This document discusses the genetics of various forms of dementia. It begins by providing background on genes, DNA mutations, and genetic inheritance. It then examines specific genes linked to early-onset Alzheimer's disease like APP, PSEN1, and PSEN2. It also discusses the ApoE4 gene variant as a risk factor for late-onset Alzheimer's. Other dementias covered include vascular dementia, dementia with Lewy bodies, and genetic factors involved in each. The goal of genetic studies of dementia is to better understand disease development and inheritance to enable earlier diagnosis, prevention and treatment.

1. Genetics of Dementia
Larry Baum, PhD
Honorary Associate Professor
Department of Psychiatry
University of Hong Kong
E-mail: lwbaum@hotmail.com

2. Talk Outline
 Theory
 Diseases

3. Genes
• Gene -- section of DNA that makes one protein
• ~20,000 genes in humans
• DNA mutation -- gene alteration that leads
to a defective gene product
• Allele -- each gene has two copies, one from
each parent

4. Genetic disease pathway
DNA Mutation
↓
• Expression level: Too much or too little
OR
• Altered protein: Gain or loss of function

5. Mutseqmorphism
 Sequence alteration, sequence change -- any
change in DNA sequence
 Polymorphism -- a common sequence alteration
 Mutation -- a sequence alteration that causes disease
Polymorphism
Sequence alteration
Mutation

6. Types of Sequence Alterations
Murphy’s Law: “Whatever can go wrong, will go
wrong.”
If you can imagine a type of alteration, it’s happened.
 Silent -- most common, and no effect on protein
 Missense -- substitutes one amino acid with
another
 Nonsense -- substitutes amino acid codon with
stop codon
 Splicing -- change of splicing signal at
intron/exon junction
 Insertion, deletion -- frameshift or add/remove
amino acids

7. Sequence Alteration Naming
 cDNA (only the nucleotides that will be translated)
 Numbering: +1 is the A in start codon
 Substitution: 2389C>T, -94G>A
 Deletion: 2033delA, 435-437del
 Insertion: 880-881insGT
 Introns: IVS4+2T>A, 552+2T>A, IVS1-1G>C
 Amino acid: Y220M, R46X

8. Haplotypes
• Group of alleles that tend to be inherited together
• Usually close together, but could be distant
SNP1
A/T
SNP2
C/T
SNP3
A/T
SNP4
C/G
Haplotype A: 23% A T T C
Haplotype B: 15% A T A C
Haplotype C: 11% T T A G
Other haplotypes: 51%

9. Genotype & Phenotype
• Genotype: the DNA sequence of an individual
• Phenotype: the properties of an individual
(appearance, disease symptoms, behavior,
etc.)
Genotype + Environment → Phenotype

10. Types of genetic disease
• Genetic: from DNA
• Familial: runs in a family
• Congenital: onset before birth
• Hereditary: from parent DNA
• Sporadic: not familial
• Late-onset: onset at older ages

11. Modes of inheritance
• X-linked vs. Autosomal -- on X vs. other
chromosomes
• Dominant vs. Recessive -- only one mutant allele
needed to
transmit disease vs. both alleles must be mutated to
transmit disease
• Mitochondrial -- on mitochondrial plasmid

12. Variability
• Penetrance -- chance that someone with a
mutation will exhibit disease
• Variable expression -- appearance of
different severity of symptoms in different
individuals

13. Genetic Diseases
Alterations
Genes
Diseases
Phenotypes
One DNA sequence alteration can cause
several diseases
Different alterations, in different genes,
can cause one disease
DNA sequence alterations may not cause
disease. In fact, most do not make any
difference

14. Goals of Studies on Genetics
 To know how a disease develops
 To discover how a disease is inherited
 To diagnose a disease earlier
 To prevent disease in mutation carriers
 To offer genetic counseling to patients
 To improve or find new treatments

15. Talk Outline
 Theory
 Diseases

16. Dementia prevalence
 All dementia: ~40 million, or ~0.6%
 Alzheimer’s disease (AD): ~1/3-1/2 of dementia
 Vascular dementia (VaD): ~1/6-1/3
 Frontotemporal lobar degeneration (FTLD): ~1/10-1/5
 Lewy body dementia: ~1/20-1/10

17. Genes in disease
 High penetrance
 Monogenic: Mutations in one gene
 Typical “genetic disease”
 Example: early onset Alzheimer’s
disease
 Low penetrance
 Polygenic, multifactorial, polymorphisms and
environmental factors
 Sometimes even surprising to find a genetic
role in the disease
 Examples: depression, stroke

18. Dementia risk factors
 Diabetes
 Hypercholesterolemia
 Kidney failure
 Vitamin B12 deficiency
 Genetic variants affect the above factors but do not show
up in genome wide association studies (GWAS) of
Alzheimer’s disease (AD), thus may be minor genetic
contributors to dementia.

19. AD Hypothesis
Aβ
Aβ
Neuritic plaque
& neurotoxicity Dementia

20. Molecular hypothesis of AD
 Aβ accumulates in brain. Why?
 Aging
 Genetic factors
 Head injury
 Inflammation
 Nerve cells are damaged
 Aβ oligomers toxic to nerve cells?
 Aβ amyloid plaques attract toxic factors or remove necessary
factors?

21. Video on AD
http://www.nia.nih.gov/alzheimers/alzheimers-disease-video

22. AD genetics
 Is Alzheimer’s disease (AD) inherited?
Yes and noYes and no
The biggest risk factor is age, but relatives of ADThe biggest risk factor is age, but relatives of AD
patients also have somewhat increased risk.patients also have somewhat increased risk.

23. AD genes
 Early onset AD (rare) due to mutations
 Amyloid Precursor Protein (APP)
 Presenilin 1 (PS1)
 Presenilin 2 (PS2)
 Late onset AD (common) due to:
 age, sex, head injury, other factors
 common gene variations (polymorphisms)
 Apolipoprotein E
 Other genes

24. APP
 APP is cut to produce Aβ protein outside cells.
 Aβ is produced in normal people.
 Function: may be to bind copper and to kill microbes
 Aβ clumps together. Oligomers damage neurons.
 Aβ accumulates in amyloid plaques in AD brain.
 Mutations increase production of insoluble Aβ.
 Most Aβ molecules are 40 amino acids long.
 Some are 42 amino acids long and aggregate more
readily.
 These mutations lower onset age of AD.
 A mutation recently found that lowers Aβ and risk of AD
 Aβ oligomers may damage brain and cause AD.

25. APP copy number
 Early-onset AD
 Some have duplication of APP gene
 Higher production of Aβ
 Down’s syndrome
 High prevalence of dementia with aging
 Due to trisomy 21
 Extra copy of APP gene
 Higher production of Aβ

26. www.alzforum.org
Aβ

27.  Presenilins cut APP to make Aβ.
 PSEN1
 PSEN2
 Mutations increase production of 42 amino acid Aβ.
Presenilins

28. ApoE
 ApoE transports lipids, Aβ, and other molecules between
cells.
 ApoE4
 3 common alleles of ApoE: E2 (~10%), E3 (~80%), E4 (~10%)
 Everyone has two copies (alleles) of each gene.
 ApoE4 increases lifetime risk of AD: 3x for one allele, 15x for two.
 ApoE4 decreases onset age of AD: ~8 years younger for one
allele and ~15 years for two.
 It is still not known how ApoE4 causes AD. Possibilities:
 Poor clearance of Aβ
 Enhances Aβ aggregation
 Cleaved into neurotoxic fragments

29. Other genes
 Variants in many other genes have effects
 Single nucleotide polymorphisms (SNPs)
 Found by genome wide association studies (GWAS)
 Effects are small
 <20% effect on risk
 Why?
 Variants may tag haplotypes that affect gene expression
 Variants may tag mutations with big effects in rare families
 May distinguish these possibilities by sequencing genes in
many patients

30. Other genes
 ApoJ, or CLU (clusterin): similar to ApoE
 Functions: several ways they might be involved in
AD, but not known which is key
 Immune response: complement receptor 1 (CR1)
 Aβ clearance: ABCA7, PICALM, BIN1, TREM2
 APP processing: SORL1, PLD3
 Overlap: Aβ itself may be involved in immune response

31. AD genes
Possibilities are so complex! What is the key?
Functions of all the
genes involve Aβ.
Mutations in APP
that raise or lower
Aβ also raise or
lower AD risk.
Thus, Aβ seems to
be key to AD.

32. Genetic diagnosis of AD
 Is there a genetic test for AD?
 Yes and no
 Early onset AD families: sequencing APP, PS1, PS2
may predict who may get AD.
 Late onset AD: detecting ApoE4 only increases risk
by 3x or 15x, and most people with ApoE4 do not get
AD, therefore not very useful. Testing other gene
polymorphisms too may increase usefulness. But
ApoE4 adds one piece of evidence to increase
confidence of a neuropsychological or neurological
diagnosis.

33. AD treatment
 Current
 Cholinergic and NMDA drugs
 Do not slow disease progression
 Future
 Trials of Aβ vaccine, drugs, and antibodies in AD failed.
 Maybe need treatment earlier
 Before Aβ damage irreversible?
 Before Aβ triggers tau aggregation and spreading?
 Trials in early-onset AD before dementia.
 Identified patients in families by genetic screening.
 Started in 2014
 Aβ antibodies

34. Vascular dementia
 A common dementia, but genetics poorly
studied
 Risk factors
 Age
 Stroke
 Carotid atherosclerosis
 Cerebral microbleeds
 Heart disease plus hypertension
 Diabetes

35. Vascular dementia: stroke
 Stroke
 Stroke ~doubles risk of dementia
 Many genetic factors for stroke
 Monogenic
 CADASIL
 Cerebral arteriopathy, autosomal dominant, with
subcortical infarcts and leukoencephalopathy
 Small vessel disease
 Caused by mutations in NOTCH3
 Other monogenic causes (see next slide)

36. Vascular dementia: stroke
Monogenic causes of stroke

37. Vascular dementia: stroke
 Complex genetics of stroke
 SNPs from GWAS
 Risks are low: odds ratios < 1.4
 Cardioembolic stroke: atrial fibrillation risk factors
 PITX2
 ZFHX3
 ABO (blood groups)
 Large vessel disease
 HDAC9
 Others
 Small vessel disease: white matter lesions
 High heritability
 But findings from GWAS and candidate gene studies need
confirmation

38. Vascular dementia: mixed dementia
 Mixed dementia
 Overlap of pathology between AD and VaD
 Neurofibrillary tangles: intraneuronal aggregates of tau protein
 Amyloid plaques
 White matter lesions
 Cerebral angiopathy
 Very common if defined broadly
 Positive feedback between causes?
 Aβ expression rises in response to brain damage

39. Dementia with Lewy bodies (DLB)
 Pathology
 Alpha-synuclein (SNCA) deposits inside neurons
 Most patients also have AD pathology
 Not much is known about genetics of DLB
 SNCA
 Mutations are rare cause of DLB
 Missense
 Gene duplication (copy number variant)
 Function: in presynaptic terminals; may aid neurotransmitter
release and vesicle turnover
 SNCA oligomers might be toxic

40. Dementia with Lewy bodies (DLB)
Continuum from AD to PD dementia, and from Aβ to SNCA pathology

41. DLB or Parkinson’s disease genes
 Glucocerebrosidase (GBA)
 Also called glucosidase, beta, acid
 Function: lysosomal enzyme that breaks down glycolipid
glucosylceramide (GlcCer) to ceramide and glucose
 Mutations in both alleles cause Gaucher disease.
 Mutation in one allele raises risk of Parkinson’s disease ~5X.
 Common: ~4-9% of PD patients
 Mechanism: impaired lysosomal degradation of SNCA?

42. DLB or Parkinson’s disease genes
 LRRK2
 Leucine-rich repeat kinase 2
 Function: cytoskeleton, synapses, dopamine, and autophagy
 Dominant, missense variants affect PD risk
 Most common PD risk variants: ~7-20% of PD
 May explain 1-5% of sporadic PD
 Incomplete penetrance
 These variants ~double the risk
 G2019S: common in Europeans but rare in Asians
 G2385R, R1628P: rare in Europeans but ~8% each in Asian PD
 Some variants may reduce the risk
 N551K, R1398H form a protective haplotype

43. DLB or Parkinson’s disease genes
 Recessive PD genes
 Parkin
 Most common recessive PD gene
 4-9% of early onset PD
 Function: protein degradation
 PINK1 and DJ-1
 Each ~1% of early onset PD
 Function
 Bind each other and protect against oxidative toxicity
 PINK1 activates parkin

44. DLB or Parkinson’s disease genes

45. Tauopathies
 Tau stabilizes microtubules in neuronal axons,
thus it is important for structure of and
intracellular transport in long neurons.
 In tauopathies, tau is aggregated in neurons.
 Examples
 AD: the most common tauopathy
 Tau is hyperphosphorylated in aggregates.
 Aggregates are called neurofibrillary tangles.
 Frontotemporal lobal dementia (FTLD)
 Progressive supranuclear palsy (PSP)
 Others

46. Tau protein
http://www.ebi.ac.uk/
• Tau is a microtubule associated
protein.
• It has an unusual, elongated
structure and is very stable (can be
boiled).
• If microtubules are like bamboo
scaffolding outside buildings, tau is
like the rope or plastic strip that ties
bamboo together to stabilize the
structure.
Tau

47. Johnson G V W and Stoothoff W H. J Cell Sci 2004;117:5721-9
©2004 by The Company of Biologists Ltd
Tau isoforms

48. Tauopathies
 Progressive supranuclear palsy
 Loss of balance, mild dementia
 ~0.006% prevalence
 Tau variants
 Mutations can cause PSP
 H1 haplotype increases risk
 80% of Europeans and 99% of East Asians, thus
not major factor here
 Lower expression of tau isoform containing N-
terminal inserts

49. Tauopathies
 Frontotemporal lobal degeneration (FTLD)
 Prevalence
 A common dementia: ~0.01% prevalence in developed countries
 ~0.02% of ages 45-65
 Phenotype
 Executive dysfunction, semantic dementia, or aphasia
 Often with psychiatric symptoms: apathy, paranoia, disinhibition
 Often with parkinsonism or motor neuron disease (MND or ALS)
 Some patients have AD symptoms but FTLD pathology and mutations.

50. Tauopathies
 Frontotemporal lobal degeneration (FTLD)
 Pathology
 Frontal and temporal lobes shrunken
 Intraneuronal aggregates of different proteins distinguish 3
subtypes
 FTLD-tau: tau protein (in Pick bodies)
 FTLD-TARDBP: TARDBP protein
 FTLD-FUS: FUS protein
 Genetics
 High genetic contribution
 Several genes known
 Same mutation may cause
different symptoms

51. FTLD genes
 FTLD genes
 Gray: unknown
 MAPT: tau
 TARDBP: TAR DNA-binding protein (<1% of
patients)
 GRN: progranulin
 C9orf72: C9 open reading frame 72
 VCP: valosin-containing protein
 CHMP2B: charged multivesicular body protein 2B
 SQSTM1: sequestosome-1
 UBQLN2: ubiquilin 2
relative frequency of mutations

52.  Tau
 Some mutations increase ratio of 4R to 3R tau.
 3R tau inclusions called Pick bodies.
 4R tau sticks to microtubules more and aggregates easier than 3R.
 TARDBP: TAR DNA-binding protein
 Codes for TDP-43 protein
 Transcription regulator
 RNA splicing and stability
 GRN
 Codes for progranulin protein
 Cleaved to granulin peptides
 Neurotrophic factor
 Mutations mostly nonsense: haploinsufficiency
 TDP-43 inclusions
FTLD genes: tau, TDP-43, GRN

53.  C9orf72: C9 open reading frame 72
 Unknown function (maybe to regulate membrane traffic)
 Mutations are expansion of a nucleotide repeat.
 In Intron 1
 Hexanucleotide GGGGCC (G4C2)
 Expansion from <~30 to >~300 repeats
 Different tissues may have different expansions since expansions unstable.
 Might not detect expansion in blood or other tissue.
 Might explain why different patients with same mutation may have different symptoms.
FTLD genes: C9orf72

54.  C9orf72: C9 open reading frame 72
 Unknown function (maybe to regulate membrane traffic)
 Mutations are expansion of a nucleotide repeat.
 In Intron 1
 Hexanucleotide GGGGCC (G4C2)
 Expansion from <~30 to >~300 repeats
 Different tissues may have different expansions since expansions unstable.
 Might not detect expansion in blood or other tissue.
 Might explain why different patients with same mutation may have different symptoms.
 Many other brain diseases are due to repeat expansion.
 Dipeptide repeat (DPR) proteins
 Abnormal translation of repeat expansion
 Repeat-associated non-ATG dependent translation (RAN translation)
 Sense or antisense: (Gly-Arg)n, (Gly-Pro)n, (Gly-Ala)n, (Pro-Arg)n, (Ala-Pro)n
 Toxicity
 RNA: highly stable guanine quadruplexes (G-quadruplexes)?
 Loss of function: less C9orf72 function?
 Gain of function: DPR aggregates in neurons?
 Arg peptides: in nucleoli; transcriptional dysregulation
 Antisense oligonucleotides reduce toxicity
FTLD genes: C9orf72

55. FTLD genes: C9orf72
Lancet Neurol 2015; 14: 291–301

56.  C9orf72: C9 open reading frame 72
 Some patients have TDP-43 inclusions.
 Mutations can also cause ALS (motor neuron disease) with FTD.
FTLD genes: C9orf72

57.  VCP: valosin-containing protein
 Codes for VCP
 Very abundant: 1% of total cellular protein
 Targets substrates for degradation by ubiquitin
 Mutations may disturb protein degradation.
 Missense mutations cause inclusion body myopathy with Paget's
disease of bone and frontotemporal dementia (IBMPFD)
 Muscle weakness (Inclusion body myopathy-IBM)
 Osteolytic bone lesions (Paget's disease of bone-PDB)
 Neurodegeneration (FTD)
 TDP-43 inclusion
FTLD genes: VCP

58.  CHMP2B: charged multivesicular body protein 2B
 Involved in protein degradation
 Mutations may disturb protein degradation.
 SQSTM1: sequestosome-1
 Codes for p62
 Regulates cell survival
 Suppresses autophagy
 Mutations may cause IBMPFD.
 UBQLN2: ubiquilin 2
 Mutations cause ALS-FTLD.
 Mutations are very rare.
FTLD genes: others

59. Protein aggregation in dementia
 Many neurodegenerative diseases due to proteins aggregating
and spreading in brain
 Analogies: prions or crystals or seeds
 Mutations change protein sequence or raise protein level to
increase aggregation
 Examples
 AD
 Aβ
 Tau
 DLB and PD: SNCA
 FTLD
 TDP43
 Tau

60. Thank youThank you
The end