Genetics of dementia

Question 1

genetic variants

Answer 1

Common, alterations in the most common DNA nucleotide sequence

Question 2

Genetic mutations

Answer 2

Rare, faulty genes leading to greater harm

Question 3

Early onset Alzheimer’s

Answer 3

Familial clustering caused by a single gene mutation

Question 4

Genes causing Alzheimer’s

Answer 4

• Amyloid protein production causes pathogenesis
• PSEN-1: chromosome 14, sx as early as 30
• PSEN-2: chromosome 1, starts later than PSEN-1
• APP: chromosome 21, affects production of beta-amyloid

Question 5

Late onset Alzheimer’s

Answer 5

Inheritance is usually due to a large amount of genetic variation

Question 6

APOE and Alzheimer’s

Answer 6

• APOE: chromosome 19, we have 2 copies and the combination of APOE e2/e3/e4 determines our risk of AD
• APOE e4: higher risk, increased risk by 2x, tend to get at younger age
• APOE e3: average risk
• APOE e2: lower risk

Question 7

CADASIL

Answer 7

mutations in NOTCH3 (found in vascular smooth muscle, promotes cell survival), inherited in a simple, single-gene patterncerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy → familial dementia

Question 8

Genetic cause of CADASIL

Question 9

Sx vascular dementia

Answer 9

Migraines, strokes, progression to dementia

Question 10

Familial frontotemporal dementia genetics

Answer 10

• <30% caused by single gene mutation
• C9ORF72: links to FTD and MND
• MAPT: gene for protein tau
• GRN: gene for protein progranulin
• Risk genes for non-familial include TMEM109B

Question 11

Familial dementia with Lewy bodies

Answer 11

• No mutations identified so far

- Risk genes: APOE e4, GBA and SNCA (also play a role in Parkinson’s disease)

Question 12

What are api-genes

Answer 12

characterised their ability to alter transcription (turn genes on or off) by adding chemical compounds

Question 13

DNA methylation

Answer 13

• Methyl added to CpG site (cytosine next to guanine and linked by a phosphate)
• Methylation silences gene

Question 14

Histone modifications

Answer 14

• If histones are modified, they can determine whether the associated chromosomal DNA will be transcribed
• Methylation: adding a methyl group to amino acid lysine
• Acetylation: adding acetyl group to lysine (acetylation → active chromatin, deacetylation → heterochromatin)