Genetics of Dementia

1. Genetics of Dementia Christian Bocti, MD, FRCP(C) Cognitive Neurology Fellow Sandra E. Black, MD, FRCP(C) Director, Cognitive Neurology Unit Professor and Head, Division of Neurology Dept. of Medicine, S&W University of Toronto

2. Objectives To review genetic aspects of the neurodegenerative dementias: Alzheimer’s Disease (AD) Sporadic Early-onset familial Late-onset familial Frontotemporal Dementia (FTD)

3. Dementia-introduction Alzheimer's Disease is the most common neurodegenerative dementia; Represents approx. 2/3 of dementias (1) Dementia associated with cerebro-vascular disease are 2nd in prevalence (10-50%)*(2) Dementia with Lewy Bodies represents 15% of all dementias – spectrum with AD and PD (3) Frontotemporal Dementia accounts for 10-15% of presenile dementias (4)

4. Background: Projected Prevalence of Dementia (x 1,000) Canada, 1991 - 2031

5. Case presentation 1 44 y.o. lady presents with a 2 yr history of gradual cognitive and behavioral disturbances Forgets much of what is said to her over minutes Irritable and immature behavior Unable to hold job or take care of household finances; impaired insight No systemic etiology after complete work-up Positive family history: father died of AD, brother (48) is diagnosed with AD

6. Alzheimer’s Disease Clinical picture (6) : Slow, progressive course of memory loss, alteration of cognitive abilities, behavioral problems. Pathology (7) : Neuronal loss Deposition of amyloid in senile plaques and cerebral blood vessels. Neurofibrillary tangles in the neurons of the cerebral cortex and hippocampus (hyperphosphorylated form of the microtubular protein tau)

7. AD Pathology Deposition of amyloid in (a) the senile plaques and (b) cerebral blood vessels.

8. Alzheimer’s Disease: pathophysiology « It appears that Alzheimer's arises because the normal processing of certain proteins goes terribly wrong, littering brain cells and the space between them with pieces of toxic protein. (…) many other neurodegenerative disorders - among them frontotemporal dementia, Parkinson's disease and Creutzfeldt-Jakob disease - are also characterized by protein processing gone haywire. » 10. St. George-Hyslop, P.H., "Piecing Together Alzheimer’s" Scientific American, December 2000; 76-83

9. Alzheimer’s Disease Sporadic form: Great majority of cases Non-hereditary factors play a role Head trauma, low education, exposure to certain drugs, cardiovascular risk factors Genetic factors also contributory Family history 1st degree relative= 3.5 times the risk (11) Several gene polymorphisms are risk factors (ie, ApoE)

10. Alzheimer’s Disease Genetics Less than 10% of cases are explained by disease-causing mutations Mutations in at least 4 genes are known to cause AD (12): AD1: mutations in the amyloid precursor gene (APP) on chromosome 21 AD2 is associated with the APOE*4 allele on chromosome 19 AD3 is caused by mutation in the gene for presenilin-1 (PS1) on chromosome 14 AD4 is caused by mutation in a gene on chromosome 1 that encodes a similar protein, presenilin-2 (PS2)

11. Alzheimer’s Disease - AD1 AD1: Chromosome 21, beta amyloid precursor protein gene (APP); (small proportion of FAD) Down syndrome patients(Trisomy 21) have high incidence of AD pathology in middle age Mutation also associated with hereditary cerebral hemorrhage with amyloidosis

12. Figure 2. Missense Mutations Causing Early-Onset Familial Alzheimer's Disease. The altered amino acid residues are near the sites of alpha-, beta-, and gamma-secretase cleavage (red triangles). Various missense mutations are shown as yellow boxes. The mutations lead to the accumulation of toxic peptide A 42 rather than the wild-type A 40 peptide.

13. Alzheimer’s Disease – AD2 Mutations in apolipoprotein E gene on chromosome 19 have been associated with late-onset familial AD (12) Homozygosity for E4 has been proved to be virtually causal when lifespan extends to age 80 in 42 families

14. ApolipoproteinE gene testing NOT USEFUL AS A CLINICAL SCREENING TOOL A person without the Apo-E4 allele can still develop Alzheimer’s Disease, and conversely, not everyone with the Apo-E4 allele will develop Alzheimer’s Disease. Sensitivity/Specificity not good enough for clinical use

15. Genetics of late-onset sporadic AD Alpha-2 macroglobulin is also a polymorphic gene that may be a genetic risk factor for sporadic AD (12) Located on Chromosome 12; involved in the formation of AB fibrils LRP1 is another candidate gene under investigation (12) (lipoprotein receptor-related protein)

16. AD3 and AD4 – Presenilins Chromosome 14, presenilin-1 (PS-1) with age of onset between 28 to 65 years. (12) The most frequent gene mutation in early onset FAD: 40 mutations, 82 families worldwide as of 2000. Chromosome 1, presenilin-2 (PS-2), with age of onset between 40 to 85 years. (12) Only a few families

18. Presenilins: what are they? Presenilins are a novel gene family with a novel proteolytic mechanism that may process transmembrane proteins There is evidence that presenilin contains the active site of gamma-secretase; presenilin may in fact be the gamma-secretase Gamma-secretase inhibitors are being actively developed as a potentially disease-modifying therapeutic strategy

19. Case presentation 2 56 y.o. man with insidious onset of abnormal behavior: socially inappropriate humor, defective judgment, verbal aggressiveness Memory, orientation well preserved No systemic etiology Family history positive: mother had similar manifestations in early 60’s

20. Frontotemporal Dementia A distinct group of non-Alzheimer’s neurodegenerative dementia (17) Earlier age of onset Amnesia is not prominent One of two patterns: Behavioral presentation: changes in personality and social conduct Language presentation: progressive aphasia, non-fluent or fluent (semantic dementia)

21. Frontotemporal Dementia Neuropathology: Atrophy and neuronal loss in the neocortex of frontal lobes and anterior temporal lobes A subset have tau positive neuronal inclusions, with or without Pick bodies (17) Others have non-specific histopathology

23. Frontotemporal Dementia 50% have a positive family history A causative autosomal dominant mutation in the tau gene on chromosome 17 has been established for several families FTDP-17 (Frontotemporal dementia with parkinsonism) is the name of this syndrome

24. FTDP-17 is a tauopathy Tau is a microtubule-associated protein Tau modulates the assembly of microtubules The mutation in tau is believed to cause an imbalance between different isoforms of tau (3R and 4R) This leads to excess tau accumulation (of different isoforms than in AD) which is believed to compromise microtubule stability The precise mechanism of neuronal loss and how it relates to tau is uncertain (18)

25. Tauopathies Other neurodegenerative disorders have been associated with abnormalities of tau: Cortico-basal degeneration Progressive supra-nuclear palsy FTD with motor neuron disease This group of disease can be conceptualized pathologically and clinically as a spectrum of tauopathies

26. Conclusions AD is the most common form of degenerative dementia (BUT: emerging evidence that cerebro-vascular co-morbidity is key) The most common form of AD is the late-onset, sporadic form, with genetic risk factors Less than 10 % of AD are purely hereditary All mutations influence the Abeta-42/40 ratio Familial AD cases provide important insight in the pathophysiology of the disease

27. Conclusions (contd) FTD is a relatively infrequent dementia Mutations on the tau gene cause an autosomal dominant form of the disease A group of neurodegenerative disorders share similar abnormalities in tau The common mechanism for many neurodegenerative disorders is accumulation of abnormal proteins in insoluble forms in specific populations of neurons

28. References Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales:MRC CFAS The Lancet 2001:357:169-175 Erkinjuntti, T. Vascular dementia: an overview. In Dementia, Second edition. O’Brien J, Ames, D and Burns A, editors. Arnold Publishers, London, 2000. Pp623-634. McKeith, I. Dementia with Lewy bodies: an overview. In Dementia, Second edition. O’Brien J, Ames, D and Burns A, editors. Arnold Publishers, London, 2000. Pp 685-697. Hodges, JR. Pick’s disease. In Dementia, Second edition. O’Brien J, Ames, D and Burns A, editors. Arnold Publishers, London, 2000. Pp747-758. CMAJ 1994; 150: 899-913. G. McKhann, D. Drachman, M. Folstein, R. Katzman, D. Price, and E. M. Stadlan. Clinical diagnosis of Alzheimer's disease: Report of the NINCDS- ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology. 34:939-944, 1984. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease. Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. Neurobiol Aging 1997 Jul-Aug;18(4 Suppl):S1-2 Department of Pathology, Diagnostic Center for Alzheimer's Disease, The University of Oklahoma Health Sciences Center’s website: http://pathology.ouhsc.edu/DeptLabs/diagnostic_center_for_alzheimer.htm Józefowicz RF, Miller JJ, Powers JM, Neuropathology and Neuroimaging Laboratory, Departments of Pathology and Neurology, University of Rochester School of Medicine and Dentistry. Website: http://www.urmc.rochester.edu/neuroslides/

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