Genetics of Alzheimer's disease

- disease and symptoms

Genetics of AD

• Early onset ‘familial’ vs late onset ‘sporadic’

• Genes ‘for’ disease vs genes ‘for’ symptoms

• Risk evaluation informed by genetics

The two Alzheimer diseases

• Autosomal dominant dementia is • VERY early• VERY rare

• Late onset AD is• VERY complex• VERY multifactorial

Autosomal dominant AD

Gene Age of onset Numbers of mutations

APP 40-50 18

PS-1 30-40 144

PS-2 50-60 10

http://www.molgen.ua.ac.be/ADMutations/

Not just AD….

• FTD and variants tau• CADASIL notch 3• TSEs PrP• Chromosome 3 dementia• Chromosome 9 dementia

Genetics of LOAD

cys arge3

argarge4

cyscyse2

112 158

APOE ………….

…………. and more than 150 others

A relational database for AD association studies

• www.alzforum.org >research > compendium >genes >AlzGene database

• Maintained by• Lars Bertram 1, Deborah L. Blacker 2,3, Matthew B. McQueen 3,

Kristina Mullin 1, Rudolph E. Tanzi 1,

(1) Genetics and Aging Research Unit at the MassGeneral Institute for Neurodegenerative Diseases, the (2) Gerontology Research Unit, Dept. of Psychiatry, Massachusetts General Hospital, Charlestown, MA, and the (3) Dept. of Epidemiology, Harvard School of Public Health, Boston, MA.

Chromosome 10 and AD

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1

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4

3

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core

Myers,A. et al. Science 290, 2304-2305 (2000).

Chromosome 10 and plasma A

Ertekin-Taner,N. et al. Science 290, 2303-2304 (2000).

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1

2

4

3

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Positional candidate study – chromosome 10

• 1,397 Single Nucleotide Polymorphisms (SNPs)• 677 genes from1270 known or predicted

• 48% putative functional mutations

• 1796 AD cases, 1768 controls and 292 pedigrees • Initial testing - WU series (422 cases / 382 controls)

• Replication in UK (368 / 404) and UCSD series (217 / 409)

• Validation in linkage (429 / 321), NIMH sets (292 pedigrees, 624 individuals)

• Post mortem confirmation (360 / 252)

Goate et al (Washington University, St. Louis), Celera Diagnostics, Cardiff University, King’s College London, University of California, Institute for Ageing and Health Newcastle Upon Tyne.

Positional candidate study – chromosome 10

Positional candidate study – chromosome 10

• 69 reached signficance (p<0.05) ; Five replicated

 • One marker significantly associated with AD

• four of six case-control series

• allelic p-value of 0.0001 from meta analysis of all six samples

 • RPS3A homologue

Goate et al (Washington University, St. Louis, Celera Diagnostics, Cardiff University, King’s College London, London, University of California, Institute for Ageing and Health Newcastle Upon Tyne.

Alzheimer’s (Auguste’s) symptoms

“The first noticeable symptom of illness shown by this 51-year-old woman was suspiciousness of her husband. [At times] believing that people were out to murder her, [she] started to scream loudly. At times she......seems to have auditory hallucinations.”

Alzheimer A 1907 (trans Jarvik & Greenson Alz.dis.Ass.Disord (1987) 1 7-8

Heritability of BPSD

• Affected sibling pair clinical study• Significant sharing of phenotype

• agitation• age of onset

• APOE ~ 4% variance

• depression

Tunstall et al (2000) B.J.Psych. 176 156-159

AD+Psychosis is an inheritable trait

• AD + P increased in relatives of those with AD+P

(OR2.4; p<0.0006)Sweet et al (2002). Neurology 58, 907-911

• Linkage of AD-psychosis suggests susceptibility regions shared with schizophrenia (2p & 6q)

Bacanu et al (2002) Neurology 59, 118-120

Genes and susceptibility to psychosis in AD

• Delusions and hallucinations common in AD• Aetiology unknown but serotonin implicated

• serotonin decrease in psychosis in AD• neuronal loss in dorsal raphe nucleus

• Serotonin receptor polymorphisms – genes for psychosis? • 5-HT2A T102C

• 5-HT2C cys23ser

5HT2 receptor study of behaviour

• Neither C102 or Ser23 none (n=28)

• Either C102 or Ser23 20% (n=142)

• Both C102 and Ser23 37% (n=41)

visual hallucinations5HT2a/c polymorphisms

Holmes et al Hum. Mol. Genet. 7, 1507-1509 (1998).

• 52% of AD+P C102/C102 vs 6.9% of AD-PNacmias et al (2001). Biol.Psychiatry 50, 472-475.

• DRD3 polymorphic variation associated with delusions

Sweet,et al (1998). Arch.Neurol. 55, 1335-1340.

Holmes,et al (2001). J.Neurol.Neurosurg.Psychiatry 71, 777-779.

AD+Psychosis genes identified ?

BPSD syndromes

• Symptom co-occurrence• Aggression with psychosis (Lyketsos et al 1999)

• Depression and psychosis (Rappoport et al 2001)

• Aggression with depression and psychosis (Holmes et al 1998)

• Are symptoms or syndromes associated with genetic variance ?

• NINCDS-ADRDA probable AD (n= 967)• Neuropsychiatric Inventory• Principal Components Analysis (PCA) and Cluster

Analysis

• Informant-based rating scale

• Frequency (0-3) X Severity (0-4) = overall score (0-144)

Neuropsychiatric Inventory

•Delusions •Hallucinations•Aggression•Anxiety•Disinhibition•Apathy

•Depression•Aberrant Motor Behaviour•Irritability•Elation•Sleeping abnormalities•Appetite abnormalities

CLUSTER

1 Frontal

Behaviour

(n=142)

2 Mood

Disturbances

(n=88)

3 Minimally Affected

(n=551)

4 Psychosis

With Frontal

Features

(n=123)

5 Psychosis

(n=63)

Frontal Behaviour

1.51

0.11

-0.52

0.83

-0.6

Psychosis -0.53 -0.27 -0.36 1.12 2.5

Mood Disturbances

-0.29

2.3

-0.23

-0.36

0.18

K-means analysis using 3 principal components

Cluster Analysis

Psychosis cluster SNP analysis

5HT2A 5HT2C DRD2 DRD1 DRD3 COMT DATPsychosis

with frontal features

ns ns ns ns p=0.013 ns ns

Psychosis ns ns ns ns ns ns ns

Both Clusters

ns ns ns ns p=0.003 ns ns

The threshold hypothesis

Neonatal insult

Drug abuse HIV/AIDS AD

Fre

quen

cy o

f ps

ycho

sis

Eg 5HT2a/c SNPs

Conclusions

• Autosomal dominant AD is• Very rare• Largely understood at a genetic level • Most frequently associated with mutations in PS1

• Other autosomal dominant dementias are• Very rare• Increasingly understood at a genetic level• Most frequently associated with mutations in MAPT (tau)

• Late onset AD is• Very common and complex• Very incomplete understanding of genetics• Most reliably associated with APOE4

• Behavioural and psychological symptoms of dementia• (partially) heritable• Evidence for 5HT2a/c association with hallucinations• Evidence for DRD3 association with delusions

Genetics of dementia

does it matter to families ?

yes it does…..

Single most frequent question to the Alzheimer’s Society helpline….

“will I inherit Alzheimer’s?”

• 58% of callers• Harvey, R. J., Roques, P., Fox, N. C., & Rossor, M. N. Non-Alzheimer

dementias in young patients. Br.J.Psychiatry 168, 384-385 (1996).

Observer 2.1.94

More than a million people may

be carrying a ‘mental timebomb’

and tests will be able to show

who is at risk.

Guardian 17.09.93Patients suffering Alzheimer’s disease

could soon be able to take a test to

predict how quickly their symptoms

are likely to progressNew Scientist 17.12.94

Early onset FAD - a rare disorder

• Prevalence of FAD 5.3/100,000 at risk

• Campion et al (1999) Am J Hum Genet 65, 664-670

• UK population ~62m• 0.22 % of population aged 40-60

• ~ 600 with FAD in England and Wales

Genetics of late onset AD

• family studies demonstrate increased risk

• APOE polymorphic variation accounts for some of that risk……

cys arge3

argarge4

cyscyse2

112 158

But by how much?

APOE e4/* - 5 x ; APOE e4/4 - 15 x

• Farrer, L. A. et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease - A meta- analysis. JAMA 278, 1349-1356 (1997).

REVEAL study

• Risk Evaluation and Education for Alzheimer’s Disease

• To evaluate feasibility, safety and behavioural responses of providing general information on risk and APOE disclosure to adult children of people with AD

• To establish risk curves:• Gender and age specific incidence curves for first degree

relatives• APOE genotype Odds-ratios estimates for each age and

gender

Cupples, L. A. et al. Estimating risk curves for first-degree relatives of patients with Alzheimer's disease: the REVEAL study. Genet.Med. 6, 192-196 (2004).

Risk curves for AD

Cupples, L. A. et al. Estimating risk curves for first-degree relatives of patients with Alzheimer's disease: the REVEAL study. Genet.Med. 6, 192-196 (2004).

Risk curves taking into account APOE status

Cupples, L. A. et al. Estimating risk curves for first-degree relatives of patients with Alzheimer's disease: the REVEAL study. Genet.Med. 6, 192-196 (2004).

Risk calculation taking into account APOE status

• Male age 65 years APOE e3/4– Risk of AD to current age

6.4%– Risk at age 80 28.2%

Cupples, L. A. et al. Estimating risk curves for first-degree relatives of patients with Alzheimer's disease: the REVEAL study. Genet.Med. 6, 192-196 (2004).

• Male age 65 years• Risk of AD to current age 2.0%• Risk at age 80 13.3%

A dementia genetics clinic

• Perceived need for high risk families • Early onset; multiply affected• Tertiary referral ; national service• Gene testing requests

• Actual need for low risk families• Late onset ; Singly affected• Majority self or GP referral ; Majority local • Genetic testing requests rare• Genetic testing performed very rarely

REVEAL study

Roberts, J. S. et al. Who seeks genetic susceptibility testing for Alzheimer's disease? Findings from a multisite, randomized clinical trial. Genet.Med. 6, 197-203 (2004).

Self-referred and systematically collected relatives

Counsellor explains potential benefits and limitations of susceptibilty testing

Purpose of study explained by telephone

Individualised counselling and consent for APOE testing

Randomisation to APOE disclosure based counselling or gender/pedigree based counselling

N=289

N=206

N=171

N=162

Progress to randomisation:

• 64% self referral• 43% systematically collected

REVEAL study

Roberts, J. S. et al. Who seeks genetic susceptibility testing for Alzheimer's disease? Findings from a multisite, randomized clinical trial. Genet.Med. 6, 197-203 (2004).

Systematically collected

Self referral

Age under 60 3.8 * 1

Female gender 1 1.2

Graduate education 3.5 * 1.2

Income >$70k 0.5 2.2

Married 1.3 0.9

More than one affected sibling 1 0.9

Worried about AD 1.1 2.3 *

Progress to randomisation

Genes – new science, old stories

Acknowledgements

KCL, KCL,

Institute of PsychiatryInstitute of Psychiatry

Petra Proitsi Petra Proitsi

Gillian Hamilton

Danae Liolitsa

Carsten Russ

Nigel TunstallJohn Powell Funders

Alzheimer’s Research TrustMRCResearch into Ageing

CollaboratorsMike Owen & Julie Williams,

Cardiff UniversityAlison Goate, Washington UniversityJohn Hardy, NIHAndrew Gruppe, Celera