Genetics of Alzheimer's disease

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Genetics of Alzheimer's disease

• - disease and symptoms

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Genetics of AD

• Early onset familial vs late onset sporadic
• Genes for disease vs genes for symptoms
• Risk evaluation informed by genetics

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The two Alzheimer diseases

• Autosomal dominant dementia is
• VERY early
• VERY rare
• Late onset AD is
• VERY complex
• VERY multifactorial

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Autosomal dominant AD
http//www.molgen.ua.ac.be/ADMutations/
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Not just AD.

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

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Genetics of LOAD
. and more than 150 others
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A relational database for AD association studies

• www.alzforum.org
• gtresearch gt compendium gtgenes gtAlzGene 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.

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Chromosome 10 and AD
Myers,A. et al. Science 290, 2304-2305 (2000).
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Chromosome 10 and plasma Ab
Ertekin-Taner,N. et al. Science 290, 2303-2304
(2000).
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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, Kings
College London, University of California,
Institute for Ageing and Health Newcastle Upon
Tyne.
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Positional candidate study chromosome 10
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Positional candidate study chromosome 10

• 69 reached signficance (plt0.05) 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, Kings
College London, London, University of California,
Institute for Ageing and Health Newcastle Upon
Tyne.
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Alzheimers (Augustes) 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
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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
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ADPsychosis is an inheritable trait

• AD P increased in relatives of those with ADP
  
• (OR2.4 plt0.0006)
• 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

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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

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5HT2 receptor study of behaviour
visual hallucinations
5HT2a/c polymorphisms

• Neither C102 or Ser23 none (n28)
• Either C102 or Ser23 20 (n142)
• Both C102 and Ser23 37 (n41)

Holmes et al Hum. Mol. Genet. 7, 1507-1509
(1998).
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ADPsychosis genes identified ?

• 52 of ADP C102/C102 vs 6.9 of AD-P
• Nacmias 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.

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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

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Neuropsychiatric Inventory

• Informant-based rating scale
• Frequency (0-3) X Severity (0-4) overall score
  (0-144)

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

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

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Cluster Analysis
K-means analysis using 3 principal components
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Psychosis cluster SNP analysis
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The threshold hypothesis
Frequency of psychosis
Eg 5HT2a/c SNPs
Drug abuse
Neonatal insult
HIV/AIDS
AD
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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 APOEe4
• Behavioural and psychological symptoms of
  dementia
• (partially) heritable
• Evidence for 5HT2a/c association with
  hallucinations
• Evidence for DRD3 association with delusions

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Genetics of dementia

• does it matter to families ?

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yes it does..

• Single most frequent question to the Alzheimers
  Society helpline.
• will I inherit Alzheimers?
• 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).

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More than a million people may be carrying a
mental timebomb and tests will be able to show
who is at risk. Guardian 17.09.93
Patients suffering Alzheimers disease could
soon be able to take a test to predict how
quickly their symptoms are likely to
progress New Scientist 17.12.94
Observer 2.1.94
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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

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Genetics of late onset AD

• family studies demonstrate increased risk
• APOE polymorphic variation accounts for some of
  that risk

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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).

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REVEAL study

• Risk Evaluation and Education for Alzheimers
  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).
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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).
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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).
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Risk calculation taking into account APOE status

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

• 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).
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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

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REVEAL study
Self-referred and systematically collected
relatives
N289

• Progress to randomisation
• 64 self referral
• 43 systematically collected

Purpose of study explained by telephone
N206
Counsellor explains potential benefits and
limitations of susceptibilty testing
N171
Individualised counselling and consent for APOE
testing
N162
Randomisation to APOE disclosure based
counselling or gender/pedigree based counselling
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).
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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).
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Genes new science, old stories
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Acknowledgements
Collaborators Mike Owen Julie Williams, Cardiff
University Alison Goate, Washington
University John Hardy, NIH Andrew Gruppe, Celera

• KCL,
• Institute of Psychiatry
• Petra Proitsi
• Gillian Hamilton
• Danae Liolitsa
• Carsten Russ
• Nigel Tunstall
• John Powell

Funders Alzheimers Research Trust MRC Research
into Ageing