Genetics of Alzheimer's disease - disease and symptoms
Transcript of Genetics of Alzheimer's disease - disease and symptoms
![Page 1: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/1.jpg)
Genetics of Alzheimer's disease
- disease and symptoms
![Page 2: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/2.jpg)
Genetics of AD
• Early onset ‘familial’ vs late onset ‘sporadic’
• Genes ‘for’ disease vs genes ‘for’ symptoms
• Risk evaluation informed by genetics
![Page 3: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/3.jpg)
The two Alzheimer diseases
• Autosomal dominant dementia is • VERY early• VERY rare
• Late onset AD is• VERY complex• VERY multifactorial
![Page 4: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/4.jpg)
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/
![Page 5: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/5.jpg)
Not just AD….
• FTD and variants tau• CADASIL notch 3• TSEs PrP• Chromosome 3 dementia• Chromosome 9 dementia
![Page 6: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/6.jpg)
Genetics of LOAD
cys arge3
argarge4
cyscyse2
112 158
APOE ………….
…………. and more than 150 others
![Page 7: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/7.jpg)
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.
![Page 8: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/8.jpg)
![Page 9: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/9.jpg)
![Page 10: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/10.jpg)
![Page 11: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/11.jpg)
![Page 12: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/12.jpg)
Chromosome 10 and AD
0
1
2
4
3
LO
D s
core
Myers,A. et al. Science 290, 2304-2305 (2000).
![Page 13: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/13.jpg)
Chromosome 10 and plasma A
Ertekin-Taner,N. et al. Science 290, 2303-2304 (2000).
0
1
2
4
3
LO
D s
core
![Page 14: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/14.jpg)
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.
![Page 15: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/15.jpg)
Positional candidate study – chromosome 10
![Page 16: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/16.jpg)
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.
![Page 17: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/17.jpg)
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
![Page 18: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/18.jpg)
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
![Page 19: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/19.jpg)
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
![Page 20: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/20.jpg)
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
![Page 21: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/21.jpg)
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).
![Page 22: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/22.jpg)
• 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 ?
![Page 23: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/23.jpg)
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
![Page 24: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/24.jpg)
• 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
![Page 25: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/25.jpg)
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
![Page 26: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/26.jpg)
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
![Page 27: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/27.jpg)
The threshold hypothesis
Neonatal insult
Drug abuse HIV/AIDS AD
Fre
quen
cy o
f ps
ycho
sis
Eg 5HT2a/c SNPs
![Page 28: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/28.jpg)
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
![Page 29: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/29.jpg)
Genetics of dementia
does it matter to families ?
![Page 30: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/30.jpg)
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).
![Page 31: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/31.jpg)
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
![Page 32: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/32.jpg)
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
![Page 33: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/33.jpg)
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
![Page 34: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/34.jpg)
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).
![Page 35: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/35.jpg)
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).
![Page 36: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/36.jpg)
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).
![Page 37: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/37.jpg)
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).
![Page 38: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/38.jpg)
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%
![Page 39: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/39.jpg)
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
![Page 40: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/40.jpg)
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
![Page 41: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/41.jpg)
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
![Page 42: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/42.jpg)
Genes – new science, old stories
![Page 43: Genetics of Alzheimer's disease - disease and symptoms](https://reader034.fdocuments.us/reader034/viewer/2022051211/555d2515d8b42ac4258b570e/html5/thumbnails/43.jpg)
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