2. Alzheimer’s disease: Causes and treatments
o What causes Alzheimer’s disease?
1. Genetics?
There is a form of AD known as ‘familial Alzheimer’s disease’ – genetic risk factors
Very rare but more common in early onset cases.
The effects on the brain are almost indistinguishable from ‘normal’ AD.
It has a clear genetic basis.
Every cell in the body contains 23 pairs of chromosomes in its nucleus.
One member of each pair is inherited from the mother, the other from the father.
Chromosomes contain our DNA (de-oxyribose nucleic acid).
A gene is a section of DNA. A typical chromosome contains
1-2,000 genes. Most genes contain the instructions for manufacturing a specific
protein -> the total of all our genes is the genome (mapped in 2003)
We have two copies of most genes: one from mother, one from father.
Often, only one of the two copies is active (‘expressed’).
Mutations occur when a gene is copied incorrectly. If the mutant gene is
dominant, its effects will be seen in the organism (‘phenotype’).
If the gene is recessive, its effects will only be seen in a person who inherits two copies
of the faulty gene, one from each parent. People with one copy are healthy “carriers”.
Familial Alzheimer’s disease is associated with mutations to 3 different genes.
They all show a pattern of autosomal dominance, i.e., if you inherit a mutant gene
from either parent, you will develop early Alzheimer’s disease.
Children will have a 50% chance of inheriting the faulty gene, and therefore
developing AD.
Familial Alzheimer’s: What percentage of people with AD? 2%
Familial Alzheimer’s: What percentage of people with early-onset AD (before aged
65)? 50%
The genes responsible for familial AD are found on 3 different chromosomes.
presenilin 1 (PS1) on chromosome 14
presenilin 2 (PS2) on chromosome 1
amyloid beta A4 precursor protein (APP) on chromosome 21
Each of these mutations causes a build-up of amyloid plaques in the brains of
affected individuals + the destruction of neurons by the new 52 tangles
Genetic testing can identify whether an individual is carrying a mutant form of one
of the genes responsible for familial AD (and will therefore develop AD).
Remember: An individual carrying a mutation knows that if they have children, each child has a
50% chance of inheriting familial AD.
Late onset AD
For the more common, late onset form of AD, having other family members with AD increases the
probability of developing the disease, but only by a small amount.
One gene has been implicated so far – apolipoprotein E (APOE), discovered in 1993. It is situated
on chromosome 19 and comes in 3 forms (APOE2, APOE3 and APOE4).
One copy of APOE4 increases the risk of late onset AD by about 4 times.
Two copies increase the risk about 10-20 times.
But some people with even 2 copies of APOE4 do not develop AD.
What is frequency of APOE4 in AD? 35%
NB: APOE4 allele = 14% in general population. So, frequency must be higher than that...
2. Environmental factors / lifestyle?
a. Diet: Gu et al. (2010) Archives of Neurology, 67, 699-706.
Analysed diets of 2,148 people aged over 65 years in New York.
After 4 years, 253 people (12%) had developed dementia.
Reduced risk with higher “Mediterranean diet”: higher in chicken, fish, salad, nuts, fruits, and
vegetables (whole foods), lower in red meat and butter.
Moderate intake of alcohol may also protect against AD.
o What causes Alzheimer’s disease?
1. Genetics?
There is a form of AD known as ‘familial Alzheimer’s disease’ – genetic risk factors
Very rare but more common in early onset cases.
The effects on the brain are almost indistinguishable from ‘normal’ AD.
It has a clear genetic basis.
Every cell in the body contains 23 pairs of chromosomes in its nucleus.
One member of each pair is inherited from the mother, the other from the father.
Chromosomes contain our DNA (de-oxyribose nucleic acid).
A gene is a section of DNA. A typical chromosome contains
1-2,000 genes. Most genes contain the instructions for manufacturing a specific
protein -> the total of all our genes is the genome (mapped in 2003)
We have two copies of most genes: one from mother, one from father.
Often, only one of the two copies is active (‘expressed’).
Mutations occur when a gene is copied incorrectly. If the mutant gene is
dominant, its effects will be seen in the organism (‘phenotype’).
If the gene is recessive, its effects will only be seen in a person who inherits two copies
of the faulty gene, one from each parent. People with one copy are healthy “carriers”.
Familial Alzheimer’s disease is associated with mutations to 3 different genes.
They all show a pattern of autosomal dominance, i.e., if you inherit a mutant gene
from either parent, you will develop early Alzheimer’s disease.
Children will have a 50% chance of inheriting the faulty gene, and therefore
developing AD.
Familial Alzheimer’s: What percentage of people with AD? 2%
Familial Alzheimer’s: What percentage of people with early-onset AD (before aged
65)? 50%
The genes responsible for familial AD are found on 3 different chromosomes.
presenilin 1 (PS1) on chromosome 14
presenilin 2 (PS2) on chromosome 1
amyloid beta A4 precursor protein (APP) on chromosome 21
Each of these mutations causes a build-up of amyloid plaques in the brains of
affected individuals + the destruction of neurons by the new 52 tangles
Genetic testing can identify whether an individual is carrying a mutant form of one
of the genes responsible for familial AD (and will therefore develop AD).
Remember: An individual carrying a mutation knows that if they have children, each child has a
50% chance of inheriting familial AD.
Late onset AD
For the more common, late onset form of AD, having other family members with AD increases the
probability of developing the disease, but only by a small amount.
One gene has been implicated so far – apolipoprotein E (APOE), discovered in 1993. It is situated
on chromosome 19 and comes in 3 forms (APOE2, APOE3 and APOE4).
One copy of APOE4 increases the risk of late onset AD by about 4 times.
Two copies increase the risk about 10-20 times.
But some people with even 2 copies of APOE4 do not develop AD.
What is frequency of APOE4 in AD? 35%
NB: APOE4 allele = 14% in general population. So, frequency must be higher than that...
2. Environmental factors / lifestyle?
a. Diet: Gu et al. (2010) Archives of Neurology, 67, 699-706.
Analysed diets of 2,148 people aged over 65 years in New York.
After 4 years, 253 people (12%) had developed dementia.
Reduced risk with higher “Mediterranean diet”: higher in chicken, fish, salad, nuts, fruits, and
vegetables (whole foods), lower in red meat and butter.
Moderate intake of alcohol may also protect against AD.
