Summary Biological definition of Alzheimer’s disease and implications for treatment

Biological definition of Alzheimer’s disease
and implications for treatment (Prof. Streffer)
1. Biological definition of AD
1.1. Successful aging
 Dementia or movement disorders are not normal features of aging, but
diseases
o Is aging a disease?
 Changing in skin  not pathological because aging is a
natural process  if aging is a disease, then everyone would
be diseased
 We can’t define the disease so it is not a disease
 Life expectancy is increasing, but moreover healthy aging is expected
 Age related changes of normal healthy aging are balanced between more
fluid processes vs crystalline processes
o Changes earlier are not necessarily pathological
o Our cognition is changing
o Younger people are much better in technology, faster,…
 When you are older: brain changes
 Brain between 30-60 years: brain is growing  from 20
years your brain is shrinking
 Make more connections, more efficient




Clinical symptoms of Alzheimer’s disease/dementia
 Dementia is defined as the progressive cognitive loss, leading to functional
deficits
 In Alzheimer’s disease memory is often the leading symptom, but not
alone




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,Neuropathological features of Alzheimer’s disease
 Alois Alzheimer described the pathological hallmarks, but as well already
changes to glial cells (inflammation)
 Atrophy = huge shrinking of the brain




Is aging a disease?
 Changes related to aging vs disease
o A disease is a pathophysiological response to internal or external
factors.
o A disorder is a disruption to regular bodily structure and function.
o A syndrome is a collection of signs and symptoms associated with
a specific health-related cause.
o A condition is an abnormal state of health that interferes with
normal or regular feelings of wellbeing.

1.1.1. From clinical observation to biological understanding
1.1.1.1. CSF biomarkers identify early disease stages and progressors
 Initial biomarkers described in AD were related to A β and Tau
 Primarily targeting prediction of progression from MCI to dementia
 Graphs
o Left
 Blue: healthy
 Red: disease  most of them moved to dementia
o Right
 Stable MCI
 MCI that moved to AD
 All the dots are in the left corner




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, 1.1.1.2. Amyloid pathology is an early marker in CSF, accompanied by
dynamic changes in CSF tau
 Differential dynamics between stable A β and dynamic Tau
 Highest tau increase is related to shortest time to dementia
 Graphs: look at the severity of biomarkers and how long does it take for an
MCI patient to progress?
o Left
 Once progressed to AD the mean ranges are low
 In a group that is prone to develop AD in the future
o Right (tau marker)
 Difficult for the tau marker
 When will I develop AD?
 High Tau marker




1.1.2. Clinical and biomarker changes in dominantly inherited
Alzheimer’s disease
 Autosomal dominant AD disease (ADAD) has 100% penetrance
 Clinical symptoms and disease course are surprisingly like sporadic disease
 EYO (expected year of onset) is very similar in specific families (same
mutation)
 Sporadic AD and ADAD biomarker patterns confirm and inform each other
in both directions

1.1.3. AD associated with Down syndrome: a genetic form of dementia
 APP gene is located on chromosome 21
 Adults with down syndrome develop the neuropathological hallmark of AD
 Very high risk of developing early onset dementia
 Diagnosis of dementia remain a clinical challenge
o Lack of validated diagnostic criteria in this population
o Symptoms are overshadowed by the intellectual disability
 Biomarkers may play a particular role in the future
 In people with down syndrome, fluid and imaging biomarkers have shown
good diagnostic performances
 Strikingly similar temporality of changes with respect to sporadic and
autosomal dominant AD
 As clinical tools are less well developed for this group, biomarkers may
play a particular role in drug development




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