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Disorders with Complex Genetics Alzheimer’s Disease

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Disorders with Complex Genetics

Alzheimer’s Disease

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Signs & Symptoms:

• Memory loss for recent events• Progresses into dementia almost total memory loss• Inability to converse, loss of language ability• Affective/personality disturbance (fatuous, hostile)• Death from opportunistic infections, etc.

Confirmation of Diagnosis:

• Neuronal (amyloid, amyloid, A amyloid) plaques• Neurofibrillary tangles• Brain Atrophy

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Neuronal Plaques in Alzheimer’s Disease


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Neurofibrillary Tangles in Alzheimer’s Disease


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Plaques and neurofibrillary tangles

From Department of Pathology, Virginia Commonwealth University

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Brain Atrophy in AD

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(1) FAD v SAD: Familial AD versus Sporadic AD

• No complete consensus• Usually FAD = at least 1 first degree relative affected• Sometimes 2 second degree relatives

(2) Early v Late Onset:

• Early onset = usually before 65• Early onset correlated with FAD• LOAD = late onset AD

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(1) Down’s Syndrome

• Have AD brain pathology in later life• Usually, do NOT have AD symptoms

(2) Pedigrees with dominant-like transmission:

• Studied these first• Concentrated on chromosome 21

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Alzheimer’s Disease, Type 1:

•Several mutations in APP gene on chromosome 21

•Most common = Val717Iso

•Produce abnormal beta amyloid fragment

•15%-20% of early onset, familial AD

•Autosomal dominant

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Alzheimer’s Disease, Type 3:

•Mutations (> 130) in the presenilin1 gene on chromosome 14

•Most mutations lead to amino acid substitution

•Overproduction of the beta amyloid fragment

•30% - 70% of early onset, familial AD

•Autosomal dominant

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Alzheimer’s Disease, Type 4:

• Mutations in the presenilin2 gene on chromosome 1

• 2 alleles: Asn141Iso and Met239Val • Overproduction of the beta amyloid fragment

• < 5% of early onset, familial AD (only a fewfamilies world wide)

• Autosomal dominant

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Alzheimer’s Disease, Type 2:

• Epsilon 4 (4, AKA E4) allele of the Apolipoprotein E (ApoE) gene on chromosome 19 confers risk

• Epsilon 2 (2, AKA E2) allele of the Apolipoprotein E geneon chromosome 19 confers protection

• Mechanism unclear; ApoE is a very low density lipoprotein that transports cholesterol

• Most cases are late onset, familial

• Susceptibility Locus

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Prevalence of APOE genotypes in Alzheimer’s disease (AD) and controls.

Genotype: Controls AD

E2/E2 1.3% 0%

E2/E3 12.5% 3.4%

E2/E4 4.9% 4.3%

E3/E3 59.9% 38.2%

E3/E4 20.7% 41.2%

E4/E4 0.7% 12.9%

Jarvik G, Larson EB, Goddard K, Schellenberg GD, Wijsman EM (1996) Influence of apolipoprotein E genotype on the transmission of Alzheimer disease in a community-based sample. Am J Hum Genet 58:191-200

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Two Major Hypotheses for AD: amyloid protein (BAP) v. tau

1. BAPtists: The accumulation of a fragment of the amyloid precursor protein or APP (the amyloid beta 42 residue fragment orAb-42) leads to the formation of plaques that someone kill neurons.

2. TAUists: Abnormal phosphorylation of tau proteins makes them “sticky,” leading to the break up of microtubules. The resultingloss of axonal transport causes cell death.

(Recently a presenilin hypothesis has been proposed by Shen& Kelleher (2007), PNAS, 104:403-408.)

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Amyloid Hypothesis(it’s the plaques, dummy)

1. The amyloid precursor protein (APP) is broken down by a series of secretases (see next two slides).

2. During this process, a nonsoluble fragment of the APP protein (called A-42) accumulates and is deposited outside the cell.

3. The nonsoluble or “sticky” nature of A-42 helps other protein fragments(including apoE) to gather into plaques.

4. Somehow the plaques (or possible the migration of A-42 outside thecell) cause neuronal death.

5. PSEN1 & PSEN2 genes subunits of secretase.

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Amyloid precursor protein (APP) is membrane protein that sits in the membrane and extends outward. It is though tobe important for neuronal growth, survival, and repair.


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Enzymes cut the APP into fragments, the most important of which for AD is called -amyloid (beta-amyloid) orA.


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Beta-amyloid is “sticky” so the fragments cling together along with other material outside of the cell, forming theplaques seen in the AD brain.


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APP Protein:

(1)-secretase cuts APP protein, giving:

(2)-secretase cuts this residue, giving:


A40 Fragment


A42 FragmentUnsoluble,

aggregates intoplaques

-secretase Pathway:(not drawn to scale)

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Tau Hypothesis(it’s the tangles, dummy)

1. Ordinarily, the (tau) protein is a microtubule-associated protein thatacts as a three-dimensional “railroad tie” for the microtubule. The microtubule is responsible for axonal transport.

2. Accumulation of phosphate on the tau proteins cause “paired helicalfilaments” or PHFs (like two ropes twisted around each other) that accumulate and lead to the neurofibrillary tangles (NFT). PHFs are themain component in NFTs.

3. Impaired axonal transport is the probable cause of cell death.

4. Focus on MAPT gene (microtubule-associated protein tau)

5. Not in favor anymore.

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Current theory: Multifactorial, involvingseveral pathways.

• Protein accumulation: placques & tangles

• Inflammation: Unregulated activation of glia

• Lipid distribution: Lipid membrane site of APP cleavage.

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From Sleegers et al. (2010) Trends in Genetics, 26, 84-94, p. 87

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Alzheimers Disease's%20Disease%20Pathway

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Current gene candidates for AD:

• Changes too rapidly to keep track of.

• Go to for latest list

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Microtubules are like railroad tracks that transport nutrition and other molecules. Tau-proteins act as “ties” that stabilize the structure of the microtubules. In AD, tau proteins become tangled, unstabilizing the structure of the microtubule. Loss of axonal transport results in cell death.

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AD: The Great Unknown

What is causing the majority of AD cases?

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Cases with no known etiology:(theoretical extremes)



CDCVCommon disease/common variant

Disease (Genetic)Heterogeneity

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• Many rare alleles with high penetrance (“Mendelian”forms of the disorder).

• Almost no person will get two or more of these ADalleles.

• Non familial cases due to phenocopies.

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Multifactorial Threshold Model

• Many common alleles with “low” penetrance.

• Most people will have several risk alleles.

• Risk alleles are additive (multiplicative).

• Many additive environmental factors.

• Genes and environment liability.

• Once liability reaches a certain value (i.e., thethreshold) a disease process begins.

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-3 -2 -1 0 1 2 3





Unaffected Affected

HGSS: Carey: Figure 6.1

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Presenilin 1

Presenelin 2


Major Locus 2



Theoretical major causes of AD:

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Mice gratia

Human APPgene

Human ApoEgene

Human Presenilingene

Animal Models

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Figure 1. Development of the Transgenic Mouse Model of Alzheimer's Disease. The transgene consists of the human APP gene containing a mutation causing a rare form of early-onset familial Alzheimer's disease (Val717Phe). The transgene, whose expression is driven by the platelet-derived growth factor (PDGF) promoter, is microinjected into mouse eggs and implanted in a pseudopregnant female mouse. After the progeny are screened for the presence of the transgene, they are bred and their offspring are analyzed for pathologic features characteristic of Alzheimer's disease. The brains of the transgenic PDAPP (PDGF promoter expressing amyloid precursor protein) mice have abundant

 -amyloid deposits (made up of the A   peptide), dystrophic neurites, activated glia, and overall decreases in synaptic density.

From NEJM Volume 332:1512-1513

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From McGowan, Erikson & Hutton (2006), Trend in Genetics, 22: 281-289.