HC6: Alzheimer’s Disease 1
Alzheimer’s disease is the most common form of dementia. In the Netherlands: About 70%
with dementia have AD and this is true for most countries. So, it's more common than other
main forms put together: vascular dementia, dementia with Lewy Bodies, frontotemporal
dementia. Alzheimer’s is therefore often used as equivalent for dementia.
Dementia also means crazy and to avoid a confusion with AD and dementia and insanity, in
many languages the preferred word is Alzheimer as equivalent.
AD is first described in 1906 by Alois Alzheimer. His first patient was Auguste Deter and was
admitted to mental hospital at age 51 severe memory impairments (presenile dementia –
early onset dementia). Alzheimer described amyloid plaques and neurofibrillary tangles in
Deter’s brain. (The term ‘Alzheimer’s disease’ was used for the first time in 1910 by
Kraepelin).
Current definition: degenerative brain disorder characterized by progressive intellectual and
behavioral deterioration.
Dementia of Alzheimer Type (DAT): symptoms associated with Alzheimer’s disease.
Clinical features:
Key difference with Mild Cognitive Impairment is the ability to function independently.
So: difficulties with daily functioning with IADL or ADL (eating, sleeping, dressing)
Key features: DSM V criteria for major neurocognitive disorders (it does not use the
term dementia) and MCI is referred to as minor neurocognitive disorders.
Criteria for major neurocognitive disorders (DSM V) independently of type!
1. Significant cognitive decline from previous level of performance based on report
patient or informant AND clear objective deficits (>2 SD below appropriate norm
population)
2. Cognitive deficits sufficient to interfere with independence
3. Cognitive deficits do not exclusively occur in context of delirium
4. Cognitive deficits can not be attributed to Axis 1 disorder (e.g., depression or
schizophrenia)
Criteria for Alzheimer’s disease (McKhann et al. 2011):
1. Insidious onset: symptoms develop gradually over months – years
2. Worsening of cognition from report or observation
3. Cognitive impairment in one of two categories:
a. Typical amnestic presentation: most common: main impairment in memory.
b. Nonamnestic or atypical presentation: main impairments in language (e.g.,
word finding difficulties) or executive functioning or visuospatial function
this category is less common and more difficult to diagnose.
c. In both categories: disorders in other cognitive functions should also be
present.
The problem is the diagnosis. A definite diagnosis of AD is only possible post-mortem (once
the person has died):
, Pathologically proven AD because the brain is being examined
o Meets clinical and cognitive criteria probably AD during life
o AD pathology present in brain
Until that time, diagnosis with different degrees of uncertainty: probable, possible. They don’t
speak of definite diagnosis in papers and literature! Until you have a postmortem
confirmation.
Probably AD dementia (more certainty than possible)
Meets the criteria for AD
No evidence for alternative explanations for symptoms
o In particular: no significant cerebrovascular disease that could explain the
cognitive impairment.
Certainty of diagnosis is enhanced by presence of 3 further sources:
o Documented decline: by information or testing. OR
o Presence of biomarkers. OR
o Presence of generic mutations that enhance AD risk
Possible AD dementia (less certainty)
Atypical course. Meets clinical and cognitive criteria, but no evidence/uncertainty of
progressive decline OR
Biomarkers obtained and negative OR
Mixed presentation: clinical and cognitive features of AD, AND evidence of e.g.,
cerebrovascular disease or features of dementia with Lewy Bodies.
Etiology/ Neuropathology
Characteristics neuropathology AD: senile plaques
and neurofibrillary tangles (plaques between nerve
cells and tangles within nerve cells)
What are we looking for in the brain postmortem?
Plaques and tangles.
Neuritic plaques (senile, dendritic, amyloid plaques) –
deteriorating neuronal material surrounding a sticky
protein, amyloid beta (beta amyloid, Abeta, Aβ)
Abeta formed when protein (amyloid precursor
protein) folds incorrectly if it folds incorrectly, Abeta
accumulates in the brain and will form plaques. These plaques interfere with the functional
healthy cells and they will eventually die. It is unclear where the process goes wrong in the
first place, that is what is making it so hard to find a drug/medicine.
In the AD brain, a group of small peptides (essentially a smaller version of a protein) referred
to as amyloid beta, or Aβ, accumulate outside of neurons in large dense structures called
amyloid plaques. Normally, enzymes called proteases can get rid of unwanted peptides and
proteins. Amyloid plaques, however, are resistant to degradation by proteases – so they
have a tendency to proliferate in the brain as the disease progresses.
Alzheimer’s disease is the most common form of dementia. In the Netherlands: About 70%
with dementia have AD and this is true for most countries. So, it's more common than other
main forms put together: vascular dementia, dementia with Lewy Bodies, frontotemporal
dementia. Alzheimer’s is therefore often used as equivalent for dementia.
Dementia also means crazy and to avoid a confusion with AD and dementia and insanity, in
many languages the preferred word is Alzheimer as equivalent.
AD is first described in 1906 by Alois Alzheimer. His first patient was Auguste Deter and was
admitted to mental hospital at age 51 severe memory impairments (presenile dementia –
early onset dementia). Alzheimer described amyloid plaques and neurofibrillary tangles in
Deter’s brain. (The term ‘Alzheimer’s disease’ was used for the first time in 1910 by
Kraepelin).
Current definition: degenerative brain disorder characterized by progressive intellectual and
behavioral deterioration.
Dementia of Alzheimer Type (DAT): symptoms associated with Alzheimer’s disease.
Clinical features:
Key difference with Mild Cognitive Impairment is the ability to function independently.
So: difficulties with daily functioning with IADL or ADL (eating, sleeping, dressing)
Key features: DSM V criteria for major neurocognitive disorders (it does not use the
term dementia) and MCI is referred to as minor neurocognitive disorders.
Criteria for major neurocognitive disorders (DSM V) independently of type!
1. Significant cognitive decline from previous level of performance based on report
patient or informant AND clear objective deficits (>2 SD below appropriate norm
population)
2. Cognitive deficits sufficient to interfere with independence
3. Cognitive deficits do not exclusively occur in context of delirium
4. Cognitive deficits can not be attributed to Axis 1 disorder (e.g., depression or
schizophrenia)
Criteria for Alzheimer’s disease (McKhann et al. 2011):
1. Insidious onset: symptoms develop gradually over months – years
2. Worsening of cognition from report or observation
3. Cognitive impairment in one of two categories:
a. Typical amnestic presentation: most common: main impairment in memory.
b. Nonamnestic or atypical presentation: main impairments in language (e.g.,
word finding difficulties) or executive functioning or visuospatial function
this category is less common and more difficult to diagnose.
c. In both categories: disorders in other cognitive functions should also be
present.
The problem is the diagnosis. A definite diagnosis of AD is only possible post-mortem (once
the person has died):
, Pathologically proven AD because the brain is being examined
o Meets clinical and cognitive criteria probably AD during life
o AD pathology present in brain
Until that time, diagnosis with different degrees of uncertainty: probable, possible. They don’t
speak of definite diagnosis in papers and literature! Until you have a postmortem
confirmation.
Probably AD dementia (more certainty than possible)
Meets the criteria for AD
No evidence for alternative explanations for symptoms
o In particular: no significant cerebrovascular disease that could explain the
cognitive impairment.
Certainty of diagnosis is enhanced by presence of 3 further sources:
o Documented decline: by information or testing. OR
o Presence of biomarkers. OR
o Presence of generic mutations that enhance AD risk
Possible AD dementia (less certainty)
Atypical course. Meets clinical and cognitive criteria, but no evidence/uncertainty of
progressive decline OR
Biomarkers obtained and negative OR
Mixed presentation: clinical and cognitive features of AD, AND evidence of e.g.,
cerebrovascular disease or features of dementia with Lewy Bodies.
Etiology/ Neuropathology
Characteristics neuropathology AD: senile plaques
and neurofibrillary tangles (plaques between nerve
cells and tangles within nerve cells)
What are we looking for in the brain postmortem?
Plaques and tangles.
Neuritic plaques (senile, dendritic, amyloid plaques) –
deteriorating neuronal material surrounding a sticky
protein, amyloid beta (beta amyloid, Abeta, Aβ)
Abeta formed when protein (amyloid precursor
protein) folds incorrectly if it folds incorrectly, Abeta
accumulates in the brain and will form plaques. These plaques interfere with the functional
healthy cells and they will eventually die. It is unclear where the process goes wrong in the
first place, that is what is making it so hard to find a drug/medicine.
In the AD brain, a group of small peptides (essentially a smaller version of a protein) referred
to as amyloid beta, or Aβ, accumulate outside of neurons in large dense structures called
amyloid plaques. Normally, enzymes called proteases can get rid of unwanted peptides and
proteins. Amyloid plaques, however, are resistant to degradation by proteases – so they
have a tendency to proliferate in the brain as the disease progresses.
