Genomics of Alzheimer Disease

Abstract

IMPORTANCE

To provide a comprehensive review of knowledge of the genomics of Alzheimer disease (AD) and DNA amyloid β 42 (Aβ42) vaccination as a potential therapy.

OBSERVATIONS

Genotype-phenotype correlations of AD are presented to provide a comprehensive appreciation of the spectrum of disease causation. Alzheimer disease is caused in part by the overproduction and lack of clearance of Aβ protein. Oligomer Aβ, the most toxic species of Aβ, causes direct injury to neurons, accompanied by enhanced neuroinflammation, astrocytosis and gliosis, and eventually neuronal loss. The strongest genetic evidence supporting this hypothesis derives from mutations in the amyloid precursor protein (APP) gene. A detrimental APP mutation at the β-secretase cleavage site linked to early-onset AD found in a Swedish pedigree enhances Aβ production, in contrast to a beneficial mutation 2 residues away in APP that reduces Aβ production and protects against the onset of sporadic AD. A number of common variants associated with late-onset AD have been identified including apolipoprotein E, BIN1, ABC7, PICALM, MS4A4E/MS4A6A, CD2Ap, CD33, EPHA1, CLU, CR1, and SORL1. One or 2 copies of the apolipoprotein E ε4 allele are a major risk factor for late-onset AD. With DNA Aβ42 vaccination, a Th2-type noninflammatory immune response was achieved with a downregulation of Aβ42-specific effector (Thl, Th17, and Th2) cell responses at later immunization times. DNA Aβ42 vaccination upregulated T regulator cells (CD4+, CD25+, and FoxP3+) and its cytokine interleukin 10, resulting in downregulation of T effectors.

CONCLUSIONS AND RELEVANCE

Mutations in APP and PS-1 and PS-2 genes that are associated with early-onset, autosomal, dominantly inherited AD, in addition to the at-risk gene polymorphisms responsible for late-onset AD, all indicate a direct and early role of Aβ in the pathogenesis of AD. A translational result of genomic research has been Aβ-reducing therapies including DNA Aβ42 vaccination as a promising approach to delay or prevent this disease.

Alzheimer disease (AD) is characterized by 2 pathological hallmarks, amyloid β (Aβ) protein-containing neuritic plaques and hyperphosphorylated tau-containing paired helical filament in neurofibrillary tangles.¹ Amyloid β protein is generated by sequential cleavages of the amyloid precursor protein (APP) by β- and Y-secretases. First, APP is proteolytically processed by β-secretase and generates a 12-kDa C-terminal stub of the APP gene (C99); second, C99 is cleaved by γ-secretase to yield 2 major species of Aβ ending at residue 40 (Aβ40) or residue 42 (Aβ42).^2,3 Multiple mutations in the gene encoding APP cause early-onset familial AD, and most of them either lead to an increase in Aβ production or in the ratio of Aβ42 to Aβ40, thus enhancing the aggregation of Aβ peptides. Compared with shorter Aβ peptides, such as Aβ40 and Aβ38, many studies have documented that the 42-residue Aβ42 enhances aggregation propensity,⁴ leading to accelerated formation of small (low-n) Aβ oligomers.⁵ Mutations in presenilin genes have similar effect in increasing the ratio of Aβ42 to Aβ40. Cells bearing familial AD mutant genes (APP or PS1/2) produced higher levels of Aβ oligomers,⁶ which were observed in plasma and postmortem brains of patients with AD.⁷

Mutation in the tau gene causes frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17).⁸ In mice, Aβ accumulation can drive tau pathology in vivo.⁹ Transgenic mice expressing mutant tau show close association between tau mutation, neurofibrillary tangle formation, and neurodegeneration.^10,11 Tau protein has been used as a marker for axonal damage, and tau levels in cerebrospinal fluids reflect these changes in the central nervous system. Tau protein levels (total tau, phosphorylated tau, and the ratio) in cerebrospinal fluid have been explored as potential markers for AD.

Translational genomic research has developed potential DNAAβ42 therapeutics for AD. A noninflammatory Th2-mediated immune response with effective levels of anti-Aβ42 antibody has been developed in transgenic AD model mice with the DNA Aβ42 vaccine and is included as a direct extension of advances in AD genomics.

Amyloid Cascade Hypothesis

Mechanisms for AD pathogenesis have been extensively explored, and the major hypothesis supported by genetic and neuropathological evidences is the amyloid cascade hypothesis.¹² It suggests that AD is caused in part by the overproduction and lack of clearance of Aβ. The most toxic species of Aβ, such as oligomer Aβ, cause direct injury to neurons, accompanied by enhanced neuroinflammation, astrocytosis and gliosis, and eventually neuronal loss. The strongest genetic evidence supporting this hypothesis derives from mutations in the APP gene. A detrimental APP mutation at the β-secretase cleavage site (the APPKM670/671NL mutation), linked to early-onset AD found in a Swedish pedigree, enhances Aβ production,¹³ in contrast to a beneficial mutation 2 residues away (Icelandic mutation A673T) in APP that reduces Aβ production and protects against the onset of sporadicAD.¹⁴The Swedish mutant APP is a better substrate for recognition and cleavage by the β-secretase, while the Icelandic mutant APP is a much poorer substrate for the β-secretase,¹⁴ and the Icelandic mutation greatly attenuates APP-β-secretase interaction.¹⁵

The amyloid cascade hypothesis is also supported by additional genetic studies with the other 2 genes associated with early-onset familial AD, the presenilin 1 and 2 genes (PS1 and PS2). To our knowledge, only 3 genes have been identified to associate with familial AD, and all of them encode the key components of the Aβ synthesis pathway. The APP gene encodes the precursor of Aβ and is the substrate of the γ-secretase, and PS1 and PS2 genes encode the proteins that carry the active site of the γ-secretase.¹⁶ γ-Secretase is composed of PS1 (or PS2), presenilin enhancer-2, anterior pharynx defective-1, and nicastrin.^17–19 PS1 itself has proteolytic activity,^20,21 which is activated by presenilin enhancer-2.^20,22 Nicastrin is the substrate receptor for APP.²³ A number of mutations in APP¹³ or PS1/2^6,24,25 that link to familial AD affect the γ-secretase cleavage of APP and shift Aβ production from Aβ40 to the more toxic and aggregation-prone Aβ42. Mutations that provide more copies of APP genelike duplications²⁶ and Down syndrome²⁷ generate more Aβ in the brains of those patients. Almost all pathogenic mutations found in the APP gene lead to increased generation of Aβ or the Aβ42 to Aβ40 ratio because Aβ42 is more toxic than Aβ40. The Swedish mutation at the β-secretase cleavage site allows APP to be more accessible to the enzyme and generates more Ap.^13,28 The Arctic mutation of APP (APP E693G) increases the aggregation propensity of Aβ and fibril formation.²⁹ Pathogenic V717F, V717I, and V717L mutations all increase the Aβ42/Aβ40 ratio.^30–32

Major AD Risk Genes and Their Involvement in Aβ Metabolism

A number of common variants associated with late-onset AD have been identified, including apolipoprotein E (APOE), BIN1, ABCA7, PICALM, MS4A4E/MS4A6A, CD2AP, CD33, EPHA1, CLU, CR1, and SORL1.^33–36 One or 2 copies of the APOE ε4 allele is a major risk factor for late-onset AD (LOAD).^37,38 The APOE gene has 3 major isoforms, APOE ε2, ε3, and ε4. Brains of patients with sporadic AD carrying the APOE ε4 allele were found to have increased density of Aβ deposits, limited capability to clear Aβ, and enhanced neuroinflammation.³⁹ Binding of APOE loaded with Aβ to cell surface receptors, such as the low-density lipoprotein receptor-related protein-1 (LRP1), is one of the mechanisms for Aβ clearance.^40,41

Clusterin (encoded by CLU) directly interacts with soluble Aβ and forms a complex to cross the blood-brain barrier.⁴² This function is similar to APOE, which acts as a molecular chaperone for Aβ. Both clusterin and APOE directly influence Aβ during its aggregation and deposition. The presence of APOE/clusterin changes Aβ conformation and its toxicity.^43,44 Therefore, APOE and clusterin may regulate the conversion of soluble Aβ into insoluble forms such as oligomers, thus suppressing Aβ toxicity and deposition. Because APOE and clusterin are involved in a complex formation with Aβ to cross the blood-brain barrier, both proteins regulate Aβ clearance.⁴⁵ Alternative pathways for Aβ clearance are mediated by microglia. When extracellular Aβ aggregates, such as Aβ, are engulfed by microglia, inflammasomes (such as NOD-like receptor family pyrin domain-containing3 [NLRP3]) are triggered, which activate caspases and promote interleukin 1β release.^46,47 These aggregates are known to activate innate immune responses via complement pathways, including complement receptor 1 (CR1), which has been associated with LOAD.⁴⁸ Those Aβ isoforms that bind to scavenger receptors expressed on microglia, such as CD36⁴⁹ and Scaral,⁵⁰ enter microglia and activate inflammation. Systems analysis of hundreds of brains with AD reveals changes in networks related to immunologic molecules and microglial cells including microglial protein TYROBP, which binds the microglial receptor TREM2 (triggering receptors expressed on myeloid cells 2) and may regulate CD33 function.⁵¹ Genetic mutations found in TREM2 triple a person’s risk for AD^52,53 and increased expression of CD33, which functions to suppress AP uptake and clearance.^54,55

Another transporter protein associated with LOAD is ATP-binding cassette transporter (ABCA7), which belongs to the ATP-binding cassette transporter superfamily that transports many substrates across cell membranes. The ABCA7 gene is involved in the efflux of lipids from cells to lipoprotein particles. In an APP transgenic mouse model (J20) that is deficient in ABCA7, levels of APOE were not changed.⁵⁶ However, both soluble and insoluble Aβ levels and thioflavine-S-positive plaques were increased in the ABCA7--deficient mice.^56,57 In cultured cells, enhanced endocytosis of APP was observed in ABCA7 knockout cells, leading to increased Aβ production.⁵⁷

Phosphatidylinositol-binding clathrin assembly protein (PICALM) plays a critical role in clathrin-mediated endocytosis and protein/lipid internalization.³³ When full-length APP at the cell surface is internalized by clathrin-mediated endocytosis, β- and γ-secretase cleavages occur, and a significant amount of Aβ is generated.⁵⁸ When endocytosis is promoted by increased synaptic activity, more APP is retrieved from the cell surface to endosomes, resulting in an increase of Aβ generation and secretion.⁵⁹ Involvement of PICALM with clathrin-mediated endocytosis directly affects APP processing and Aβ synthesis.

Bridging integrator 1 (BIN1) is highly expressed in brain, and all BIN1 isoforms interact with clusterin and are involved in surface protein endocytosis. While it is possible that BIN1 influences APP endocytosis and Aβ production, its functional interaction with tau was demonstrated in a drosophila model where knockdown of the BIN1 ortholog Amph could suppress the rough eye phenotype caused by overexpression of human tau.⁶⁰

Genetic variants in the sortilin-related receptor SORL1 gene are associated with LOAD.⁶¹ Reduction of SORL1 expression was observed in vulnerable regions in brains with AD.^62,63 In cultured cells, SORL1 interacts with APP and both proteins colocalize in endosomal and Golgi compartments.^61,63 They also interact with vacuolar protein sorting-associated protein 35 (VPS35); VPS35 promotes cargo selection in the retromer through SORL1. When expression of SORL1 is increased, SORL1 regulates differential sorting of APP into the retromer recycling pathway, thus reducing Aβ production; when expression of SORL1 is reduced, APP trafficking is directed toward endosome-lysosome compartments that facilitate Aβ production.⁶¹ Deficient SORL1 expression in knockout mice resulted in increased levels of Aβ in animal brains.^62,63

The PCDH11Xgene is a cell surface receptor molecule belonging to the protocadherin gene, which is a subfamily of the cadherin superfamily. Like other cadherins, it mediates cell-cell adhesion and is cleaved by γ-secretase.⁶⁴ Cadherins, such as E- and N-cadherins, form the complex with PS1/γ-secretase⁶⁵ and regulate cell-cell interaction after the cleavage by γ-secretase, this process is inhibited by familial AD mutations in PS1.⁶⁶ Therefore, PCDH11X is believed to play a role in cell signaling that is critical in the development of the central nervous system.⁶⁷ Genetic variation in PCDH11X is associated with LOAD.⁶⁸

The MS4A4E/MS4A6A genes belong to the MS4A gene cluster on chromosome 11. The proteins encoded by these similar genes have a common transmembrane domain and likely are cell surface proteins. Their involvement in Aβ production is not known. The EPHA1 gene is a member of the ephrin receptor family. Both ephrins and Eph receptors play important roles in cell and axon guidance, and another member of this family, EphA4, is cleaved by Y-secretase induced by synaptic activity.⁶⁹ The CD2-associated protein (CD2AP) is a scaffold/adaptor protein and mediates receptor-regulated endocytosis.⁷⁰ In cultured cells, reducing CD2AP expression results in decreased levels of Aβ and a lower Aβ42/Aβ40 ratio. Knockout of CD2AP in transgenic mice overexpressing PS1 and APP (PS1APP mice) decreased the Aβ42/Aβ40 ratio in the brain, expressing 1 copy of CD2APP in PS1APP mice does not affect Aβ deposition.⁷¹

Imbalanced Aβ homeostasis, ie, increased Aβ production and/or decreased Aβ clearance, is an upstream event of neurodegeneration that is directly affected by AD risk gene products (Figure 1). The SORL1, PICALM, and CD2AP genes are involved in endocytic internalization of cell surface APP for β-and Y-secretase cleavages to generate Aβ, while APOE, CLU, TREM2, ABCA7, PICALM, CD33, CD2AP, and CR1 are all involved in Aβ clearance through multiple mechanisms. These risk genes, in addition to familial AD-linked mutant genes APP, PS1, and PS2, all point to the direct and early role of Aβ in the pathogenesis of AD. Amyloid-β-reducing therapies, including DNA Aβ42 vaccination, have a therapeutic potential to delay or prevent the disease (Table).

Figure 1. Proteolytic Processing of Amyloid Precursor Protein (APP) by β- and γ-Secretases to Generate Amyloid β (Aβ) Protein.

When APP undergoes nonamyloidogenic proteolytic cleavage by α- and γ-secretases, p3 instead of Aβ is generated. A small number of APP molecules is proteolytically processed by β-secretase and generates an N-terminal soluble APP and a 12-kDa C-terminal stub of APP, which is cleaved by γ-secretase to yield Aβ and amyloid intracellular domain. The PS1 and PS2 genes carry the active site of γ-secretase complex. Proteins encoded by multiple risk genes associated with late-onset Alzheimer disease are involved in Aβ clearance. The SORL1, PICALM, and CD2AP genes regulate APP endocytosis (vs retromer-mediated APP recycling) and Aβ generation in endosome-lysosomes.

Table.

Genotype to Phenotype Relationship Between Mutant Amyloid Precursor Protein (APP) and Amyloid β (Aβ) Generation

Mutation	Aβ Generation	Reference
Swedish pathogenic KM1670/671NL	Better substrate for β-secretase and increase Aβ generation	72,73
Icelandic Protective A673T	Attenuate APP-β-secretase interaction and reduce Aβ production	14,15
Pathogenic D678H and Tottori D678N	Increase Aβ production and Aβ42/Aβ40 ratio; increase oligomerization	74,75
Pathogenic E682K	Increase in total Aβ and in Aβ42/Aβ40 ratio	76
Pathogenic K687N	Increase Aβ40 and Aβ42 and toxic heteromeric Aβ oligomer	77
Flemish pathogenic A692G	Increase Aβ40 and Aβ42	78
Arctic, Dutch, and Italian pathogenic E693G, E693Q, and E693K	Increase the aggregation propensity of Aβ	79,80
Pathogenic D694N	Increase the aggregation propensity of Aβ	81
Pathogenic T714I	Increase Aβ42/Aβ40 ratio	82
Pathogenic V715A and V715M	Increase Aβ42/Aβ40 ratio	83,84
Florida Pathogenic I716F and I716V	Increase Aβ42/Aβ40 ratio	85,86
Pathogenic V717F and London V717I and V717L	Increase Aβ42/Aβ40 ratio and increase Aβ42, decrease Aβ40	30–32
Pathogenic L723P	Increase Aβ42	87
Pathogenic K724N	Increase Aβ42, decrease Aβ40, and increase Aβ42/Aβ40	88

DNA and Peptide Aβ42 Vaccination: Translational Therapy From Genomics

The amyloid cascade hypothesis postulates that Aβ deposition in the brain is a primary event necessary in the multifactoral pathogenesis of AD.^12,89,90 It has been demonstrated that Aβ deposition precedes AD symptoms by at least 20 years.⁹¹ Therapeutic approaches using active and passive immunizations against Aβ have a high possibility to be effective in removing amyloid from the brain and thereby delaying or preventing downstream pathologies. Since 2000, a number of clinical trials for AD immunotherapy have started, have failed, and are continuing.^92–99 Amyloid β protein at resiude 42 peptide vaccination with adjuvant in the clinical trial AN1792 ^92,93,99 resulted in an autoimmune meningoencephalitis with T cells infiltrating the brain of affected vaccinated patients, and the study was stopped. A clinical trial^94,100 with the monoclonal antiamyloid antibody bapineuzumab reduced the level of amyloid accumulation as seen by amyloid imaging but had no clinical benefit in patients expressing clinical signs of AD.

New studies started between 2013 and 2015 focus on therapy in patient cohorts before the onset of clinical symptoms of AD.¹⁰¹ These include the Dominantly Inherited Alzheimer Network study,¹⁰² the Alzheimer Prevention Initiative, and the Treatment of Asymptomatic Alzheimer.¹⁰³ A major achievement will occur if passive Aβ immunotherapy for AD can be shown to have clinical benefit. If and when these new prevention studies using passive immunizations with anti-Aβ antibodies provide clinical benefit by delaying or preventing AD, active vaccination, potentially with a DNA Aβ42 vaccine, will increase in interest because it induces an effective and noninflammatory immune response and is applied more efficiently and economically to large populations.

A translational result of genomic research has been the development of immunization, with a full-length DNA Aβ42 plasmid in mice generating a polyclonal multivalent vaccine.¹⁰⁴ Studies in out-breed animals, such as rabbits and dogs, have shown that the im-mune response to fibrillar Aβ is diverse and reflects the polymorphic structure of the antigen itself. These studies also lead to the conclusion that single therapeutic monoclonal antibodies with 1 specific epitope may not be able to target all the different aggregates to have an effect on diminishing disease progression.^105,106

We have developed an Aβ42 plasmid encoding 3 copies of the full-length Aβ42 sequence. Transcription of Aβ42 is initiated by the transcription factor Gal4, which is encoded by a second plasmid that is delivered simultaneously by cotransfection (Figure 2). This approach had been shown to increase the expression of the Aβ42 sequence without causing Aβ42 cytotoxicity in the transfected cells.¹⁰⁷

Figure 2. Double DNA Plasmid System Incorporating GAL4/Upstream Activating Sequences to Increase Amyloid β 42(Aβ42) Expression.

It consists of 2 plasmids, an activator plasmid encoding the yeast GAL4 transcription factor and a responder plasmid encoding Aβ1–42 for which its expression is driven by binding of GAL4to upstream activating sequences (UAS sites) in front of a minimal promoter. The open reading frame for Aβ42 was synthesized 3 times in a row, encoding DNA Aβ42 trimer. Aβ42-trimer/UAS responder plasmid and GAL4 activator plasmid are mixed in a ratio of 1 to 0.75 for preparation of the DNA-coated gold particles. The GAL4 protein binds as a homodimer to UAS sites present on the responder plasmid. GAL4 binding enhances transcription of the Aβ42 trimer sequence, which is cloned into a DNA fragment containing an adenovirus E3 leader sequence and an endosomal targeting sequence derived from the mouse MHC class II gene, H2-DM. The final protein product has a size of about 21 kD.²⁰

Immunization with Aβ1–42 is strongly influenced by the fact that this is a self-antigen, and tolerance against self-antigens has to be broken. In wild-type mice, human Aβ42 is a foreign antigen owing to 3 amino acid alterations in the N-terminal segment of the peptide, and wild-type mice produce high levels of anti-Aβ antibodies following immunization. Higher levels of antibody produced in the wild-type mouse are owing to the fact that the DNA in the plasmid coding for Aβ42 peptide is of human type. This explains the differences in the comparison of the antibody responses in wild-type mice and human APPtransgenic mice. As in the APP transgenic mouse receiving the DNA Aβ42 plasmid, the expressed Aβ42 peptide in the brain and in the vaccinated skin cells is both of human type. The eFigure in the Supplement shows the analysis of double transgenic and wild-type mice that have been immunized 9 times with the DNA Aβ42 vaccine via gene gun administration. The wild-type mice in this group reached antibody levels with a mean (SD) of 63 (18.16) μg/mL of plasma and the transgenic mice had antibody levels with a mean (SD) of 13.51 (9.18) μg/mL of plasma (P < .001).

In AD mouse models, we have demonstrated up to a 50% reduction in brain amyloid following full-length DNA Aβ42 vaccination.^108–110 In Figure 3, the results shown were from 2 double transgenic mouse cohorts, from which amyloid levels in the brain had been analyzed 2 weeks following the last immunization (Figure 3A) or 4 months after the last immunization (Figure 3B). Group A showed an amyloid reduction of 65% and group B showed a reduction of Aβ1–42 brain levels of 25%. In both groups, the amyloid reduction was substantial in comparison with the control DNA (Luc)-immunized mice (Mann-Whitney test: P = .006 and P = .007, respectively). The marked difference between these 2 groups is explained by the time differences between final immunizations and brain level analyses (14 days and 4 months following the last immunization; 12 and 16 months of age) and the marked differences in total Aβ42 levels in the brain owing to the 4-month age difference between groups A and B. Concentration of Aβ42 in the brain increased from 10 μg/g wet tissue to 50 μg/g in the Luc control mice owing to increased AD pathology with the age progression in these mice.

Figure 3. Reductions of Amyloid β 42 (Aβ42) in DNA Aβ42 Trimer Immunized Amyloid Precursor Protein/Presenilin 1 (APP/PS1) Double Transgenic Mice and the Respective Control DNA Immunized Mice.

Shown is the amount of Aβ42 peptide per gram of wet brain tissue (μg/g). Immunization was started in both groups in 3-month-old mice and was continued for 11 immunizations until the mice were 12 months old. Group A was killed for final analyses (plasma antibody levels, brain Aβ histology and biochemistry) 14 days following the last immunization, while mice in group B were killed 4 months following the 11th immunization. In both groups, a significant reduction of Aβ1–42 levels in the brain was found in comparison with the respective control groups (DNA Luc control DNA immunized mice). Group A showed an amyloid reduction of 65% to 53% while group B showed a reduction of Aβ1–42 brain levels of 25%. Reproduced with permission from ImmunoTargets and Therapy.¹¹⁰

With DNA Aβ42 vaccination, a Th2-type noninflammatory immune response was achieved, with a downregulation of Aβ42-specific T effector (Th1, Th17, and Th2) cell responses at later immunization times.^111–116 On the other hand, DNA Aβ42 vaccination upregulated T regulator cells (CD4+, CD25+, and FoxP3+) and the cytokine interleukin 10, resulting in downregulation of T effectors. In distinction, Aβ42 peptide vaccination induced the opposite effect, with upregulation of T effectors (CD4+, CD25+, and FoxP3-) and no effect on T regulator cells. Thus, the immune response following DNA immunization differs quantitatively and qualitatively from the immune response elicited by Aβ42 peptide immunization. DNA Aβ42 immunization with downregulation of T effectors (Th1, Th17, and Th2 cells) would significantly reduce the opportunity for cytotoxic T cells from migrating and transiting through brain, which was evident in the Aβ42 peptide vaccine clinical trial AN1792, resulting in meningoencephalitis.^92,115

Immunizations of 16 New Zealand white rabbits produced after 5 vaccinations anti-Aβ42 antibodies at mean levels of250 μg/mL of serum. The isotyping of the serum antibody showed IgG, IgM, and IgA anti-Aβ42 antibodies. In autopsies of 9 rabbits, there was no evidence of meningoencephalitis. Immunizations of 6 rhesus monkeys produced after 4 vaccinations of anti-Aβ42 antibodies at mean levels of 112.6 μg/mL of serum and they have remained healthy with no adverse effects (D.L.-W. and R.N.R., preliminary unpublished observations).

Conclusions

Research into the genetics and genomics of AD has made major strides in the past decade. The PS1, PS2, and APP gene mutations have been documented to result in aggressive, early-onset autosomal dominant disease. Polymorphisms in multiple genes have been shown to increase the risk for the disease. A polymorphism in the APP gene, preventing binding of β-secretase to APP in APOE4 persons and impairing production of Aβ42 peptide being processed from the parent APP molecule, prevents the clinical expression of AD and is in strong support of the amyloid cascade hypothesis. Amyloid imaging has provided the accurate means to identify asymptomatic at-risk persons accumulating amyloid to test antiamyloid therapies.¹¹⁷ Active vaccination with a DNA Aβ42 vaccine offers a potential effective and noninflammatory approach and is one of several active vaccination approaches after demonstration of clinical benefit from passive antiamyloid antibody therapy.¹¹⁸ The magnitude of defining the genomic and epigenomic factors involved in the pathogenesis of AD and new therapeutic strategies that will occur as a result are large in number and complexity. The Human Alzheimer Disease Project, an undertaking at the level of commitment and funding equivalent to the Human Genome Project, is necessary and required to stem the crescendo of anticipated increases in the prevalence of this disease in the foreseeable future.¹¹⁹

Key Points.

Question

What is the current genomic understanding of amyloid β protein-directed therapies for Alzheimer disease?

Findings

In this review, mutations associated with Alzheimer disease, polymorphisms increasing risk, and amyloid β protein-reducing therapies are defined. The magnitude of defining the genomic and epigenomic factors involved in the pathogenesis of Alzheimer disease and new therapeutic strategies as a result are large in number and complexity.

Meaning

Effective therapy to delay or prevent Alzheimer disease may be based on a defined genomic understanding.