This document provides an overview of Alzheimer's disease (AD), including its history, pathogenesis, genetics, and discussion. The key points are: - AD is a progressive brain disorder that causes memory loss and cognitive decline. It results from amyloid beta plaques and neurofibrillary tangles that damage neurons. - The amyloid cascade hypothesis proposes that amyloid beta formation from amyloid precursor protein cleavage is the key initiating event leading to AD. Aggregation of amyloid beta and tau proteins into plaques and tangles ultimately kills neurons. - Genetic factors like mutations on chromosomes 21, 14 and 1 can cause early-onset familial AD, while the APOE ε4 allele increases risk for late-onset

1. ALZHEIMER'S DISEASE
(AD)
Jinnah University for Women

2. INTRODUCTION &
HISTORY OF ALZHEIMER'S
DISEASE

3. INTRODUCTION
 Alzheimer – neurological disorder in which the
death of brain cells and shrinkage of brain causes
memory loss and cognitive decline.
 Disease starts mild and gets progressively worse.
 Besides memory loss, Alzheimer's patients show;
 Dramatic personality changes,
 Disorientation,
 Declining physical coordination, and
 Inability to care for themselves.
 Leading cause of neurodegenerative type of
dementia (memory loss).

5. INTRODUCTION
 Leading cause of death in developed nations.
 AD victims – dies of infection secondary to AD
(usually pneumonia & UTIs).
 AD is much more prevalent in women.
 AD probably results from the inflammatory
response induced by extracellular Aβ deposits,
which later become enhanced by aggregates of tau.
 Genetic defect in chromosome 21 – leads to AD.

6. INTRODUCTION
 Diagnosed – by the presence of amyloid plaque &
neurofibrillary tangles.
 Incurable – leads to death with avg of 8 years after
diagnosis.
 The last 3 of which are typically spent in an
institution.
 In final stages, victims are confined to bed with lose
urinary and bowel control.

7. HISTORY
 Alois Alzheimer when, in November 1907,
reported – an unusual illness of the cerebral
cortex).
 His paper gives a brief description of the clinical
history in a case of dementia with onset at age
51 and the unique pathological findings of
plaques and tangles.
 The failure to pay much attention to this
hallmark paper continued for a further seven
decades.

8. HISTORY
 The decade from 1982 to 1992 was a
groundbreaking era for unraveling the mysteries of
AD.
 Up to then, age was the only known risk factor.
Below age 65 AD was found to be rare.
 There was no explanation then, nor is there now, as
to why age is so critical.

9. AMYLOID CASCADE
HYPOTHESIS

10. AMYLOID CASCADE HYPOTHESIS
 The amyloid cascade hypothesis is widely accepted
as the centerpiece of Alzheimer disease (AD)
pathogenesis.
 Proposes that key event leading to AD – formation
of amyloid beta (beta amyloid, Aß).
 Aß clusters into amyloid plaques – on the blood
vessels and on the outside surface of neurons –
ultimately leads to the killing of neurons.

11. AMYLOID PRECURSOR PROTEIN (APP).
 The amyloid beta peptide is created by enzyme
cleaving of the normal neuron membrane protein
known as Amyloid Precursor Protein (APP).
 Natural neuro-protective agent.
 Cleaved by various types of secretases such as α,
β and γ.

12. APP
α secretase
No Aß
formation
No amyloid
clump
β secretase
γ
secretase
Cleavage on
trans-Golgi
network
Aß 40
(mostly
harmless &
soluble)
Cerebrovascu
lar plaques
Cleavage on
E.R
Aß 42
(insoluble &
clumps
together)
Neuritic
Amyloid
plaque
cleavage
Cleavage Of Amyloid Precursor Protein

13. DEATH OF NEURONS
 Following amyloid
plaque formation two
processes play an
important role in
causing the death of
neurons:
1. Inflammation and
oxidative damage,
and
2. NeuroFibrillary
Tangles (NFTs).

14. INFLAMMATION AND OXIDATIVE DAMAGE
 The two major types of brain cells that participate in
the inflammatory response are astrocytes &
microglia.
 Produces damaging free radicals and lead to the death of
neurons.
 Oxidative damage to DNA – caused by reactive
oxygen species (ROS)
 produced by irradiation or by metabolic bi-products.
 Most prominent biomarker of oxid8ative damage is
8-oxo-hydroxyoxyguanosine.
 Levels of 8-OHdG are 18 times higher in CSF of
Alzheimer's Disease individuals than normal.

15. NEUROFIBRILLARY TANGLES (NFTS).
 Tau – important protein that stablizes
microtubules of neurons by binding to
them.
 But in AD the tau proteins become
hyper-phosphorylated – lose the
capacity to bind to microtubules of
brain cells.
 The phosphorylated tau proteins - bind
to each other, tying themselves in
"knots" known as NeuroFibrillary
Tangles (NFTs).
 Neurons full of NFTs rather than
functional microt ubules soon die.

16. CASCADE
APP
Aß42
Amyloid
plaques
Inflammation,
oxidative
damage and
NFTs
Neuron
death

17. ALZHEIMER'S DISEASE
GENETICS

18. ALZHEIMER'S DISEASE GENETICS
 Alzheimer's disease is an
irreversible, progressive brain
disease.
 It is characterized by the
development of amyloid plaques
and neurofibrillary tangles, the loss
of connections between nerve
cells, or neurons, in the brain, and
the death of these nerve cells.
 There are two types of Alzheimer's-early-
onset and late-onset. Both
types have a genetic component

19. EARLY-ONSET ALZHEIMER'S DISEASE
 Early-onset Alzheimer's disease occurs in people
age 30 to 60.
 It is rare, representing less than 5 percent of all
people who have Alzheimer's.
 Most cases are inherited, a type known as familial
Alzheimer's disease (FAD).
 Familial Alzheimer's disease is caused by any one
of a number of different single-gene mutations on
chromosomes 21, 14, and 1. Each of these
mutations causes abnormal proteins to be formed.

20. Mutations
Chromosome
21
Abnormal
amyloid
precursor
protein (APP).
Chromosome
14
Abnormal
presenilin 1 to be
made,
Chromosome
1
Abnormal
presenilin 2
formation
 These mutations plays a role in the breakdown of
APP – generates harmful forms of amyloid
plaques, a hallmark of the disease.
 A child whose mother or father carries a genetic
mutation for FAD has a 50/50 chance of inheriting
that mutation.

21. LATE-ONSET ALZHEIMER'S DISEASE
 Most cases of Alzheimer's are the late-onset form i.e
develops after age 60.
 Causes – not yet completely understood,
 But they likely include a combination of
 genetic,
 environmental, and
 lifestyle factors
that influence a person's risk for developing the disease.
 Single-gene mutations – not seem to be involved in late-onset
Alzheimer's.
 Researchers have not found a specific gene that causes
the late-onset form of the disease.
 However, one genetic risk factor does appear to
increase a person's risk of developing the disease.

22. LATE-ONSET ALZHEIMER'S DISEASE
 This increased risk is related to the apolipoprotein E
(APOE) gene found on chromosome 19.
 APOE makes a protein that helps carry cholesterol and
other types of fat in the bloodstream.
 APOE comes in several different forms, or alleles.
 Three forms occur most frequently
1. APOE ε2,
2. APOE ε3,
3. APOE ε4
 APOE ε2 is relatively rare and may provide some
protection against the disease. If Alzheimer's disease
occurs in a person with this allele, it develops later in life
than it would in someone with the APOE ε4 gene.

23. LATE-ONSET ALZHEIMER'S DISEASE
 APOE ε3, the most common allele – play a neutral role
in the disease – neither decreasing nor increasing risk.
 APOE ε4 is called a risk-factor gene because it
increases a person's risk of developing the disease.
 APOE ε4 is present in about 25 to 30 percent of the
population and in about 40 percent of all people with
late-onset Alzheimer's. People who develop Alzheimer's
are more likely to have an APOE ε4 allele than people
who do not develop the disease.
 However, inheriting an APOE ε4 allele does not mean
that a person will definitely develop Alzheimer's.

24. METAL TOXICITY & FREE
RADICALS

25. METAL TOXICITY & FREE RADICALS
 Epidemiological studies -- indicated a correlation of
aluminum in drinking water with the prevalence of
AD,
 Whereas studies of aluminum occupational
exposure and aluminum in antacids have shown no
correlation
 Aluminum concentration is elevated in NFTs &
amyloid plaques, but this may be an effect of AD
rather than a cause.
 Mercury is also elevated in the AD brain.

26. METAL TOXICITY & FREE RADICALS
 Zinc, copper & iron — all of which are enriched in
amyloid-beta plaques in AD.
 All three metals lead to Aß aggregation, but
chelation can completely reverse metal-induced
precipitation of Aß
 Copper particularly mediates Aß toxicity, whereas
zinc inhibits toxicity
 Aß is not toxic to neurons in the absence of Cu2+
 Aß converts Cu2+ and Fe3+ to Cu+ and Fe2+, both of
which generate free radicals.

27. METAL TOXICITY & FREE RADICALS
 Fe3+ induces aggregation of phosphorylated NFTs,
but this aggregation can be reversed by reducing
Fe3+ to Fe2+
 Copper & iron in these plaques generate hydrogen
peroxide leading to oxidative damage.
 Membranes containing oxidatively damaged
phospholipids also promote amyloid ß-sheet
formation

28. METAL TOXICITY & FREE RADICALS
 Amyloid-beta aggregation by acidic conditions and
by copper, iron, zinc & aluminum results - the highly
toxic ß-sheets.
 Copper binds more strongly to Aß42 than to Aß40
and copper is a greater catalyst of free radical
formation than are the other metals

29. DISCUSSION

30. DISCUSSION
 AD not gained universal support, for more than 20
years – since the amyloid cascade hypothesis was
first put forward.
 Because of many unsuccessful attempts to develop
disease-modifying treatments.
 One problem – failure to recognize that it is the
inflammatory response to Abeta deposits, and later
cortical tau aggregation, which drives the
pathology.
 Etiology and pathogenesis of AD – not fully
understood, but several factors have been
implicated in the progression of AD.

31. DISCUSSION
 Among these factors – oxidative stress has been
shown to be involved in AD pathogenesis.
 Biomarkers of oxidative damage in DNA are highly
expressed in patients with AD.
 Accumulation of DNA damage and the impairment
of its repair mechanism is a prominent feature of
AD.
 Although additional studies are required to better
understand the pathogenic mechanisms, especially
the early stages of AD

32. DISCUSSION
 Early administration may be the key to success.
Such agents are relatively safe and highly
available.
 Recent biomarker studies indicate that disease
onset commences as much as 10–15 years before
clinical symptoms become manifest.
 If simple methods of preclinical diagnosis can be
achieved, a 10-year window may exist for
measures to be instituted that prevent, delay, or
ameliorate the disease.

33. DISCUSSION
 NSAIDs and ibuprofen, provide the best practical
opportunity for therapeutic management of this
principle.
 Ibuprofen and related NSAIDs – widely used for the
relatively minor condition of osteoarthritis,
 Shown to reduce the risk of AD in multiple
epidemiological studies.
 Also – reduce the pathology in even more
numerous transgenic mouse models of AD.

34. THANK YOU!!!