ALZHEIMER DISEASE AND IT'S GENETICS

1. ALZHEIMER’S DISEASE AND
GENETICS
Genetic mutations and Role of genetic risk factors involved in the
manifestation of Alzheimer’s Disease
AKRETI TANDON
18/5432
Department of Biochemistry,
Deshbandhu College

2. INDEX
1. INTRODUCTION
2. DISCOVERY OF ALZHEIMER’S DISEASE
3. AMYLOID CASCADE HYPOTHESIS
4. TYPES OF ALZHEIMER’S DISEASE
5. APOE4 allele - A genetic risk factor
6. HALLMARK OF AD - Aβ PLAQUES
7. APP ,PSEN 1 , PSEN 2
8. RARE GENETIC RISK FACTORS
FOR ALZHEIMER’S DISEASE
9. RECENTLY IDENTIFIED GENETIC
VARIANTS FOR AD PATHOLOGY
10. CRISPR nanoparticle

3. INTRODUCTION
● Dementia is a group of symptoms associated with
decline in mental abilities and cognitive functions
including perception, attention, memory and
logical reasoning severe enough to reduce a
person’s ability to perform everyday activities
● AD, the most common form of Dementia is a
progressive neurodegenerative disorder
characterized by selective neuronal loss in the
hippocampus and temporal cortex.
● AD is associated with idiosyncratic pathologies like
neurofibrillary tangles (NFTs) - created by hyper
phosphorylated Tau protein and senile plaques
due to deposition of β- Amyloid (impaired cleavage
of Amyloid Precursor Protein (APP)).
● NFTs disturb the intracellular traffic and cause the
neuronal degeneration and the pathological
symptoms of Alzheimer’s Disease..
● What is DEMENTIA?
● What is ALZHEIMER’S DISEASE?
● What causes ALZHEIMER’S
DISEASE?
Healthy Brain Severe AD
Brain

4. Discovery of Alzheimer’s
Disease
Alzheimer’s disease is named after Dr. Alois Alzheimer.
In 1906, Dr. Alzheimer noticed changes in the brain tissue
of a woman who had died of an unusual mental illness.
Her symptoms included memory loss, language problems,
and unpredictable behavior. After she died, he examined
her brain and found many abnormal clumps (now called
amyloid plaques) and tangled bundles of fibers (now
called neurofibrillary, or tau, tangles).

5. ‘Amyloid Cascade
Hypothesis’ of AD etiology
Hypothesis- Increased production/decreased
elimination of the Aβ peptide is the trigger
initiating a series of events ultimately leading to
the pathology and clinical manifestations of AD.
Genetic evidence supporting this hypothesis -
● Many people with Down syndrome develop
AD as they get older, with symptoms
appearing in their 50s or 60s. Researchers
believe this is because they are born with an
extra copy of chromosome 21, which carries
the APP gene.
● Also people with mosaicism for trisomy 21,
or duplications of the APP gene 15 can all
develop AD pathology.

6. TYPES OF
ALZHEIMER’S
DISEASE
● Late-Onset Alzheimer's Disease
● Early-Onset Alzheimer's Disease
● Familial Alzheimer's Disease
EOAD cases <5%
LOAD cases 90-95%
FAD cases <1%
Percentage of patients showing different types
of Alzheimer’s disease based on age of onset

7. ● Rare, representing less than 5 percent of all people with AD.
● Typically manifests between a person’s 30s and mid-60s. Often, they’re in their 40s or 50s when
they’re diagnosed with the disease.
● The three single-gene mutations associated with early-onset Alzheimer’s disease are:
● Amyloid precursor protein (APP) on chromosome 21
● Presenilin 1 (PSEN1) on chromosome 14
● Presenilin 2 (PSEN2) on chromosome 1
Each of these gene mutation plays a role in the breakdown of APP.
★ Impaired cleavage of APP by 𝛃 secretase generates harmful forms of amyloid plaques, a
hallmark of Alzheimer’s disease.
A child whose biological mother or father carries a genetic mutation for one of these three
genes has a 50/50 chance of inheriting that mutation. If the mutation is in fact inherited, the
child has a very strong probability of developing EOAD.
EARLY ONSET ALZHEIMER’S DISEASE (EOAD)

8. LATE ONSET ALZHEIMER’S DISEASE (LOAD)
● Symptoms become apparent to people in
their mid-60s and later.
● 90-95 % of AD cases
● It’s heritability (proportion of disease
vulnerability due to heritable genetic
factors)— estimated between 58% and 79%
● Rarely caused by mutations transmitted in
Mendelian fashion.
● Having a genetic variant of the
apolipoprotein E (APOE) gene on
chromosome 19 does increase a person's risk.
These APOE gene alleles produce slightly
different forms of the protein
Apolipoprotein E

9. ApoE 4/4 - A strong risk factor for Alzheimer’s disease
The APOE gene - involved in making a protein that helps carry cholesterol and other types of fat in
the bloodstream. It has role in the transportation of forms of Aβ including Aβ42. In humans, the
gene for ApoE (APOE) is highly polymorphic. Different APOE alleles have differential effects on
risk of late-onset AD -
● APOE ε3, the most common allele, - neither decreases nor increases risk.
● APOE ε4, 2nd most common allele,
- associated with earlier age of disease onset
- 1 or 2 APOE ε4 alleles increases the risk for Alzheimer's.
- About 25% of people carry 1 copy of APOE ɛ4
- Only 2 to 3 % people carry 2 copies of APO ɛ4
● APOE ε2, relatively rare
- may provide some protection against the disease.
- If Alzheimer's disease manifests with this allele, it usually develops later in
life than it would in someone with the APOE ε4 gene.
Ideogram of human
chromosome 19
showing
cytogenetic
location of APOE
gene

10. APOE ε4 is called a genetic
risk-factor because it increases a
person's risk of developing the
disease. However, inheriting an
APOE ε4 allele does not mean
that a person will definitely
develop Alzheimer's. Some
people with an APOE ε4 allele
never get the disease, and others
who develop Alzheimer's do not
have any APOE ε4 alleles.
A meta-analysis revealed
that female carriers
bearing one APOE4
(Apolipoprotein) allele
cause 4 times higher
possibility for AD than
females homozygous
bearing APOE3.

11. FAMILIAL ALZHEIMER’S DISEASE (FAD) : MENDELIAN FORMS
● FAD makes up less than 1% of all cases of
Alzheimer's and is inherited in a Mendelian
fashion.
● In families that are affected, members of at least
two generations must have had the disease.
● Most people who have EOAD have FAD. 3
genes that cause this fully penetrant, early-onset,
autosomal dominant form of the disease:
amyloid precursor protein (APP), presenilin 1
(PSEN1), and presenilin 2 (PSEN2) were
identified using linkage studies.
A pedigree showing Familial Alzheimer’s
Disease running in a family due to a unique
L250S mutation in PSEN1 gene present on
chromosome 14

12. HALLMARK OF ALZHEIMER’S DISEASE - β AMYLOID
PLAQUES
Pathogenic alterations of these genes all contribute to the increased absolute or
relative production of the Aβ42 version of the amyloid-β [Aβ] peptide
(42-amino-acid–length cleavage product of APP), which is a major constituent
of the plaques that characterize the illness.

13. AMYLOID PRECURSOR PROTEIN
➢ Mutations in the APP gene - currently the 2nd most common cause of
Familial AD.
➢ 24 pathogenic mutations - concentrated near the β-secretase &
γ-secretase cleavage site of APP affect the amount of Aβ produced by
cells. More efficient self assembly as a result of these mutations,
ultimately result in more rapid aggregation of Aβ proteins in the brain.
V717I substitution in APP, occurring near the γ-secretase site, was the
1st described familial AD mutation which has arisen independently in
white, Japanese, and Mexican populations.
Duplication of the APP locus, resulting in increased production &
accumulation of Aβ peptides, causes autosomal dominant early-onset
Alzheimer disease (ADEOAD) with cerebral amyloid angiopathy
(CAA) through a “gene dose” effect.
A673T substitution in APP near the β-secretase cleavage site is recently
discovered mutation in AD patients.
Ideogram of human
chromosome 21
showing
cytogenetic
location of APP
gene

14. PRESENILIN 1
➢ Presenilin 1 - described as the proteolytic subunit of γ-secretase.
➢ Mutations in the PSEN1 gene - most common cause of Familial AD.
➢ 185 pathogenic mutations - majority of these are missense mutations causing
amino acid substitutions in the coding region of the gene, although a few
consist of insertions or deletions of portions of the protein.
➢ The existence of familial-AD families of specific ethnic and geographic
origins containing specific gene mutations-
E280A substitution - Columbian families
G206A substitution - Caribbean Hispanics, mostly originating from Puerto
Rico.
A431E substitution - identified in the state of Jalisco in Mexico
➢ PSEN1 mutations tend to cause the younger age of symptom onset (average
44–46 years)
-

15. PRESENILIN 2
➢ Mutations in PSEN-2 gene - causes rarest form of Familial AD
- tend to have the oldest and most variable age of onset
➢ 8 pathogenic mutations -
N141I substitution - large Volga-German founder effect mutation
(origin of this mutation from German emigrants who settled
near the river Volga in Russia are referred to as the Founders
of this mutation)
- mean age of onset is 54 years
Ideogram of
human chromosome
1 showing
cytogenetic
location of PSEN 2
gene
Auguste Deter , 1st identified Alzheimer Disease
patient is hypothesized to carry this N141I
mutation as she was homozygous for ApoE3, and
that her APP gene had no known AD mutations

16. Genome Wide Association Study (GWAS) & meta -analysis revealed -
➢ 3 novel genes or loci in 2009:
● CLU (clusterin)- ubiquitously expressed chaperone protein, is involved in transport,
aggregation, and clearance of Aβ, and is present in Aβ deposits.
● CR1 (Complement receptor 1) - an inflammatory marker of AD, and possibly protective against
Aβ-induced neurotoxicity. Interestingly, the genetic susceptibility at this locus is probably linked to a
copy-number polymorphism.
● PICALM (phosphatidylinositol binding clathrin assembly protein) - key component of
clathrin-mediated endocytosis is thought to be involved in Aβ clearance, possibly via
endothelial cells.
➢ 6 novel genes in 2011
● ABCA7 (linked to lipid metabolism)
● MS4A6A/MS4A4E (linked to innate immunity)
● EPHA1 (linked to innate immunity)
● CD33 (linked to innate immunity)
● CD2AP(intracellular transport)
● BIN1(linked to pathway of Aβ production and clearance
Other rare genetic factors
linked to AD -
CASS4, CELF1, FERMT2,
HLA-DRB5, INPP5D, MEF2C,
NME8, PTK2B, SORL1,
ZCWPW1, S1C24A4.
RARE GENETIC RISK FACTORS FOR ALZHEIMER’S DISEASE

17. 1) MAPT (microtubule-associated protein tau) gene
- A mutation in this gene causes abnormalities in tau protein, resulting in formation of tau
tangles inside neurons.
- Inheriting a mutation in MAPT gene implies a person will almost surely develop a
frontotemporal disorder.
- A rare coding variant (A152T) in this gene has been associated with the risk of both AD and
FTD (Frontotemporal dementia) in a study involving more than 15,000 subjects.
2) TREM2 (triggering receptor expressed on myeloid cells 2)
- Innate immune receptor expressed on the cell membrane of microglia (which produce APP).
- two recent reports indicated that rare variants in the (TREM2) gene increase the risk for AD.
.
Recently Identified Genetic Variants for AD pathology
Additional possible sources of susceptibility variants that
have not been studied extensively in AD include -
de novo variants, copy-number variation, structural
variation, and mosaicism

18. BUT, What is the whole point to study genetic mutations
involved in the pathogenesis of Alzheimer’s Disease?
❖ Study of the pathways through which these genes (which
might carry mutations) contribute to AD pathology is an
avenue towards the identification of potential therapeutic
targets.
Though, genetic factors are responsible for no more than 10% of all early-onset & only up to
25% of all late-onset AD cases
But, Genes play a strong role in AD pathology as heritability of late-onset AD is 58-79% and
early-onset AD shows over 90%.
To date, AD pathogenesis seems to be related to more than 50 mutations, suggesting that
AD is a disease of multiple components, as supported by analyses of following pathways-
immunity, endocytosis, cholesterol transport, ubiquitination, amyloid-β and tau
processing

19. Hailed as the biggest
biotech discovery of the
21st century, CRISPR has
the ability to cure disease by
directly and permanently
modifying the human genome.
Nanoparticles (encapsulating
CRISPR components)
designed by Korean
researchers has shown
improved cognitive effects in
mice models of AD. These
nanoparticles inhibit Bace 1
gene - which stimulates beta
amyloid production in brain!

20. 1) https://www.nia.nih.gov/health/alzheimers-di
sease-fact-sheet
2) https://www.nia.nih.gov/health/alzheimers-di
sease-genetics-fact-sheet
3) https://www.ncbi.nlm.nih.gov/pmc/articles/P
MC3915548/
4) https://pubmed.ncbi.nlm.nih.gov/26837465/
5) https://www.webmd.com/alzheimers/guide/a
lzheimers-types
6) https://www.jillcarnahan.com/2017/03/26/wil
l-get-alzheimers-disease-apoe/
7) http://www.journalijar.com/article/18534/alzh
eimer/?s-disease:-facts-and-findings.
8) http://depts.washington.edu/mbwc/adrc/pag
e/genetics
9) https://jnnp.bmj.com/content/64/1/44
REFERENCES