates intracellular trafficking and processing into amyloidogenic-beta peptides (Aβ). Overexpression of SORLA in neurons reduces while inactivation of gene expression accelerates amyloidogenic processing and senile plaque formation. Brain-derived neurotrophic factor (BDNF) is a major inducer of SORLA that activates receptor gene transcription through the ERK (extracellular regulated kinase) pathway. Expression of the receptor is significantly impaired in mouse models with genetic (Bdnf(-/-)) or disease-related loss of BDNF activity in the brain (Huntington’s disease). Exogenous application of BDNF reduced Aβ production in primary neurons and in the brain of wild-type mice in vivo, but not in animals genetically deficient for Sorla. According to these findings reported by Rohe et al. [38], the beneficial effects ascribed to BDNF in APP metabolism act through induction of Sorla which encodes a negative regulator of neuronal APP processing. The presence of the BDNF Val allele in itself and in combination with the APOE-4 allele can be risk factors for AD, Lewy body dementia and Pick’s disease [39]. \nAnother interesting gene is DHCR24 (3β-hydroxysterol-δ-24-reductase) or Seladin-1, a key element in the cholesterologenic pathway in which the DHCR24 enzyme catalyzes the transformation of desmosterol into cholesterol [40,41]. Seladin-1 was originally identified as a gene whose expression was down-regulated in the AD brain, demonstrating a neuroprotective effect against neurodegeneration. Recent studies indicate that Seladin-1/DHCR24 is an LXR (liver X nuclear hormone receptor) target gene potentially involved in the regulation of lipid raft formation [40]. Polymorphisms in the cholesteryl ester transfer protein (CETP) gene have been associated with exceptional longevity and lower cardiovascular risk, but associations with memory decline and dementia risk are unclear. Sanders et al. [42] tested the hypothesis that a SNP at CETP codon 405 (isoleucine to valine V405; SNP rs5882) is associated with a lower rate of memory decline and lower risk of incident dementia, including AD. Compared with isoleucine homozygotes, valine homozygotes had significantly slower memory decline and lower risk of dementia. \nAnother gene, with potential therapeutic interest as a tau kinase, might be the GSK3 gene. Analysis of the promoter and all 12 exons revealed that an intronic polymorphism (IVS2-68G \u003e A) occurred at over twice the frequency among patients with frontotemporal dementia (10.8%) and patients with AD (14.6%) than in aged healthy subjects (4.1%). This is the first evidence that a gene known to be involved in tau phosphorylation is associated with risk for primary neurodegenerative dementias [43]. Promoter polymorphisms modulating HSPA5 expression might also increase susceptibility to AD. Endoplasmic reticulum chaperone heat shock 70 kDa protein 5 (HSPA5/GRP78) is known to be involved in APP metabolism and neuronal death in AD. Of the three major polymorphisms (-415G/A (rs391957), -370C/T (rs17840761), -180del/G (rs3216733)), the HSPA5-415G/A and -180del/G variants showed significant differences between AD cases and controls. Subjects harboring the -415AA/-180GG genotype or the -415A/-180G allele might be less susceptible to develop AD [44]. The rs5952C and rs1568566T alleles of the APOD rs5952T/C and rs1568566C/T variants increase the risk for AD, whereas the rs5952T-rs1568566C haplotype reduces it [45]. \nApoD is a lipoprotein-associated glycoprotein which is increased in the hippocampus and CSF of AD patients [45]. CALHM1 encodes a multipass transmembrane glycoprotein that controls cytosolic Ca2+ concentrations and Aβ levels. The CALHM1 P86L polymorphism (rs2986017) has been associated with AD [46]. \nHarold et al. [47] undertook a two-stage genome-wide association study (GWAS) of AD involving over 16,000 individuals, and found association with SNPs at two loci not previously associated with the disease, at the CLU (Clusterine, APOJ) gene (rs11136000) and 5' to the PICALM gene (rs3851179). In another GWAS with patients from France, Belgium, Finland, Italy and Spain, Lambert et al. [48] found association with CLU and with the CR1 gene, encoding the complement component (3b/4b) receptor 1, on chromosome 1 (rs6656401). \nJun et al. [49] determined whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by APOE genotypes in 7070 cases with AD, 3055 with autopsies; and 8169 elderly cognitively normal controls, 1092 with autopsies, from 12 different studies, including white, African American, Israeli-Arab, and Caribbean Hispanic individuals. They confirmed in a completely independent data set that CR1 (rs3818361), CLU (rs11136000), and PICALM (rs3851179) are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE-4-positive subjects. Thus, APOE and PICALM synergistically interact. Two new loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 and rs597668 near EXOC3L2/BLOC1S3/MARK4 [50]. \nKramer et al. [51] conducted a GWAS to identify genetic mechanisms that distinguish non-demented elderly with a heavy NFT burden from those with a low NFT burden. Both a genotype test, using logistic regression, and an allele test provided consistent evidence that variants in the RELN gene are associated with neuropathology in the context of cognitive health. Immunohistochemical data for reelin expression in AD-related brain regions added support for these findings. Reelin signaling pathways modulate phosphorylation of tau, the major component of NFTs, either directly or through beta-amyloid pathways that influence tau phosphorylation. Up-regulation of reelin may be a compensatory response to tau-related or beta-amyloid stress associated with AD even prior to the onset of dementia [51]. Aβ induces synaptic dysfunction in part by altering the endocytosis and trafficking of AMPA and NMDA receptors. Reelin is a neuromodulator that increases glutamatergic neurotransmission by signaling through the postsynaptic ApoE receptors ApoER2 and VLDLR and thereby potently enhances synaptic plasticity. Reelin can prevent the suppression of long-term potentiation and NMDA receptors, which is induced by levels of Aβ comparable to those present in an AD-afflicted brain. This reversal is dependent upon the activation of Src family tyrosine kinases. Durakoglugil et al. [52] have proposed that Aβ, Reelin, and ApoE receptors modulate neurotransmission and thus synaptic stability as opposing regulators of synaptic gain control.\nA variable-length, deoxythymidine homopolymer (poly-T) within intron 6 of the TOMM40 gene was found to be associated with the age of onset of LOAD by Roses et al. [53]. This result was obtained with a phylogenetic study of the genetic polymorphisms that reside within the linkage disequilibrium (LD) block that contains the TOMM40, APOE, and APOC1 genes from patients with LOAD and age-matched subjects without disease [54]. These new data explain the mean age at disease onset for patients with the APOE4/4 genotype and differentiate two forms of TOMM40 poly-T polymorphisms linked to APOE, with each form associated with a different age at disease onset distribution. When linked to APOE3 (encoding the epsilon3 isoform of APOE), the longer TOMM40 poly-T repeats (19–39 nucleotides) at the rs10524523 (hereafter, 523) locus are associated with earlier age at onset and the shorter TOMM40 523 alleles (11–16 nucleotides) are associated with later age at onset. According to Roses (2010) [55], the data suggest that the poly-T alleles are codominant, with the age at onset phenotype determined by the two inherited 523 alleles, but with variable expressivity. \nOhe and Maeda [56] reported that overexpression of high-mobility group A protein 1a (HMGA1a) causes aberrant exon 5 skipping of the presenilin-2 (PSEN2) pre-mRNA, which is almost exclusively detected in patients with sporadic AD. An electrophoretic mobility shift assay confirmed aberrant U1 small nuclear ribonucleoprotein particle (snRNP)-HMGA1a complex formation (via the U1-70K component), with RNA containing a specific HMGA1a-binding site and an adjacent 5' splice site. The HMGA1a-induced aberrant exon skipping is caused by impaired dissociation of U1 snRNP from the 5' splice site, leading to a defect in exon definition. \nKelley et al. [57] characterized a kindred with a familial neurodegenerative disorder associated with a mutation in progranulin (PGRN). PGRN analysis revealed a single base pair deletion in exon 2 (c.154delA), which caused a frameshift (p.Thr52HisfsX2) and, therefore, creation of a premature termination codon and a likely null allele. In this large kindred, most affected individuals had clinical presentations that resembled AD or amnestic mild cognitive impairment associated with a mutation in PGRN and underlying frontotemporal lobar degeneration with ubiquitin-positive neuronal cytoplasmic and intranuclear inclusions (FTLD-U). Mutation in the PGRN gene can cause frontotemporal dementia (FTD9). Yu et al. [58] identified 58 genetic variants that included 26 previously unknown changes. 24 variants appeared to be pathogenic, including eight novel mutations. The frequency of PGRN mutations was 6.9% of all FTD-spectrum cases, 21.4% of cases with a pathological diagnosis of FTLD-U, 16.0% of FTD-spectrum cases with a family history of a similar neurodegenerative disease, and 56.2% of cases of FTLD-U with a family history. Haploinsufficiency of PGRN is the predominant mechanism leading to FTD.\nPolymorphisms within the promoter region of the vascular endothelial growth factor (VEGF) gene might elevate the risk for AD. In a Tunisian population, Smach et al. [59] found that the distribution of genotype and allele frequencies of the VEGF (-2578C/A) and (-1154G/A) polymorphisms did not differ significantly between AD and control groups. In the subgroup of APOE-4 carriers, the -2578A was observed to be significantly higher in the AD patients than in the control individuals. Endothelin converting enzyme (ECE-1) is also a candidate AD susceptibility gene. Individuals homozygous for the C-338A polymorphism (AA) within the ECE1 gene promoter region are at reduced risk of developing late onset AD (LOAD). A further polymorphism, T-839G, is present within the ECE1 promoter region but there is no significant association between T-839G and LOAD; however the combined 839T/338A haplotype is associated with decreased risk of LOAD, suggesting that the ECE1 338A allele is protective against LOAD in a Chinese population [60].\nDown-regulation of somatostatin (SST) expression in the human brain during early stages of aging may lead to an elevation in the steady-state levels of Aβ and therefore may be involved in AD progression. Alterations in the SST gene might alter its expression or function and also play a role in the pathogenesis of sporadic AD (SAD). C/T polymorphisms (rs4988514) in the 3' untranslated region of the SST gene were screened. The C allele of the rs4988514 polymorphism had an increased incidence in the SAD group compared to the control group in the Chinese population. In subjects with the APOE-4 allele, the presence of both the CC genotype and the C allele of this polymorphism were elevated in the SAD group compared to the control group. The C allele of the rs4988514 polymorphism may increase the risk for AD in the Chinese population and possibly have additive effect with the APOE-4 allele [61].\nThe receptor for advanced glycation end products (RAGE) is associated with several pathological states including AD pathology, while its soluble form (sRAGE) acts as a decoy receptor. Li et al. [62] studied a SNP in the RAGE gene (G82S; rs2070600), and a SNP associated with increased ligand affinity of RAGE. Analysis of a Chinese cohort showed a higher prevalence of the RAGE 82S allele and GS + SS genotype in EOAD patients. RAGE contributes to transport of Aβ from the cell surface to the intracellular space. Pretreatment of cultured neurons from wild-type mice with neutralizing antibody to RAGE, and neurons from Rage knockout mice displayed decreased uptake of Aβ and protection from Aβ-mediated mitochondrial dysfunction [63]. \nThe TAR-DNA binding protein (TDP-43) has been postulated as the disease protein in amyotrophic lateral sclerosis and frontotemporal lobar dementia with ubiquitin-positive inclusions. TDP-43 may also play a role in the pathogenesis of AD. Shibata et al. [64] identified an association between a specific haplotype (G-A-A-G) of the TDP-43 gene and risk for AD. \nImmune dysfunction and aberrant inflammatory reactions are present in AD neuropathology. Neurons express enzymes such as cyclooxygenases (COXs) and 5-lipoxygenase (5-LO) which are considered important in inflammatory cells. It has been suggested that COX-2 and 5-LO enzymes may play a role in the pathophysiology of AD. A significant difference was observed in the distribution of the -765G COX-2 and -1708A 5-LO alleles between AD cases and controls. COX-2 -765G and 5-LO -1708A alleles were overrepresented in AD patients and underrepresented in controls [65]. The HLA-A*01 variant might also be associated with AD [66]. SNPs in the regulatory regions of the cytokine genes for tumor necrosis factor alpha (TNFalpha), interleukin (IL)-6 and IL-10 have been suggested to influence the risk of AD with conflicting results. Heterozygotes (AG) or combined genotype (AG + AA) for IL-10 -1082 were associated with approximately two-fold increase in the risk of AD. Carriers of A alleles of both TNFalpha-308 and IL-10 -1082 had 6.5 times higher risk for AD in comparison with non-carriers. Concomitant presence of both mutant TNFalpha-308 A and IL-6 -174 C alleles raised three-fold the AD risk, whereas there was no notable risk for AD afflicted by IL-6 -174 polymorphism alone [67,68].\nInterleukin-33 (IL-33), a newly described member of the IL-1 family, is located on chromosome 9p24, a chromosomal region of interest in AD. Three intronic rs1157505, rs11792633, and rs7044343 SNPs within IL-33 have been reported to be associated with risk of AD in Caucasian and Chinese populations [69]. \nAromatase gene polymorphisms have also been associated with AD [70]. Polymorphisms in genes encoding amyloid beta-peptide (Aβ)-degrading enzymes neprilysin (NEP) and insulin-degrading enzyme (IDE) individually affect the susceptibility to AD among the Finnish population [71]. Nicastrin (NCSTN) is a type I trans-membrane glycoprotein and an essential component of γ-secretase, a multiprotein complex required for the production of the mature form of Aβ. Overexpression of wild-type NCSTN increases Aβ production, indicating that the strict regulation of NCSTN expression may play a fundamental role in the pathogenesis of AD. Zhong et al. [72] investigated the effect of a SNP (rs10752637) located in the promoter region of the NCSTN gene, on NCSTN promoter activity. The distributions of the rs10752637 genotypes and allele frequencies were significantly different between the AD and control groups, with the -922T allele significantly associated with the occurrence of AD. Reporter assays indicated that the rs10752637 -922T allele had a significantly increased promoter activity relative to the -922G allele. The rs10752637 SNP can probably influence the expression of NCSTN, and this may be an influencing factor during the pathogenesis of AD.\nThe FISH (five SH3 domains) adapter protein and ADAM12 (a disintegrin and metalloprotease) may mediate the neurotoxic effect of Aβ. Both genes are located on chromosome 10, within a region linked to AD (for SH3PXD2A) or nearby (for ADAM12). Two variants of these genes (rs3740473 for SH3PXD2A and rs11244787 for ADAM12) have been associated with increased risk for developing AD, but these findings could not be confirmed in different populations [73]. \nParaoxonase 1 (PON1) L55M and Q192R genetic variants might affect individual susceptibility to environmental events, such as exposure to cholinesterase inhibitors. The L55M Met allele exerts an AD risk-enhancing effect only in men, whereas both men and women carrying the M55M/Q192Q genotype exhibit increased survival and later age of onset. These genetic variants are also individually and significantly associated, sometimes in opposite directions for both genders, with beta-amyloid levels, senile plaque accumulation and choline acetyltransferase activity in brain areas [74].\nLiu et al. [75] studied the potential association of polymorphisms in NMDA receptor subunits NR3A and NR3B, encoded by the GRIN3A and GRIN3B genes, with AD, on the basis that memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, may provide some clinical benefit in AD patients. Two SNPs, 3104G/A (rs10989563) and 3723G/A (rs3739722), in the GRIN3A gene, and two GRIN3B gene polymorphisms, 1210C/T (rs4807399) and 1730C/T (rs2240158), were analyzed. Upon genotyping of the exonic polymorphism in the GRIN3A gene, the G allele was present at a higher rate than the A allele at position 3723 in AD patients compared with normal groups. Three haplotypes (designated Ht1-3) were identified from these 2 polymorphisms (3104G/A and 3723G/A), and the distribution of Ht2 (AG) differed between AD patients and controls. The 2 GRIN3B gene variants 1210C/T and 1730C/T did not show association with AD. These observations suggest that the genetic variation of the NR3A, but not NR3B, subunit of the NMDA receptor may be a risk factor for AD pathogenesis among the Taiwanese population. di Maria et al. [76] reported that the occurrence of delusions and hallucinations in AD is associated with variations in the G72/DAOA gene (rs2153674), which is supposed to play a key role in the glutamate pathway regulated through the NMDA receptors. Martínez et al. [77] studied the influence of the catechol-O-methyltranferase (COMT) gene (polymorphism Val158 Met) as a risk factor for AD and mild cognitive impairment of amnesic type (MCI), and its synergistic effect with APOE variants in the Basque Country. Neither COMT alleles nor genotypes were independent risk factors for AD or MCI; however, the high activity genotypes (GG and AG) showed a synergistic effect with the APOE-4 allele, increasing the risk of AD. \nPeptidyl-prolyl isomerase, NIMA-interacting 1 (PIN1) plays a significant role in the brain and is implicated in numerous cellular processes related to AD and other neurodegenerative conditions. Analysis of 18 PIN1 common polymorphisms and their haplotypes in EOAD, LOAD and FTD individuals in comparison with the control group did not reveal their contribution to disease risk. In six unrelated familial AD patients four novel PIN1 sequence variants were detected. The c.58 + 64C \u003e T substitution identified in three patients, was located in an alternative exon. In silico analysis suggested that this variant highly increases a potential affinity for a splicing factor and introduces two intronic splicing enhancers. In the peripheral leukocytes of one living patient carrying the variant, a 2.82 fold decrease in PIN1 expression was observed [78]. \nAlzheimer’s and prion diseases are neurodegenerative disorders characterized by the abnormal processing of Aβ peptide and prion protein (PrPC), respectively. PrPC may play a critical role in the pathogenesis of AD. PrPC interacts with and inhibits the β-secretase BACE1, the rate-limiting enzyme in the production of Aβ. PrPC was also identified as a receptor for Aβ oligomers and the expression of PrPC appears to be controlled by the amyloid intracellular domain (AICD). PrPC exerts an inhibitory effect on BACE1 to decrease both Aβ and AICD production, and the AICD upregulates PrPC expression, thus maintaining the inhibitory effect of PrPC on BACE1. According to Kellett and Hooper [79], this feedback loop is disrupted in AD, and the increased level of Aβ oligomers binds to PrPC and prevents it from regulating BACE1 activity. It is also likely that PRNP gene mutations contribute to AD pathogenesis [8]. \nHECTD2 maps to 10q and has been implicated in susceptibility to human prion disease. A HECTD2 intronic tagging SNP, rs12249854 (A/T), has been studied in AD. The rs12249854 minor allele (A) frequency was higher (5.8%) in AD as compared to controls (3.9%). No significant difference was seen in minor allele frequency in the presence or absence of the APOE-4 allele. According to these results, it appears that the common haplotypes of HECTD2, tagged by rs12249854, are not associated with susceptibility to LOAD [80].\nUbiquitin-conjugating enzyme E2I (Ubc9) ligates small ubiquitin-related modifier (SUMO) to target proteins, resulting in changes of their localization, activity, or stability. Sumoylation of APP was reported to be associated with decreased levels of Aβ aggregates, suggesting that sumoylation may play a role in the pathogenesis of AD. Ahn et al. [81] investigated the association between genetic variations of Ubc9 gene (UBE2I) and LOAD in Koreans. The genotype distribution of a polymorphism in intron 7 (rs761059) differed between AD cases and controls and one haplotype (ht2 CAGAG) was found in 14.0% of the AD patients and in 11.1% of the controls. Stratification by the APOE-4 allele gave no significant difference between the groups. When the samples were stratified by gender, the genotypes of two SNPs (rs8052688, rs8063) were significantly associated with the risk of MCI among women. \nTo gain insights into the evolution of the regulatory mechanisms of the aged brain, Persengiev et al. [82] compared age-related differences in microRNA (miRNA) expression levels in the cortex and cerebellum of humans, chimpanzees and rhesus macaques on a genome-wide scale. In contrast to global miRNA downregulation, a small subset of miRNAs was found to be selectively upregulated in the aging brain of all three species. miR-144 appeared to be associated with the aging progression. miR-144 plays a central role in regulating the expression of ataxin 1 (ATXN1), a gene which is associated with spinocerebellar ataxia type 1 (SCA1). miRNA activity, including miR-144, -101 and -130 processing, was increased in the cerebellum and cortex of SCA1 and Alzheimer’s patients relative to healthy aged brains. The activation of miRNA expression in the aging brain might serve to reduce the cytotoxic effect of polyglutamine expanded ATXN1 and the deregulation of miRNA expression might be a risk factor for neurodegeneration. Bettens et al. [83] also obtained evidence for association between rs179943, an intronic SNP in ATXN1 at 6p22.3, and AD. \nThe cholesterol transporter ATP-binding cassette transporter A1 (ABCA1) moves lipids onto apolipoproteins including ApoE. Donkin et al. [84] reported that in amyloid mouse models of AD, ABCA1 deficiency exacerbates amyloidogenesis, whereas ABCA1 overexpression ameliorates amyloid load, suggesting a role for ABCA1 in Abeta metabolism. Agonists of Liver X Receptors (LXR), including GW3965, induce transcription of several genes including ABCA1 and APOE, reduce Abeta levels and improve cognition in AD mice. Treatment of APP/PS1 mice with GW3965 increased ABCA1 and ApoE protein levels. ABCA1 was observed to require significantly elevated ApoE levels in brain tissue and CSF upon GW3965 treatment. APP/PS1 mice treated with either 2.5 mg/kg/d or 33 mg/kg/d of GW3965 showed a clear trend toward reduced amyloid burden in hippocampus and whole brain, whereas treated APP/PS1 mice lacking ABCA1 failed to display reduced amyloid load in whole brain and showed trends toward increased hippocampal amyloid. Treatment of APP/PS1 mice with either dose of GW3965 completely restored novel object recognition (NOR) memory to wild-type levels, which required ABCA1. These results reported by Donkin and co-workers suggest that ABCA1 contributes to several beneficial effects of the LXR agonist GW3965 in APP/PS1 mice.\nThe phospholipid transfer protein (PLTP) reduces phosphorylation of tau in human neuronal cells. Patients with AD have significantly higher levels of PLTP in brain tissue and significantly lower PLTP-mediated phospholipid transfer activity in cerebrospinal fluid. PLTP also affects ApoE secretion from glial cells. Kuerban et al. [85] investigated whether SNPs of the PLTP gene are associated with AD in the Japanese population, and found no genetic association between PLTP and AD. \nGenome-wide association studies (GWAS) in AD highlight over two dozen novel potential susceptibility loci beyond the well-established APOE association, including GAB2 (GRB2-associated binding protein 2), galanin-like peptide (GALP), piggyBac transposable element derived 1 (PGBD1), tyrosine kinase, non-receptor 1 (TNK1), and at least three replicated loci in hitherto uncharacterized genomic intervals on chromosomes 14q32.13, 14q31.2 and 6q24.1, probably implicating the existence of novel AD genes in these regions [86]. \n(c) Diverse mutations located in mitochondrial DNA (mtDNA) through heteroplasmic transmission can influence aging and oxidative stress conditions, conferring phenotypic heterogeneity [8,87]. The human presequence protease (hPreP) was recently shown to be the major mitochondrial Aβ-degrading enzyme. Genetic variation in the hPreP gene PITRM1 has been investigated by Pinho et al. [88]. No genetic association between any of the SNPs and the risk for AD was found; however, functional analysis of four non-synonymous SNPs in hPreP revealed a decreased activity compared to wild-type hPreP. Using Aβ, the presequence of ATP synthase F1β subunit and a fluorescent peptide as substrates, the lowest activity was observed for the hPreP(A525D) variant, corresponding to rs1224893, which displayed only 20–30% of wild-type activity. Genetic variation in the hPreP gene PITRM1 might contribute to mitochondrial dysfunction in AD. Recent data suggest the possible contribution of heme deficiency to the progressive derangement of mitochondria in AD brain; shortage of heme, and particularly of heme-a, actually leads to loss of mitochondrial cytochrome c oxidase (COX), abnormal production of reactive oxygen species and altered amyloid precursor protein metabolism. Differences in the amount and/or functioning of COX assembly subunit 10 (COX10) and 15 (COX15), the key enzymes involved in heme-a biosynthesis, could be linked to variations of the individual risk to develop AD. Vitali et al. [89] analyzed mRNA expression in the hippocampus from AD patients and controls, as well as nucleotide variations in DNA sequences in AD. COX15 mRNA was significantly more abundant in the cerebral tissue of AD patients, and the IVS-178G \u003e A SNP in COX10 and the c + 1120C \u003e T SNP in COX15 were significantly less represented in AD, suggesting a possible protective role.\nJapanese AD patients are associated with the haplogroups G2a, B4c1, and N9b1. Takasaki [90] compared mitochondrial haplogroups of AD patients with those of other classes of Japanese (centenarians, Parkinson’s disease (PD), type 2 diabetes mellitus (T2D), and non-obese young males). The four classes of people were associated with the following haplogroups: Japanese centenarians with M7b2, D4b2a, and B5b; PD patients with M7b2, B4e, and B5b; T2D patients with B5b, M8a1, G, D4, and F1; and Japanese healthy non-obese young males with D4g and D4b1b. The haplogroups of the AD patients differed from those of the other four categories. \nSantoro et al. [91] applied for the first time a high resolution analysis to investigate the possible association between mtDNA-inherited sequence variation and AD in 936 AD patients and 776 cognitively assessed normal controls from central and northern Italy. Among over 40 mtDNA sub-haplogroups analyzed, they found that sub-haplogroup H5 is a risk factor for AD, particularly in females, independently of the APOE genotype. The H5a subgroup of molecules, harboring the 4336 transition in the tRNAGln gene was about threefold more represented in AD patients than in controls (2.0% vs. 0.8%), and it might account for the increased frequency of H5 in AD patients (4.2% vs. 2.3%). The complete re-sequencing of the 56 mtDNAs belonging to H5 revealed that AD patients showed a trend towards a higher number of sporadic mutations in tRNA and rRNA genes when compared with controls."}