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Who is at Risk?

The Genetic Susceptibility to Alzheimers Disease


G. William Rebeck, PhD Department of Neuroscience Georgetown University Medical Center

Alzheimers Disease: Risk Factors


RISK FACTOR Family History - First degree relative Gender - Female RISK 3.5 1.5

Education - <8 years : >11 years


Head injury - loss of consciousness NSAID use Red wine; 1-2 glasses per day

2.0
2.0 0.50 0.55

Types of Biomarkers in Dementia


Neuropsychometic testing Neuroimaging CSF and blood measures Genetics

Usefulness of Biomarkers
Prediction of who will develop the disease. Help in differential diagnoses. Measure of rate of disease progression. Analysis of new therapeutics.

AD pathological changes

Plaques (Ab)

Tangles (phospho-tau)

CSF proteins as diagnostic markers


Mattsson, N. et al. JAMA 2009;302:385-393.

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

CSF biomarkers
Low Ab42 levels
Indicative of the presence of amyloid plaques.

High Tau levels


Indicative of neuronal loss.

Detection of brain amyloid with PET scans


Radioactive amyloid binding molecule

Genetic factors
Causative mutations in DNA Polymorphisms in DNA that change the risk of AD

Rare familial Alzheimers disease mutations

Mutations that cause AD


Amyloid Precursor Protein (APP)
Protein that is cleaved to generate Ab.

Presenilins (1 & 2)
Part of protein complex that cleaves APP to generate Ab. Large extended family in Colombia.

Strongest genetic risk factor for AD: APOE

APOE alleles: APOE-e2 (8%) APOE-e3 (78%) APOE-e4 (14%) Polymorphisms in the APOE gene affect the amino acids that make up the apoE protein.

APOE genotype alters the risk of AD


APOE e2/e2 e2/e3 e2/e4 e3/e3 e3/e4 e4/e4 control 1% 11% 2% 64% 23% 1% AD <1% 5% 3% 33% 42% 16%

APOE e4 increases risk of AD by about 3-fold


1993/1994 AlzGene Meta-analysis

APOE e2 decreases risk of AD by about 40%

APOE is a component of lipoproteins and interacts with lipoprotein receptors

MJ LaDu

Traumatic brain injury

Phospho-tau in TBI brains

McKee, JNEN 2009


Jordan, JAMA 1997

Worse outcome of TBI in APOE-e4 individuals

Genome-Wide Association Studies (GWAS)


-log10(P)

APOE

Other genetic factors that alter the risk of Alzheimers Disease


19 22

Genomic position by chromosome

ID of risk genes

Tens of thousands of polymorphisms on each chromosome.


Nat Genet 43:436 (2011)

An APOJ polymorphism decreases risk by about 15%

2009

www.alzgene.org
BIN1 ABCA7 CR1 PICALM MS4A6A CD33 MS4A4E CD2AP

APOE CLU (APOJ)

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

Relatively minor effects of about ten genes


SNP Closest gene Rs9349407 CD2AP 1.11 Rs9296559 CD2AP 1.10 rs11767557 EPHA1 0.90 Rs2588969 ARID5B 1.06 Rs4948288 ARID5B 1.07 Rs3865444 CD33 Chr. 6
6 7 10 10 19

MAF 0.29
0.29 0.21 0.40 0.26 0.31

Cases 6,283
6,283 6,283 6,283 6,992 6,283

Controls P 7,165 8.0 104


7,165 12,935 7,165 13,472 7,165 1.5 103 3.4 104 3.3 102 3.6 103 2.2 104

OR

0.89

SNP: single nucleotide polymorphism MAF: minor allele frequency OR: Odds Ratio

Nat Genet 43:429-435 (2011)

Conclusions
CSF measures of Ab and tau may be helpful on diagnosis of AD. APOE is the main genetic risk factor for AD. Other genes (e.g. APOJ) contribute to AD risk, and provide information for basic research.

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