Review ArticleContinuum 2013;19(2):358–371

New Genes and New Insights from Old Genes: Update on Alzheimer Disease

John M. Ringman, MD, MS; Giovanni Coppola, MD

Dr Suredra Khosya D.M. Student IHBAS

INTRODUCTION

Alzheimer disease (AD) is most common cause of dementia

This review

Understanding of the genetic underpinnings of AD

Clinical relevance where applicable

How guiding future research into treatments and prevention of AD

Alzheimer's disease first described by Alois Alzheimer in 1907

AD divided into 2 subtypes : early-onset AD (EOAD) and late-onset AD (LOAD).

EOAD accounts 1% to 6% of all cases ranges from 30 to 60 or 65yr

LOAD most common form of AD, an age onset later than 60 or 65yr

Both EOAD and LOAD may occur in people with a positive family history of AD.

60% of EOAD have multiple cases of AD within family,13% inherited in an autosomal dominant manner with at least 3 generations affected

AD is a complex disorder that is likely to involve multiple susceptibility genes and environmental factors

Amyloid Precursor ProteinMutations in the APP gene first mutations in familial AD

N-terminal (the ᵦ-secretase cleavage site) and C-terminal (the γ-secretase cleavage site) ends of the Aᵦ portion of APP, and

affect theamount of Aᵦ produced by cells The V717I substitution in APP, occurring near the γ-secretase

site, wasthe first described familial AD MutationDuplications of the APP in familial AD associated with cerebralAmyloid angiopathy (CAA)Variant near the ᵦ-secretase cleavage site (A673T) in APP

associatedwith decreased production of Aᵦ and decreased risk for late-

onsetAD

Aβ42 peptides form soluble oligomers of ~4 to 40 peptides.

These oligomers interact with other proteins and precipitate to form

amyloid plaques.

Soluble oligomers of Aβ42 (containing ~12 to 40 peptides) are toxic to

neurons.

Because of its higher rate of fibrillization and insolubility, Aβ42 is

more abundant than Aβ40 within the plaques.

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Soluble Oligomers of Aβ42

Normal function of presenilin’s g-secretase activity:

Notch signaling?

APP cleavage would be a “side effect”

Components of the core γ-secretase proteolytic complex:

Presinilin (either PS1 or PS2),

anterior pharynx-defective 1 (APH-1),

nicastrin (NCT), and

presenilin enhancer 2 (PEN-2)..Barthet et al, Progress in Neurobiology 2012

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Red circles: presenilin 1 and APP mutations associated with familial AD

Hardy and Selkoe, 2002, Science

presenilin 1 is part of -secretase, a membrane-associated protease

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Presenilin 1

PSEN1 mutations are the most common cause of familial AD

The Presenilin 1 protein (PS1) catalytic site of the γ-secretase

complex in APP protein to produce Aᵦ fragments

PSEN1 mutations lead increased absolute or relative production of Aᵦ42

PSEN1 mutations cause the youngest age of symptom onset (44-46yrs)

PSEN1 have atypical features including spastic paraparesis, earlymyoclonus, and seizures.

PSEN1 tended to be younger (42 versus 56 years of age at onset)

More likely memory complaints as the presenting feature (84% versus 58% ,nonfamilial frequently presenting with visuospatial and language deficits)

More likely have significant headaches, myoclonus, gait abnormalities, and pseudobulbar affect

The presence of such features in a young-onset case of AD when the family history is unavailable clinician to consider genetic testing

Presenilin 2

PSEN2 gene are rarest and have the oldest and most variable age of onset PSEN2 have mean age of onset of 54 years range from 39 to 75yr

People with the N141I mutation, seizures were present in 31%

Because the pathogenicity of variants in PSEN2 is not always clear

Caution needs to be interpreting results of such testing with patients and their families

APOLIPOPROTEIN-E ApoE involved in lipid transport that acts as a scaffold in HDL

Highly expressed in the liver and in the CNS

Addition to transporting lipids, it also has a role in the transportation

Of forms of Aᵦ including A ᵦ42

ApoE (APOE) is highly polymorphic; the APOE*E3 allele is the

most common, followed by the *E4 allele, which is in turn more

common than the *E2 allele.

*E4 conferring a greater risk than *E3, which in turn confers a

Higher risk than the *E2 allele

Multiple ways of influencing the Aᵦ clearance through the ApoE pathway have been suggested like ApoE mimetic

↑ Production with peroxisome proliferator-activated receptorgamma (PPARγ) agonists and the liver X receptor (LXR) agonist bexarotene

Prevalence of the *E4 allele in the population typically in the range of 15% to 20%, Among people with AD, the prevalence is around 50%

Having two copies of APOE*E4 increases the risk of a younger age of AD onset and makes the development of AD by age 80 highly probable

Polymorphism within the neighboring TOMM40 gene explains part of the risk traditionally attributed to the APOE locus

OTHER RISK FACTORS FOR ALZHEIMER DISEASE Common Variants

Clusterin (CLU), phosphatidylinositol binding clathrin assembly protein (PICALM), and complement receptor type 1 (CR1)

Bridging integrator protein-1 (BIN1)

ABC transporter member 7 (ABCA7) membrane-spanning 4-domains, subfamily A, member 4(MS4A4A)/ membrane-spanning 4-domains, subfamily A, member 4E (MS4A4E)/membrane-spanning 4-domains, subfamily A, member 6A (MS4A6A)

Ephrin receptor ephA1 (EPHA1), CD33 antigen (CD33), and CD2-associated protein (CD2AP)

Like ApoE, Clu involved in lipid transport in both the periphery and the brain

Clu also is hypothesized to act as an extracellular chaperone that influences Aβ-aggregation and receptor-mediated Aβ clearance by endocytosis

Unlike APOE, there are no known coding variants that account for the observed genetic association, suggesting that genetic variation in expression levels may be responsible for altered risk for AD

Clusterin (CLU)

phosphatidylinositol binding clathrin assembly protein (PICALM),complement receptor type 1 (CR1)

PICAM encodes a clathrin assembly protein

The protein is involved in AP2-dependent clathrin-mediated endocytosis at the neuromuscular junction

The polymorphisms of this gene are associated with the risk of Alzheimer disease.

Complement component (3b/4b) receptor 1 (CR1), the main receptor of complement C3b protein, binds Aβ and thus may promote clearance 

SORL1 encodes a protein SorLA

Important in intracellular APP trafficking When cell-surface APP is re-cycled via the endocytic pathway

SorLA directs APP to processing by presenilins to produce Aβ

Another function of SorLA related to AD is as a lipoprotein receptor that can bind Apo E Clu, also known as apolipoprotein J (ApoJ)

SORL1 

ABCA7 encodes protein belonging to ABC superfamily of transporters.

Function in the efflux of phospholipids and possibly cholesterol

ABCA7 levels are regulated by sterol-responsive/regulatory element binding protein in response to cholesterol levels

While ABCA7 is clearly involved in lipid metabolism, how this protein is connected to AD will require additional work

ABCA7

Guidelines for Genetic Testing in Alzheimer Disease

1. A comprehensive family history should be obtained to reveal the likelihood, considering causes of death, of a family history of AD or other causes of dementia

2. Patients should be fully informed regarding the limits of the understanding of the genetics of AD and of the ability to treat or prevent it

3. Testing for AD in the pediatric population is not recommended

4. Testing for risk-susceptibility genes such as APOE is not widely recommended except in the context of fully informed patients and families, as in research studies.

Regard testing for APP, PSEN1, or PSEN2 in symptomatic patients Testing should be offered in the context of a family history of autosomal dominant inheritance in which one or more cases are of early onset, or in young-onset cases with unknown family history

Regarding the implications for asymptomatic people1.Asymptomatic first-degree relatives have 50% likelihood of inheriting the mutation and disease in the case of a pathogenic mutation being identified in an affected patient2.Testing for asymptomatic at-risk subjects should be performed in accordance with the International Huntington Association and World Federation of Neurology Research Group on Huntington’s Chorea Guidelines3. People thought to be asymptomatic should undergo cognitive and psychological evaluations to better define their status and ability to comprehend and cope with results.

SUMMARY

In the last 30 years there have been substantial advances in understanding of the genetic basis of AD, although genetic assessment is currently of limited utility in clinical practice because of the low frequency (Mendelian mutations) or small effect size (common risk factors) of the currently known susceptibility genes.

However, genetic studies are identifying with confidence a number of novel risk genes that will improve understanding of disease biology and possibly the identification of therapeutic targets.

APRAHAMIAN et al: NEW TREATMENTS FOR AD 451 Natural history of AD with treatment possibilities.

APRAHAMIAN et al: NEW TREATMENTS FOR AD 453

Compound Target/treatment Current phase

ANI 1792 21-23

CAD10624 bapineuzumab

Solanezumab23

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Vaccine - active immunization

Vaccine - active immunization beta-amyloid monoclonal antibody

beta-amyloid monoclonal antibody

Interrupted at phase I (severe side effects as meningoencephalitis) Phase I (ongoing)

Phase III (ongoing)

Phase III (ongoing)

Ponezumab 26

Gantenerzumab

Crenezumab27

Semagacestat26

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beta-amyloid monoclonal antibody

beta-amyloid monoclonal antibody

beta-amyloid monoclonal antibody

Gamma-secretase inhibitor

Interrupted at phase II (no efficacy)

Phase I (ongoing)

Phase I (ongoing)

Interrupted at phase III (no efficacy and risk for skin cancer)

Avagacestat 28

GRL-83429

TAK-07030

Gamma-secretase inhibitor

beta-secretase inhibitor

beta-secretase inhibitor

Phase II (ongoing)

Ongoing

Ongoing

CHF5074 31

DAPT 31

Curcumin22

Nonsteroid antinflammatory agent

Prototypal gamma-secretase inhibitor

Anti-amyloid aggregator

Ongoing

Ongoing

Ongoing

DAPT, [N-(3, 5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester

Compounds targeted to anti-beta-amyloid treatment

Neurotransmitter-based Acetylcholine Serotonin Norepinephrine/Dopamine GAbA Glutamate Glycine Glial modulating drugs Direct glial target

RAGE receptor antagonists TNF alpha antagonists Neuroprotection Antioxidants Miscellaneous Anti-tau or tau modulators Microtubule stabilizers

Kinase inhibitors (GSK-3, GSK-3, CDK 5)

Miscellaneous

Agents under research ST 101, AF 267b, AbT 089, AZD 3480, MEM 3454, EVP-6124, Posiphen, Huperzine 5-HT4 partial agonists, 5-HT1A agonists/antagonists, 5-HT6 antagonists

MAO A and MAO b inhibitors GAbAb antagonists AMPA potentiators Partial agonists

G and GM CSF, Nitroflurbiprofen, ONO-2506, Tacrolimus TTP 488 Enbrel

Vitamin C and E, alpha lipoic acid, CoQ10 Phosphodiesterase inhibitors, PPAR agonists and insulin, SIRT1 activators, Growth factors (bDNF and NGF), Dimebon

NAP (AL-108) and Methylene blue (Rember) Lithium, AZD-1080, minocycline

Phosphodiesterase-4 inhibitors, immunotherapies

GAbA, gamma-aminobutyric acid; RAGE, receptor for advanced glycation endproducts; TNF, tumor necrosis factor; GSK, glycogen synthase kinase; CDK, cyclin-dependent kinase; 5-HT (4, 1A and 6), 5-hydroxytryptamine (receptor subtypes); MAO (A and B), monoamine oxidase (A and B subtypes); AMPA, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; PPAR, peroxisome proliferator-activated receptors; SIRT1, sirtuin (silent mating type information regulation 2 homolog)-1; bDNF, brain- derived neurotrophic fator; NGF, nerve growth factor; NAP, neuronal microtubule-interacting agent (a peptide of eight amino acids, NAPVSIPQ)

treatments other than anti-amyloid therapy under research for Alzheimer's disease1

Gene name

Gene symbol

Inheritance

Location Onset range

Amyloid precursor protein

APP autosomal dominant

21q21.3 38–69

Presenilin 1

PSEN1 autosomal dominant

14q24.2 25–65

Presenilin 2

PSEN2 autosomal dominant, reduced penetrance

lq42.13 41–88

Autosomal Dominant AD genes

Gene Chr.: Mb Top SNPs P, ORs (C.I.)APOE 19:45.4 rs4420638a,b;

rs7412 & rs429358c;rs2075650bb,d

1.1 × 10−266, 3.84(3.56–4.14)a

1.04 × 10−295, 2.53 (2.41–2.66)d

CLU 8:27.5 rsl532278a;rs11136000d

8.3 × 10−8, 0.89 (0.85–0.93)a

1.62 × 10−16, 0.85 (0.82–0.88)d

CR1 1:207.8 rs6701713a

rs6656401e

4.6 × 10−10, 1.16(1.11–1.22)a

3.5 × 10−9, 1.21(1.14–1.29)PICALM 11:85.8 rs561655a

rs3851179d

7.0 × l0−11, 0.87 (0.84–0.91)3

3.16 × 10−12, 0.87 (0.84–0.91)d

BIN1 2:127.9 rs7561528a

rs744373d

4.2 × 10−14, 1.17 (1.13–1.22)3

3.16 × 10−12, 0.87 (0.84–0.91)d

CD33 19:51.7 rs3865444a 1.6 × 10−9,0.91 (0.88–0.93)a,f,g

ABCA7 19:1.1 rs3752246a

rs3764650e

5.8 × 10−7, 1.15 (1.09–1.21)3

5.0 × 10−21, 1.23(1.17–1.28)f,g

EPHA1 7:143.1 Rs11767557a 6.0 × 10−10, 0.90 (0.86–0.93)a,f,g

CD2AP 6:47.5 rs9349407a 8.6 × 10−9, 1.11 (1.07–1.15)a,f,g

MS4A4A/MS4A6A/MS4A4E

11:60.0 rs4938933a

rs610932e

rs670139e

8.2 × 10−12, 0.89 (0.87–0.92)3

1.2 × 10−16, 0.91 (0.88–0.93)f,g

1.1 × 10−10, 1.08 (1.06–1.11)f,g

SORL1 11:121.3 rs668387h

rs3781835a

0.001, 1.08 (1.03–1.13)h

2.9 × 10−4, 0.72 (0.60–0.86)a

AD susceptibility genes

First, APP, PSEN1, and PSEN2 genes as autosomal dominant causes of AD with early-onset AD

 Second the late-onset AD risk loci are replicable across independent data sets using cohorts ascertained by a variety of approaches and cases diagnosed in numerous research centers.

Third APOE is by far the largest effect loci for late-onset AD. A better estimate of effect size comes from studies where the SNPs responsible for the ε2/ε3/ε4 alleles are directly genotyped and different genotypes considered separately

 Fourth small effect risk loci will be identified for late-onset AD, This will require larger sample sizes. To achieve this, an international effort called the International Genomics Alzheimer’s Project (IGAP) is underway with participation of the ADGC, CHARGE, GERAD, and EADI consortia

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Pathogenic hypotheses for mostly synaptic toxicity in Alzheimer’s disease

Loss of synapses correlates better than plaques or tangles with cognitive deficits

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