A progress report on
Alzheimer's Disease
research
Molecular View of Human Anatomy
Karl Herrup, Ph.D.
Professor and Chair
Cell Biology and Neuroscience
Alzheimer's disease
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The bad news
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Common
Devastating to individual and their caregivers
Progressive
Currently no cure
The good news
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A triumph of modern medicine
Diagnosis has improved
Research is pointing towards future prevention
Alzheimer’s disease
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The most common cause of late life dementia.
4.5 million people now at some stage of AD
350,000 patients and caregivers affected in NJ alone
After age 65, the percentage of AD doubles every 5 yrs.
By 2050, 13.2 million older Americans are expected to
have AD.
The national cost of caring for people with AD is about
$100 billion every year.
Alzheimer’s disease
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Memory
Language
Spatial perceptions
Executive functions
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Judgment
Problem solving
Behavior
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Attention
Depression
Aggression
Apathy
Alzheimer’s disease
  How
does Alzheimer's start?
  Mild cognitive impairment (MCI)
  Detectable
clinical impairment
  No reduction in activities of daily living
  70%
of MCI 'converts' to AD
  Some
to other dementia
  Some 'resolve'
Alzheimer’s disease
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Alois Alzheimer, 1906
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Plaques
Tangles
Synaptic density loss
Cell loss
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Hippocampus
Basal nucleus
Locus coeruleus
Dorsal raphe
Alzheimer’s disease
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Regional variations
Alzheimer’s disease
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Neuropathology
hippocampus
basal nucleus
Emotional
control
dorsal raphe
locus coeruleus
Alzheimer’s disease
Emotional
control
Alzheimer’s disease
Preclinical
Mild AD
Severe AD
Alzheimer’s disease
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Early onset (<10%)
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Before age 65
Nearly always familial
3 major genes
  Amyloid
precursor protein (APP): ~1%
  Presenilin-1 & 2 (PSEN1/2): ~8%
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Late onset (>90%)
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Sporadic
Some risk factor genes
  ApoE,
IDE, others
Alzheimer’s disease
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APP at the heart of the disease
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APP sticks through the neuron membrane.
Enzymes cut the APP into fragments of protein, including
β-amyloid.
Beta-amyloid fragments come together in clumps to form
plaques.
1.
2.
3.
Alzheimer’s disease
γ-secretase (PSEN is active part)
β-secretase
Alzheimer’s disease - tau
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The role of tau
No genetic implication
No clear link to Aß
Frontotemporal dementia
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FTDP-17
Other genes
The importance of splicing
Alzheimer’s disease - tau
Alzheimer’s disease
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Factors that cut your risk
NSAIDS
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indomethacin, ibuprofen, naproxin
Not aspirin or acetominophen
Statins
Estrogens
Anti-oxidants – vitamin E
Life style choices
‘Origins’: early cognitive performance
NOT aluminum pots and pans
Progress: first steps
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Basal nucleus
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Projects to hippocampus
>75% lost in AD
Cells use acetylcholine
Cholinesterase inhibitors
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Symptomatic relief
Progress: first steps
Aricept, Reminyl, Cognex,
Tacrine
Acetyl cholinesterase inhibitors
block the breakdown of acetyl
choline
Progress: first steps
Aricept, Reminyl, Cognex,
Tacrine
Acetyl cholinesterase inhibitors
block the breakdown of acetyl
choline
Memantine/Namenda
NMDA inhibitors
block receptors for glutamate
Progress: next steps
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The amyloid hypothesis
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The disease starts with incorrect cutting of the APP
protein
ß-amyloid is made
ß-amyloid aggregates into plaques
ß-amyloid and plaques are bad for neurons and kill them
Progress: next steps
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Animal models - plaques but no tangles or cell loss
Progress: next steps
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A vaccine for Alzheimer’s?
Progress: next steps
Untreated
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Vaccinated with Aβ
Plaques can be prevented or cleared
Cognition improved
Can be active or passive immunization
Works in primates
Progress: next steps
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Clinical trial 1
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30 patients
Test for safety
Clinical trial 2
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>300 patients at several sites
Changed the adjuvant
Test for efficacy
Trial halted due to 'adverse events’
Progress: next steps
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Clinical trials redux
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All subjects continue to be followed
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Four individuals died (of unrelated causes)
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At autopsy plaque density was lower than expected
Imaging
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Some made antibody (responders); some did not
Brain size reduced by ~3% in ‘responders’
Cognitive decline was less in ApoE4 carriers
What have we learned
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An outstanding clinical trial: good design/all the data
Facts are facts - we can clear the plaques
We think we know how to manage the adverse events
Progress: next steps
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Adult neurons never divide normally
Forcing them to divide kills them
Neurons in AD brain are 'trying' to divide
AD hippocampal pyramidal cells
Progress: next steps
We have strong evidence of how neurons die
  Divide and die - in mouse and man
  Gives us a marker -- mouse cells divide too
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NSAIDS block the cycle
Morphology
Mac1
CD45
Inflammatory markers Amyloid Deposition Neuronal Cell Cycle Progression
Birth
3
6
Ibuprofen in chow
9
12
15
18
21
Progress: next steps
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Other evidence based approaches
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Life style changes
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Beta-secretase inhibitors
Gamma-secretase inhibitors
Other plaque busters
Tau aggregation inhibitors
Early diagnosis (imaging) and intervention
Others
Mental and physical exercise (maintain your brain)
The future looks promising