1. Types of dementia, Pathphysiology of Alzheimer’s disease,
New diagnostic criteria and guidelines for Alzheimer’s
disease, Current and future psychopharmacological
interventions in Alzheimer’s disease.

2. Dementia – a growing epidemic
 In 2012 -5.4 million Americans have dementia of all
causes.
 In 2050- it is estimated that 15 million Americans will
live with dementia.
 Every 68 seconds someone in America develops
dementia.
 It is estimated that nearly 500,000 new cases will be
diagnosed this year alone.
 Worldwide 36 million people are believed to live with
dementia. By 2050, if breakthroughs are not
discovered, the rates could exceed 115 million.

3. Definition
Dementia consists of:
 memory impairment (amnesia),
 deficits in either language (aphasia), or
 motor function (apraxia),
 recognition (agnosia), or
 executive function, such as working memory and
problem solving.
 personality changes can also be present (sometimes
even before the memory impairment)

4. Not Every Memory Disturbance Is
Dementia
 Age-related memory-impairment (ARMI)
 Self perceived memory loss
 Over age 65 – prevalence around 40% = 16 million in US
 About 1% of which eventually develop dementia
 Minor Cognitive Impairment (MCI)
 More severe memory loss, little/no functional impairment
 Around 10% over 65 – does not necessarily develop to AD
 Alzheimer’s Disease (AD)
 Around 15% of those with MCI convert

5. Not All Dementias are Alzheimer’s
Disease

6. Mixed Dementias
 It is possible to have more than one dementia, and in fact many patients have
both Alzheimer’s disease and either dementia with Lewy bodies or vascular
dementia.

7. Pathology of Alzheimer’s Dementia
In order for a dementia to be called Alzhheimer’s disease
it has to present with both:
 AMYLOID PATHOLOGY - Beta amyloid plaques
(extracellular)
 TAU PROTEIN PATHOLOGY - Neurofibrillary tangles
(abnormal phosphorylation of tau proteins)
(intracellular)

8. Amyloid Plaques

9. NORMAL PATHWAY: Processing of Amyloid
Precursor Protein into Soluble Peptides

10. ABNORMAL PATHWAY: Processing of
Amyloid Precursor Protein into A beta
Peptides

11. Beta Secretase Inhibitors
 Merck: MK-8931
 Lilly: LY450139

12. Gamma Secretase Inhibitors
 Merck: MK-8931
 Eisai: E 2609
 Lilly: LY2886721

13. Monoclonal Antibodies against
Abeta 42
*Solanezumab (Lilly)
*Bepaneuzumaub (Pfizer)

14. AMYVID (Flobetapir)
Visualizing Amyloid
 Indicated for PET imaging of the brain to estimate the
density of beta amyloid plaques in adult patients with
cognitive impairment who are being evaluated for
Alzheimer’s disease and other causes of cognitive
impairment.

16. Amyloid Cascade Hypothesis, Part One: increased
production of Abeta42

17. Amyloid Cascade Hypothesis, Part Two: A beta 42
Oligomers Form and Interfere with Synaptic
Function

18. Amyloid Cascade Hypothesis, Part Three: formation of
amyloid plaques causing inflammation

19. Amyloid Cascade Hypothesis, Part Four: amyloid plaque
induces formation of tangles

20. The Role of Tau Protein

21. Tau Pathology

22. Amyloid cascade Hypothesis, Part Five: neuronal
dysfunction and loss

24. DIAGNOSIS: 2011 Diagnostic Criteria for AD
(emphasis on prevention)

25. Two kinds of AD: Familial and
Incidental
Autosomal dominant, early onset (5-10%)
(mutations in the APP or gamma secretase)
CHROMOSOME GENE
1 Presenilin 2
14 Presenilin 1
21 Amyloid PP
Incidental is non-genetic it does not run in
families.

26. Pre-symptomatic Entities
1. Pre clinical AD ( recommendations are intended for
research purposes).
2. MCI (Minor Cognitive Impairment).

27. More Sensitive Screening

28. Core clinical criteria
Neuropsychiatric symptoms that:
1. Interfere with the ability to function
2. Represent a decline from the previous level of functioning
3. Are not explained by delirium
4. Cognitive impairment is detected by history taking and objective cognitive
assessment
5. Impairment involves a minimum of two of the following domains:
 Impaired ability to acquire and remember new information
 Impaired reasoning and handling of complex tasks, poor judgment
 Impaired visuospatial abilities
 Impaired language functioning
 Changes in personality or behavior

29. Diagnostic Overview
1. Possible AD dementia
2. Probable AD dementia
3. Probable or possible AD dementia with
evidence of the AD pathophysiological process.

30. Incorporation of Biomarkers into
AD Dementia Criteria
Biomarkers may be useful in three circumstances:
1. Investigational studies
2. Clinical trials
3. And as optional clinical tools for use where
available and when deemed appropriate by the
clinician.

31. CSF: Decreased Aβ42
Amyloid
Pathology
PET : Amyloid imaging with
Amyvid
Biomarkers CSF: Increased total or
phosphorylated tau
PET: hypoperfusion
Tau Pathology temporoparietal, precuneus
MRI: Medial temporal lobe
atrophy, Hippocampal atrophy,

32. William Utermohlen 1933-2007
 Diagnosed with Alzheimer’s disease in 1995.
1967 (self portrait)

33. 1995

34. 1997

35. 1998

36. 1999

37. 2000

39. Cholinesterase inhibitors offer
modest results
 The usual response to cholinesterase inhibitor therapy
in Alzheimer’s disease is initial improvement that is
statistically detectable on cognitive testing and
perhaps noticeable to the caregiver but not necessarily
to the patient.
 Such a response usually lasts about 6 months, at
which point cognitive functioning as measured on
cognitive testing is back to where it was before
beginning the drug.

40. Donepezil (Aricept)
 Selective inhibitor of AChE, allowing more ACh to
accumulate
 Once daily dosing
 Severe AD
 Benefits for all outcomes at 6 months
 Some indication of positive changes on ADL and severe impairment battery
(SIB) scores
 More selective for brain than periphery
 GI side-effects usually moderate and transient - nausea, vomiting, diarrhea
 No liver toxicity
 Hallucinations twice as common as placebo .

41. Rivastigmine (Exelon)
 Inhibits both AChE and the peripheral
butylcholinesterase (BuChE)
 May be more selective for hippocampal AChE
 May be more useful for late stage AD, when gliosis
increases BuChE
 Might interfere with plaque formation
 Increased incidence of GI side-effects, especially
during dose optimization/increase

42. Galantamine (Razadyne, previously
Reminyl)
 Natural product isolated from daffodils and snowdrops
 Inhibits AChE; allosteric modulator of nicotinic receptors;
synergistic at cholinergic synapses
 Nicotinic action may boost attention and behaviors caused
by deficiencies of other neurotransmitters.
 Studies:
 16 or 24mg/day, 24 wks, benefits in cognitive and global function
 Moderate AD gained more advantage than mild AD
 BUT may be higher mortality than with the other AChEs

43. Memantine (“Artificial Magnesium”)
 Voltage-dependent NMDA antagonist that targets
glutamatergic system
 Mild side effect profile
 Dizziness, confusion, headache, constipation
 Dosing schedule:
 Week 1 - 5 mg/day, Week 2 - 5 mg twice a day, Week 3 - 10 mg
twice a day, Week 4 - 15 mg twice a day
 Administered with or without food
 No PK/PD interactions with donepezil or other renally-
excreted drugs