The Genetics
Of
Alzheimer’s
Sue Griffin, PhD
Dillard Professor and Vice Chair
Donald W. Reynolds
Department of Geriatrics
University of Arkansas
For Medical Sciences
Research Director
GRECC VAMC
Little Rock, Arkansas

Genes are on chromosomes present in the nucleus of every cell

The genetic code has four letters:
A=adenine, T=thymine, G=guanine, C=cytosine

Chromosomes in the nucleus
The yellow ribbon is held together by A — T and C — G

Chromosomal
DNA (genes) carry the code for all proteins necessary to make our body

Facts:
• A complementary strand (messenger RNA) is made to nuclear DNA—an A on the mRNA is paired with a T on the gene and C with G, over and over to code for the building blocks (amino acids) needed to make every protein!
• Every amino acid has a unique code

Diversity of Genetic Diseases
Simplistic:
• One gene mutation causes every case.
More Complex:
• Multiple gene mutations cause all cases.
Most Complex:
• Multiple gene mutations cause some cases.
• Multiple polymorphisms increase risk.
• Multiple environmental factors increase risk.

• The genes you inherit (nature)
• Wear and tear of time (aging)
• The way you handle your inheritance (nurture)

When You’re
Old but Okay

Nerve Cells and
How They Work
In Normal Brain
• The nucleus
• The cytoplasm
• The processes
• The transmission of information

When your brain is hot and fine

Progression from Hearing to
Speaking and from Reading to
Mulling It All Over

Affected Regions at Different
Stages of Alzheimer’s Disease
MILD MODERATE SEVERE

When the Brain “Cools Down”
Clincally Normal Alzheimer’s disease

The Problem in
Alzheimer’s
Disease from
One of His
Own Cases
MB Graeber 1997 Neurogenetics

*
Plaques in Alzheimer Brain
10 µm
Aβ plaques, activated glia, neuronal DNA

What is that sticky insoluble stuff in plaques?
• The b -pleated sheet protein b -amyloid (A b )
• George Glenner sequenced the protein and Konrad
Beyreuther, Dmitry Goldgaber, and St. George-Hyslop and colleagues mapped the A b precursor protein
( b APP) gene to chromosome 21
• This is important!!

b APP is Cleaved to Form b
-amyloid
Functions of b
APP
• Responds to injury
• Membrane Functions
• Interacts with PS1

Reasoning Behind This Discovery?
Fact:
• People with Trisomy 21 have Alzheimer A b plaque pathology by middle age (Wisniewski, 1989)
Hypothesis:
• Plaques in Down’s as in Alzheimer’s are the product of b APP cleavage, so it’s logical that mutations in b APP cause the disease in families with lots of Alzheimer’s. Tanzi and others took this candidate gene approach (Plan A in genetic studies).

Plan A
Sequence a Specific Gene
Studies of Alzheimer families that were based on a pathological characteristic of the disease
• Because A b plaques were the most prominent neuropathological feature, b APP was the targeted gene in AD in these families.
• At least three offending b APP mutations in DNA from family members have been identified by searching for mutations by mapping of this gene.

b
. . How did we come to know this??

But that was only 1989 and . . .

Family Association Studies
• Then they asked: Do all family members with the mutation have the disease? Yes
• Do family members who don’t have the mutation have the disease? No (Maybe?)
If yes on the first and no on the second = Disease associated,
Causative, and Dominant!

Not all familial Alzheimer’s disease families have mutations in this gene
And all of the known b APP mutations taken together don’t account for all of the people (>5%) with familial Alzheimer’s

So Plan B - Mapping Studies -
Identified Two Other Causative Genes
• Taking a more unbiased approach—that is, not looking for a missense sequence in a specific protein—researchers used endonucleases to cleave DNA for restriction fragment length polymorphism (RFLP) studies to identify aberrant cleavage sites. This type of chromosome mapping, identified two more mutated genes (Presenilin-1 and -2) that, like b APP mutations, are causative for Alzheimer’s disease.

Notes on RFLP Studies
• Restriction endonucleases are enzymes that cleave DNA at specific sites.
• Absence of a cleavage site can be used to identify a missense or mutated site

Plan B Also Identified one of three
Apolipoprotein E polymorphisms ( e 4)
Associated with Increased Alzheimer Risk
• RFLP mapping of DNA from a case control study identified a chromosome 19 region that associated with, but not causative of , Alzheimer’s disease. The variant was ApoE e 4.

Several in the b APP Gene
Presenilin 1 and 2 Genes
b APP e.g. Down’s syndrome
Apolipoprotein E Genes
Inflammatory Genes

ApoE Facts
• ApoE is important in transport of lipoproteins.
But its specific role in neurons is unknown.
• There are three variants— e 2, e 3, and e 4.
• The ApoE ε 4 gene carries a high relative risk:
• Inheritance of e 4 increases Alzheimer risk 3-9X.
• More than half of Alzheimer patients have one or more e 4 alleles.
• Inheritance of the e 2 allele may be protective.

Some ApoE 2, 3, and 4 Facts
These isoforms differ from each other only by single amino acid substitutions at positions 112 and 158 of the 299 amino acid protein but have profound physiological consequences.
E2 is uncommon but is associated with both increased and decreased risk for atherosclerosis. Approximately 64 percent of the population carries one or two E3 genes. E3 is the
"neutral" Apo E genotype. E4 has been implicated in atherosclerosis and Alzheimer's disease, impaired cognitive function, and reduced neurite outgrowth.
ApoE is a target gene of liver X receptor, a nuclear receptor member that plays a role in metabolic regulation of cholesterol, fatty acid, and glucose homeostasis. Look in Wikipedia

b APP is Cleaved to Form b
-amyloid
Functions of b
APP:
• Expression increases in response to injury and in aging
• Membrane Functions
• Interacts with PS1

ApoE Regulates b APP Expression
Neurons
In Culture
ApoE3 ApoE4
Alzheimer
Brain

Plaque proximity = less neuronal b APP
A b b
APP Nuclei

One Important Driver

What Does IL-1 Do?
• To Neurons
Increases production of: i) b APP ii) Faulty tau (hyperphosphorylated) iii) Enzymes that breakdown neurotransmitters
Decreases production of: i) synaptophysin

Neurofibrillary
Tangles
(red)
IL-1 in
Microglia
(green)

a
1.TNF and IL-1 are both elevated in Alzheimer’s disease.
2. They induce each other and act as neuroinflammagens.
3. Both act as gliotransmitters.

Are their heritable variants of the genes that encode these drivers that might increase risk for Alzheimer’s disease?

IL-1 Genotype and Age at
Alzheimer’s Onset
Factor Odds Ratio
ApoE e
4 5.5
IL-1A 2,2 4.9
Grimaldi, Griffin, et al. Ann Neurol, 2000

1. Breitner JC et al Neurology 1994;44:227
2. in ’t Veld BA et al Neurobiol Aging 1998;19:607
3. Zandi PP et al Neurology 2000;54:2066
4. Vlad SC et al Neurology 2008;70:1672
5. Szekely, C. A. Neurology 2008;70:17

Adjusted odds ratios of Alzheimer’s for ibuprofen ( ) and naproxen ( )

• Prevention:
Exercise
Diet and Stop Smoking
Combat Inflammation
• Treatment:
Education and Cognitive Reserve
Meds: Aricept, Namenda

We are our genes

But we get to decide what we do about our genetics!