Definition Statistics of AD A brief introduction Signs and symptoms of AD NMDA receptors Classification Causes Risk Factors Pathophysiology AD… The great unknown Treatment Options Future Trends

1. ALZHEIMER’s DISEASE

2. Contents
 Definition
 Statistics of AD
 A brief introduction
 Signs and symptoms of AD
 NMDA receptors
 Classification
 Causes
 Risk Factors
 Pathophysiology
 AD… The great unknown
 Treatment Options
 Future Trends

3. Definition
“A progressively degenerative neurological
disorder leading to dementia with increasing
mental confusion, emotional instability, and
premature death.”

4. Statistics of Alzheimer’s disease:
• Generally, it is diagnosed in people over
65 years of age, although the less-prevalent
early onset of Alzheimer’s can occur much
earlier.
• In 2006, there were 26.6 million sufferers
worldwide.
• Alzheimer’s is predicted to affect 1 in 85
people globally by 2050.

5. A Brief Introduction
Alzheimer’s is the most common cause of
dementia in adult life and is associated with the
selective damage of brain regions and neural
circuits critical for memory and cognition
The pathogenesis of this disease is complex, and
involves many molecular, cellular, and
physiological pathologies
The neurons in the neocortex, hippocampus,
amygdala, and the basal forebrain cholinergic
system are the most affected brain regions.

6. Signs & Symptoms:
• Memory loss for recent events
• Progresses into dementia  almost total
memory loss
• Inability to converse, loss of language ability
• Affective/personality disturbance
• Death from opportunistic infections, etc.

7. Alzheimer’s Disease:
Postmortem Analysis
normal advanced Alzheimer’s

9. Stages:

10. NMDA receptors
Definition
“The N-methyl-D-aspartate receptor (also
known as the NMDA receptor or NMDAR)
A glutamate receptor
Predominant molecular device for controlling
synaptic plasticity and memory function.”

11. NMDA receptors
Introduction
 The NMDAR is a specific type of ionotropic glutamate
receptor.
 NMDA (N-methyl-D-aspartate) is the name of a
selective agonist that binds to NMDA receptors but not
to other 'glutamate' receptors.
 Activation on the opening of an ion channel that is
nonselective to cations with an equilibrium potential
near 0 mV.
 A property of the NMDA receptor is its voltage-
dependent activation, a result of ion channel block by
extracellular Mg2+ & Zn2+ ions.

12. This allows the flow of Na+ and small amounts of
Ca2+ ions into the cell and K+ out of the cell to be
voltage dependent.
Calcium flux through NMDARs is thought to be
critical in synaptic plasticity, a cellular mechanism
for learning and memory.
The NMDA receptor is distinct in two ways:
1. First, it is both ligand-gated and voltage-
dependent;
2. Second, it requires co-activation by two ligands:
glutamate and either d-serine or glycine.

13. NMDA receptors

14. Classification:
(1) FAD v SAD:
(2) Familial AD versus Sporadic AD
(2) Early v Late Onset:
• Early onset = usually before 65
• Early onset correlated with FAD
• LOAD = late onset AD

15. Causes of AD
Multiple causes for Alzheimer's disease
Some causes may not have been discovered
yet. In fact, the causes for any given person
vary greatly and are difficult to determine.
However, researchers have come up with a list
of risk factors that may make a person more
likely to develop Alzheimer's disease.

16. Similarly, researchers have identified factors
that decrease the risk of developing
Alzheimer's disease. And finally, researchers
have ruled out certain popular myths about
what causes the disease.
Genetic and environmental factors are the
major contributors.

17. Risk Factors
• Age
 Primary risk factor for Alzheimer's disease. The
number of cases of Alzheimer's disease doubles
every 5 years beyond age 65.
 According to the U.S. Alzheimer’s Association, 1 in 8
people age 65 and older have Alzheimer’s disease.
About 6% of people age 65 to 74 have Alzheimer’s
and nearly half (45%) of people age 85 years and
older have the disease.
 While less common, Alzheimer’s can also affect
younger people. About 200,000 Americans younger
than age 65 have early-onset Alzheimer’s disease.

18. • Gender
More women than men develop Alzheimer’s
disease but this is most likely because women tend
to live longer than men.
• Race and Ethnicity
African Americans and Hispanics are at greater
risk for developing Alzheimer’s disease than
whites.
This may be in part because they have a higher
prevalence of medical conditions such as high
blood pressure and diabetes, which are
associated with increased risk for Alzheimer’s.

19. • Family History
People with a family history of Alzheimer's are
at higher than average risk for the disease.
• Heart and Vascular Diseases
Risk Factors

20. Pathophysiology of AD
There are 3 consistent neuropathological
hallmarks:
Amyloid-rich senile plaques
Neurofibrillary tangles
Neuronal degeneration

21. Amyloid Plaque Formation
• Alzheimer’s patients show numerous plaques which
are composed of 4 kD Amyloid-beta (A-beta) peptides,
which are derived from beta amyloid precursor
proteins (APPs)
• APP is a membrane associated glycoprotein of 110-135
kDa that is proposed to normally behave in the brain as
a cell surface signaling molecule
• A-beta peptides are generated in the endosomal
compartment and in the endoplasmic reticulum or
Golgi complex by endoproteolytic cleavage of APP by
Beta, alpha, and gamma secretases

22. Neuronal Plaques in Alzheimer’s Disease

23. Presenilins
• Presenilin 1 (PS1) and presenilin 2 (PS2) are
highly homologous 43-50 kD proteins with eight
transmembrane domains
• Presenilin’s make crucial contributions to
neurodegeneration in AD
• Presenilin’s are crucial components of the
enzymes that work to cleave APP, and mutations
in presenilins cause the production of A-beta42
and A-beta43 peptides (insoluble forms of A-
beta)

24. Neurofibrillary pathology
• Intracellularly, alzheimer’s patients show
neurofibrillary pathology
• Affected neurons accumulate tau and
ubiquitin immunoreactivities within
neurofibrillary tangles, in cell bodies and
dendrites, and in dystrophic neuritis

25. Neurofibrillary Tangles in Alzheimer’s Disease

26. Plasmin
• In the brain, plasminogen and its proteolytic
fragment are abundant in the hippocampus
• It has been hypothesized that brains of
patients with AD may have lower levels of
plasmin
• The higher production of amyloid peptide
together with less efficient degradation would
to A-beta accumulation and aggregation

27. Brain Atrophy in AD

28. Amyloid Hypothesis
• The trigger for Alzheimer's disease is the A-
beta peptide, and the accumulation of this
peptide in the form of plaques is the initiating
molecular event
• The plaques trigger an inflammatory
response, neuronal cell death, and gradual
cognitive decline
• The rest of the disease process, including
formation of neurofibrillary tangles containing
tau protein, is caused by an imbalance
between A-beta production and A-beta
clearance

32. Calcium Hypothesis
• Calcium modulates many neural processes, including
synaptic plasticity and apoptosis
• Dysregulation of intracellular calcium signaling has
been implicated in the pathogenesis of alzheimer’s
disease
• Increased intracellular calcium elicits the
characteristic lesions of this disorder, including the
accumulation of amyloid-beta, the
hyperphosphorylation of TAU and neuronal death
• Every gene that is known to increase susceptibility to
Alzheimer’s disease also modulates some aspect of
calcium signaling

33. Calcium Hypothesis
• The disruption of calcium homeostasis might
be one of the principal mechanisms by which
A-beta manifests its neurotoxicity
• A-beta has been shown to destabilize
neuronal calcium homeostasis, generally
leading to an increase in cytosolic calcium
which can then trigger neuronal apoptosis

34. Acetylcholine Hypothesis
• Acetylcholine (ACh) is an important
neurotransmitter in areas of the brain
involved in memory formation
• Loss of Ach activity correlates with the
severity of AD

35. AD: The Great Unknown
What is causing the
majority of AD cases?

36. Cases with no known etiology:
(theoretical extremes)
Mendelian/
Phenocopy
Disease (Genetic)
Heterogeneity
Multifactorial/
Threshold
CDCV
Common disease/
common variant

37. Treatment Options
• Pharmacological
• Non- pharmacological
• Specific symptom management
• Resources

38. Future Trends
• Alzheimer’s as a multifactorial
syndrome
• Pendulum of history
• Vaccine
• Gene therapy