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Who is at Risk?The Genetic Susceptibility to

Alzheimers Disease

G. William Rebeck, PhD

Department of NeuroscienceGeorgetown University Medical Center

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Alzheimers Disease: Risk FactorsRISK FACTOR RISK

Family History - First degree relative 3.5

Gender - Female 1.5

Education - 11 years 2.0

Head injury - loss of consciousness 2.0

NSAID use 0.50

Red wine; 1-2 glasses per day 0.55

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Types of Biomarkers in

Dementia

Neuropsychometic testing

Neuroimaging CSF and blood measures

Genetics

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Usefulness of Biomarkers

Prediction of who will develop thedisease.

Help in differential diagnoses.

Measure of rate of disease progression.

Analysis of new therapeutics.

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AD pathological changes

Plaques (Ab) Tangles (phospho-tau)

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Mattsson, N. et al. JAMA

2009;302:385-393.

CSF Ab42:P-Tau Ratio versus CSF T-Tau

CSFproteins

as

diagnosticmarkers

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CSF biomarkers

Low Ab42 levels

Indicative of the presence of amyloid

plaques.

High Tau levels

Indicative of neuronal loss.

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Detection of

brainamyloid

with PETscans

Radioactive

amyloidbindingmolecule

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Genetic factors

Causative mutations in DNA

Polymorphisms in DNA that change the

risk of AD

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s disease mutations

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Mutations that cause AD

Amyloid Precursor Protein (APP)

Protein that is cleaved to generate Ab.

Presenilins (1 & 2)

Part of protein complex that cleaves APPto generate Ab.

Large extended family in Colombia.

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Strongest genetic risk factor for AD:

APOE

APOE alleles: APOE-e2 (8%)

APOE-e3 (78%)APOE-e4 (14%)

Polymorphisms in the APOE gene affect theamino acids that make up the apoE protein.

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APOE genotype alters the

risk of ADAPOE control AD

e2/e2 1%

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APOE e4increases

risk of AD byabout 3-fold

1993/1994AlzGeneMeta-analysis

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APOE e2decreases

risk of ADby about

40%

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APOE is a component of lipoproteins and

interacts with lipoprotein receptors

MJ LaDu

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Traumatic brain injury

Phospho-tau in TBI brains McKee, JNEN 2009

Worse outcome of TBI in APOE-e4 individuals Jordan, JAMA 1997

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Other

geneticfactors thatalter the risk

ofAlzheimers

Disease

-log

10

(P)

Genomic position by chromosome

1 2 3 19 22

APOE

Genome-WideAssociation

Studies (GWAS)

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ID ofrisk

genes

Nat Genet 43:436 (2011)

Tens of thousands of polymorphisms on each chromosome.

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An APOJ polymorphismdecreases risk by about 15%

2009

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www.alzgene.org

APOE

CLU (APOJ)

BIN1

ABCA7

CR1PICALM

MS4A6A

CD33MS4A4E

CD2AP

Bertram L, McQueen MB, Mullin K, Blacker D,Tanzi RE. (2007) "Systematic meta-analyses ofAlzheimer disease genetic association studies: theAlzGene database." Nat Genet 39(1): 17-23

http://www.alzgene.org/http://www.alzgene.org/

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Relatively minor effects of

about ten genesSNP Closest gene Chr. MAF Cases Controls P OR

Rs9349407 CD2AP 6 0.29 6,283 7,165 8.0 1041.11

Rs9296559 CD2AP 6 0.29 6,283 7,165 1.5

10

3

1.10

rs11767557 EPHA1 7 0.21 6,283 12,935 3.4 1040.90

Rs2588969 ARID5B 10 0.40 6,283 7,165 3.3 1021.06

Rs4948288 ARID5B 10 0.26 6,992 13,472 3.6

10

3

1.07

Rs3865444 CD33 19 0.31 6,283 7,165 2.2 104 0.89

SNP: single nucleotide polymorphism

MAF: minor allele frequency

OR: Odds Ratio

Nat Genet 43:429-435 (2011)

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Conclusions

CSF measures of Ab and tau may behelpful on diagnosis of AD.

APOE is the main genetic risk factor forAD.

Other genes (e.g. APOJ) contribute to

AD risk, and provide information forbasic research.