Genetics of Alzheimer’s Disease by Denise Harold

Genetics of Alzheimer’s DiseaseDenise Harold

MRC Centre for Neuropsychiatric Genetics & Genomics Cardiff University

The Escalating Problem of Dementia

Protein Deposits in the Brain

Senile Plaques (β-amyloid)

Neurofibrillary Tangles

Alzheimer’s Disease Process

Tangles and protein deposits

Brain cell loss Brain atrophy, neurotransmitter loss

Symptoms

Genetics and Alzheimer’s Disease

• A family history of Alzheimer’s disease increases a person’s risk of developing the disease themselves

• 2-3 fold increased risk of AD in 1st degree relatives of AD patients

• Although environmental factors play a role, twin studies indicate that 60-80% of disease is due to genetics

Genetic Variation


Early-Onset AD (Dominantly Inherited)

Early-Onset AD (Complex

Inheritance)

Late-Onset AD (Complex

Inheritance)

Cause:Inherited Genetic

Mutations

Genetic and Environmental

Risk Factors


Risk Factors

Age at Onset: Usually 30-60 years <65 years >65 years

Proportion of Cases:

~1% ~4% ~95%

Genetics and Environmental Factors

Threshold

Liability/Risk

Alzheimer’s disease




Inheritance)


Inheritance)


Mutations


Risk Factors


Risk Factors



~1% ~4% ~95%

Dominantly Inherited Early-Onset AD

• Mutations in 3 genes identified: APP, PSEN1 & PSEN2

• If a parent is affected, child has 50:50 chance of inheriting the mutation

• Presence of the mutation directly causes disease




Inheritance)


Inheritance)


Mutations


Risk Factors


Risk Factors



~1% ~4% ~95%

Genetic Association Studies

Late-Onset Alzheimer’s Disease

• Candidate gene studies: APOE

• Genome-wide association studies: CLU, PICALM, CR1, BIN1, ABCA7, MS4A, CD2AP, EPHA1, HLA, PTK2B, SORL1, SLC24A4, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, CASS4

• Sequencing studies: TREM2

CLU PICALM CR1 BIN1 ABCA7 MS4A CD2AP

EPHA1 HLA PTK2B SORL1 SLC24A4 INPP5D MEF2C NME8 ZCWPW1 CELF1

FERMT2 CASS4

From 2009-2013, Alzheimer’s Research UK helped fund studies that discovered 19 variants in genes linked to an altered risk of Alzheimer’s.

Over half the population may carry these variants, but each one has a small effect on risk. Some of them reduce the risk of Alzheimer’s slightly, whereas others may make a person around 1.2 times more likely to develop the disease.

Around 2% of the population have two copies of APOE4, which could make them more than 10 times more likely to develop the disease.




Inheritance)


Inheritance)


Mutations


Risk Factors


Risk Factors



~1% ~4% ~95%

• About 4% of AD cases have an early-onset of symptoms but do not have a dominantly inherited mutation in APP, PSEN1 and PSEN2

• The more extreme phenotype could result from risk variants with a stronger effect than those seen in late-onset AD

• MRC funding to ascertain and sequence EOAD individuals from the UK

• Sample collection and sequencing over the course of the next 3 years

Sequencing in Early-Onset AD (Complex)

CLU PICALM CR1 BIN1 ABCA7 MS4A CD2AP

EPHA1 HLA PTK2B SORL1 SLC24A4 INPP5D MEF2C NME8 ZCWPW1 CELF1

FERMT2 CASS4

From 2009-2013, Alzheimer’s Research UK helped fund studies that discovered 19 variants in genes linked to an altered risk of Alzheimer’s.

Over half the population may carry these variants, but each one has a small effect on risk. Some of them reduce the risk of Alzheimer’s slightly, whereas others may make a person around 1.2 times more likely to develop the disease.

Around 2% of the population have two copies of APOE4, which could make them more than 10 times more likely to develop the disease.

• Diagnosis?

• Identifying disease pathways

• Drug targets

• Gene-environment interactions

Utility of Genetic Findings

• >20 genes influencing Alzheimer’s disease risk identified

• Effects on disease risk are individually subtle but work in aggregate

• Risk genes highlight processes that may be dysfunctional in Alzheimer’s disease

Progress!

Thank you!Thank you to all the patients and their families who have

volunteered to be part of our research

Alzheimer’s Research UK

Alzheimer’s Society

Welsh Government

Medical Research Council

The Wellcome Trust

Genetics of Alzheimer’s Disease by Denise Harold

Health & Medicine

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