Alzheimer’s Disease
Stephen S. Flitman, MD
Medical Director
21st Century Neurology
a division of Xenoscience, Inc.
Phoenix, Arizona
Alzheimer’s Disease
• The leading cause of dementia in the US
• Progressive loss of cognitive functions:
– Memory
– Language
– Motor control (praxis)
– Spatial ability
– Executive function and behavior
Risk Factors in AD
• Age - Between the ages of 65 and 85, the
prevalence of AD doubles with each
increase of 5 years.
• Head Injury - AD patients report higher
incidence of prior head injury than non-AD
individuals.
• Genetics - Several genes are associated
with AD
Protective Factors in AD
•
•
•
•
•
Estrogen
Antioxidants (Vitamin E)
Anti-inflammatory Agents
Education?
Smoking?
NINCDS-ADRDA Criteria for AD
• Probable Alzheimer’s Disease
–
–
–
–
–
Dementia with onset between ages 40 & 90
Cognitive deficits in two or more areas
Progressive memory and cognitive deterioration
No other illness that could account for such deficits
No disturbance of consciousness
• Definite Alzheimer’s Disease
– Clinical criteria for probable AD
– Histopathologic evidence from autopsy or brain biopsy
Prevalence of Alzheimer’s
• Using NINCDS-ADRDA criteria:
–
–
–
–
Age 65-74:
Age 75-84:
Age 85+:
Overall over age 65:
3.0%
18.7%
47.2%
10.3%
• Fourth leading cause of death in the US
after heart disease, cancer, and stroke
Prevalence of Dementia
(Framingham Study)
237.5
Rate per 1,000
250
200
150
105.3
100
35.8
50
3.5
9.0
61 - 64
65 - 69
17.9
0
70 - 74
75 - 79
Years of Age
Source: Bachman et al. Neurology. 1992;42:115-119.
80 - 84
85 - 93
Signs and Symptoms at Different Stages of AD
Mild
Confusion and
memory loss
Impaired
activities
Moderate
of
daily living
Loss of speech
Severe
Disorientation Problems with
in space
routine tasks
Changes in
personality and
judgment
Anxiety,
paranoia,
agitation
Sleep
disturbances
Cannot
recognize family
and friends
Loss of
appetite;
weight loss
Loss of bladder
and bowel
control
Total
dependence on
caregiver
Source: Gwyther LP. American Health Care Association and Alzheimer’s Disease
and Related Disorders Association, Chicago, IL:1985.
Pathology
Anatomic Progression
• Phase I - Entorhinal Cortex
– connectivity correlates with progression
• Phase II - Hippocampus CA1 region
• Phase III - Neocortex, plus
– Hippocampus CA4 region and Subiculum
– Cortical Medial Nuclei of Amygdala
– Putamen
Brain of Alzheimer Patient shows numerous plaques of amyloid betaprotein in specific brain areas. These plaques become centers for the
degeneration of neurons.
Axial CT scan section through
the temporal lobes:
.
(A) Normal; (B) Alzheimer’s Disease
Anterior
(A)
Anterior
(B)
Posterior
Posterior
Courtesy of James King-Holmes and Science Photo Library
Alzheimer’s disease vs.
Pick’s disease
Neuropathology of Alzheimer’s
• Neuritic plaques consist of a core of bamyloid formed by beta protein fibrils from
the aggregated 42 amino acid A/b peptide,
surrounded by swollen, dystrophic neurites.
• Neurofibrillary tangles fill the interior of
degenerating neurons. The presence of
plaques and tangles at autopsy is used to
confirm a diagnosis of AD.
Plaque of Amyloid Beta-Protein. Visible as a black
globular mass when stained. The plaque is surrounded
by abnormal neurites and degenerating neurons.
Plaques and Neurofibrillary Tangles
Light micrographs of human brain in Alzheimer’s Disease
Plaque surrounding
amyloid deposit
Neurons filled with
neurofibrillary tangles
Courtesy of James King-Holmes and Science Photo Library
Inflammation
• Evidence for inflammatory processes
– Acute phase proteins in serum and plaques
– Activated microglia, inflammatory cytokine 
– Complement components on degenerating
neurites, including membrane attack complex
• Serum cortisol levels reported higher in AD
– HPA axis abnormalities
Amyloid Precursor Protein
Amyloid Beta-42
http://molbio.info.nih.gov
•
•
•
•
42 amino acid A/b peptide
Produced from APP by b/g secretase
Will self-associate to form toxic fibrils
Insoluble and resistant to proteolysis once
aggregated
Tau Protein
• Six isoforms in adult CNS (single gene)
– Abnormal tau in AD is phosphorylated
– Normally dephosphorylated by phosphatases
• Binds and stabilizes microtubules normally
–
–
–
–
Fails to bind when phosphorylated
Paired helical filaments form  tangles
Axonal transport blocked  degeneration
Deglycosylation straightens filaments
Genetics in Alzheimer’s
• Susceptibility Polymorphisms
– ApoE on chromosome 19
– A2M and LRP on chromosome 12
• Autosomal Dominant Mutations
– Presenilin-1 (PS-1) on chromosome 14
– Presenilin-2 (PS-2) on chromosome 1
– APP on chromosome 21 (same as Down’s)
Apolipoprotein E
•
•
•
•
Modulate low-density lipoprotein levels
E4/E4 - high risk of MI in young patients
Apolipoprotein E4  tau phosphorylation
Apolipoprotein E2  tau phosphorylation
APOE genotype-specific risk of remaining unaffected
Presenilins
• Transmembrane proteins
– now identified as g-secretases, directly
producing Ab42
• PS1, PS2 mutations  familial AD
–
–
–
–
All show plasma Ab42 levels
Not seen in sporadic AD
Suggests mutations result in Ab42 secretion
Mutations operate outside CNS as well
Diagnostic Workup
Traditional Diagnosis
• Exclusion - Eliminate all other possible
causes of dementia; “Probable AD”.
• Cognitive tests
• Neurological work-up
• EEG
• Scans - MRI, CAT, PET, SPECT
• Autopsy - Definitive
Diagnostic Panel for AD
• Rule out reversible etiologies for dementia
–
–
–
–
–
Hypothyroidism - TSH, T4
B12 Encephalopathy - B12 level; or MMA, HC
Neurosyphilis - RPR
CNS Vasculitides - ESR, ANA, RF
Headache? R/O Chronic Meningitides - LP
Apolipoprotein E
• Increase confidence in the diagnosis if E4
present
• ApoE2/E4 – 94%
• ApoE3/E4 – 97%
• ApoE4/E4 – 100%
Cerebrospinal fluid
• CSF Ab42/tau
– 95% specific for AD
– Meets Reagan criteria for a surrogate marker
• AD7c
– Neural thread protein
– Not clearly specific for AD, published 87%
sensitivity
– Urine test also offered
FDA Approved Treatments
Cholinergic Drugs
• L-Dopa approach: Lecithin
• Reversible central cholinesterase inhibitors
–
–
–
–
tacrine (CognexTM)
donepezil (AriceptTM)
rivastigmine (ExelonTM)
galanthamine (ReminylTM)
• Muscarinic agonists
QID, LFTs
QD, LFTs nl
BID, LFTs nl
BID, LFTs nl
ADAS-Cog using Donepezil
Mean Change from Baseline
ADAS-Cog Rating
Withdrawal phase
3
2
Clinical
Improvement
1
0
Clinical
Decline
-1
10 mg/day
5 mg/day
Placebo
-2
-3
-4
0
6
12
18
24
Weeks of Drug Treatment
30
ADAS-Cog using Rivastigmine
Mean Change from Baselinea
-4
*
-2
0
2
*
*
* *
*
*
*
*
4
*
6
8
10
12
6-12 mg
1-4 mg
Placebo
14
16
All Patients
Receive Rivastigmine
18
0
13
26
39
52
65
78
91
Study Week
A negative value indicates improvementa
Study B352 (OC) Patients with baseline GDS >5
*p<0.05 Rivastigmine vs. Placebo
104
MLR 130301
ADAS-Cog in Galantamine
–4
Improvement
–3
–2
Mean (± SE)
Change
From
Baseline in
ADAS-cog
Score
*
–1
0
1
2
Placebo (n = 157)
Galantamine 24 mg (n = 131)
3
Deterioration
4
1
2
3
Months
*P < .001 vs placebo.
Raskind MA et al. Neurology. 2000;54:2261-2268.
4
5
6
Adverse Events
Adverse event
Donepezil
%
Rivastigmine
%
Galantamine
%
Dizziness
0
11
0
Headache
0
12
0
Nausea
4
12
13
Vomiting
2
6
6
Diarrhea
7
11
12
Anorexia
2
3
6
Abdominal pain
0
6
0
On The Horizon
Neuromodulators
• Many compounds acting at multiple sites
• Like cholinergic agents, may improve
function but not disease process
• Most dramatic: AMPAkines
– AMPA receptor positive allosteric modulators
– Improve memory performance in normals 2-3x!
– Highly investigational
Anti-Inflammatory Agents
• Steroids
– No effect anecdotally
– AD may have  sensitivity
• NSAIDs
– Indomethacin and others reported beneficial
– Ongoing trials
– Reasonable to use aspirin
Amyloid Vaccine
• Immunization with Ab42 in PDAPP mice
– Prevents plaque formation if given to young
– Caused plaque to regress if given to old mice
– Replicated in rabbits
• Clinical trials in progress
– Demonstrated safety & tolerability in humans
– Not yet shown to have efficacy for prevention
or treatment
Schenk et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like
pathology in the PDAPP mouse. Nature, 400(6740):173-7, 1999.
Further On
• Gene therapy for PS1, PS2, APP, ApoE4
• Regenerative therapies
– Stem cell replacement for cortical atrophy
• Secretase inhibitors
– Prevent elaboration of Ab42 (Howlett et al.)
• Other means of amyloid clearance
– Manufactured antibodies (Sierks et al.)
– Mechanical clearance (CSFluids COGNIshunt)
Questions?