Genetics of dementia

Question 1

Amyloid precursor protein

Answer 1

• chromosome 21
• may contribute towards 50% of familial Alzheimers Disease beginning before the age of 60
• related to Downs syndrome and explains the higher prevalence of AD in patients with Down’s syndrome

Question 2

Presenilin 1 and 2

Answer 2

• chromosome 14 and 1 respectively

- may contribute to up to 50% of familial AD

Question 3

Apolipoprotein E

Answer 3

• APOE
• highest risk for AD
• gene is on chromosonme 19q
• has 3 codominant alleles -2, 3 and 4

Question 4

First degree relative of someone with AD (under 85)

Answer 4

• 15-19%

- controls are 5%

Question 5

Dementia over the age of 80

Answer 5

30-50% chance of developing dementia

same regardless of being a relative or not

Question 6

Concordance rates in twins

Answer 6

• concordance rate of 40% for DZ

- 84% for MZ

Question 7

CADASIL

Answer 7

• form of amyloid angiopathy that can present with Alzheimer’s like features
• NOTCH3 is the only gene currently known to be associated with CADASIL
• most mutations are on exon 4
• mutation detection rate is 96% in CADASIL
• defective gene is identified as NOTCH3 in 19p13.1-13.2

Question 8

Frontotemporal lobar degeneration

Answer 8

• show tau protein based pathological changes
• in familial cases, mutations are identified on microtubule-associated protein tau gene (MAT) on chromosome 17q21
• in tau-negative cases ubiquitin-immunoreactive neuronal cytoplasmic inclusions are seen- some mutations have been seen on progranulin PGRN on chromosome 17q21

Question 9

Progranulin

Answer 9

widely expressed growth fasctor that plays a role in wound repair and inflammation by activating signalling cascades in cell cycle
-progranulin has also been linked to tumorigenesis

Question 10

Lewy body dementia

Answer 10

• no specific genetic associations have been established

- synucleinopathy- where synuclein molecules aggregate in presynaptic terminals producing Lewy bodies

Question 11

PARK1 and PARK 4

Answer 11

• 4q21 gene
• responsible for alpha-synuclein
• shows dominant inheritance, not seen in sporadic cases of PD
• onset in 40s
• nigral degeneration with Lewy bodies

Question 12

PARK2

Answer 12

• 6q25
• codes for Parkin gene
• shows recessive inheritance
• nigral degeneration without Lewy bodies
• onset 40-60 (most early onset cases of PD, l-dopa responsive)

Question 13

PARK 8

Answer 13

• 12 cen (pericentromeric)
• LRRK2 gene
• shows dominant inheritence
• onset of PD is around 60
• variable alpha-synuclein and tau pathology

Question 14

PARK 6

Answer 14

• 1p35-37
• PTEN-INduced Kinase (PINK1) in mitochondria
• autosomal recessive; onset 30-40 (1-2% earlky onset PD, l-dopa responsive)

Question 15

PARK 7

Answer 15

-1p38 DJ-1
-Autosomal recessive; onset 30-40
PD