Who is at Risk?

The Genetic Susceptibility to Alzheimer’s Disease
G. William Rebeck, PhD Department of Neuroscience Georgetown University Medical Center

Alzheimer’s 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 Alzheimer’s 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 Alzheimer’s Disease
19 22

1

2

3…

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 × 10−4
7,165 12,935 7,165 13,472 7,165 1.5 × 10−3 3.4 × 10−4 3.3 × 10−2 3.6 × 10−3 2.2 × 10−4

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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