HC 1 – Alzheimer’s and dementia from clinical perspective
Sebastiaan Engelborghs
Contents
• Dementia and Alzheimer's disease (AD): epidemiology
• How is AD diagnosed?
• How is AD treated?
o Present
o Future?
• Can we prevent AD and dementia?
1. Dementia: Epidemiology
Since 2023, dementia has become the leading cause of death in Belgium, and approximately 1 in 5 people will develop it
during their lifetime. Since aging is the strongest risk factor, the number of cases is expected to almost double by 2070,
making dementia a rapidly growing medical health issue.
Dementia is not a single disease, but an umbrella term for a group of symptoms including memory loss, personality changes,
spatial impairment, lack of insight, and loss of independence.
Ê It is defined by 3 key domains: cognitive decline, behavioral changes, and functional impairment in daily activities.
Main causes of dementia:
- Alzheimer’s disease (most common – 60–75%)
- Vascular dementia (20–30%)
- Lewy body dementia (10–25%)
- Frontotemporal lobar degeneration (10–15%)
- Other, less frequent causes
2. AD - Amyloid Cascade Hypothesis
New disease-modifying treatments for Alzheimer’s are built on the amyloid cascade hypothesis, which suggests that abnormal
amyloid accumulation triggers the entire disease process.
(1) Amyloid pathology: the amyloid precursor protein (APP) is normally processed in the brain, but in Alzheimer’s a toxic Aβ42
fragment accumulates and aggregates, forming insoluble amyloid plaques between neurons.
(2) Tau pathology: Tau protein normally stabilizes neuronal microtubules. In Alzheimer’s, Tau becomes (hyper)phosphorylated
which causes it to lose its normal function and to form aggregates and deposits inside neurons, known as neurofibrillary
tangles.
(3) Neuronal degeneration: these amyloid and tau changes lead to synaptic loss and neuronal death, causing cognitive decline.
(4) Brain atrophy: These pathological changes start years before clinical symptoms appear. Brain volume decreases,
with maximal atrophy in the temporal lobe, especially in the hippocampus, explaining early recent-memory failure and
repeated questioning.
Ê Therapeutic implications: If the formation of amyloid plaques can be prevented or cleared, disease progression can
be partially slowed, but not fully stopped.
2.1 Sequence of spread of neurofibrillary tangles
The progression of Alzheimer’s disease follows a predictable spread of neurofibrillary tangles, and this pattern reflects the
gradual transition from subtle memory problems to full dementia.
1) Mild Cognitive Impairment (MCI): MCI is the first symptomatic stage of Alzheimer’s, despite the fact that the disease
process has already been ongoing for 10–20 years before symptoms appear.
Ê Patients show mild recent-memory problems, but daily functioning is largely preserved and behavior remains unchanged.
They do not yet meet the criteria for dementia -> only for very mild cognitive decline, making this stage a key target for
early intervention and prevention.
2) Dementia (early stage): when dementia develops -> long-standing and progressive accumulation of neurofibrillary tangles.
,2.2 The Alzheimer Continuum
Alzheimer’s disease unfolds gradually over a long continuum, beginning many
years before symptoms become clinically visible. AD exist of 3 phases:
1) Preclinical Stage – pathology without symptoms
Most of the course of Alzheimer’s disease occurs during the preclinical
stage, when no symptoms are yet visible. Despite the absence of
symptoms, pathological changes in the brain are already ongoing.
2) Mild Cognitive Impairment (MCI) – first clinical signs
MCI is the first symptomatic stage of Alzheimer’s. Patients show mild recent-memory problems, but daily functioning is
largely preserved and behavior remains unchanged. They do not yet meet the criteria for dementia -> only for very mild
cognitive decline. Because the brain is not yet severely damaged, this stage is considered the key therapeutic window.
Ê Therapeutic relevance: new disease-modifying treatments mainly target MCI, aiming to slow disease progression
before irreversible damage occurs.
3) Dementia -> long-standing and progressive accumulation of neurofibrillary tangles.
3. Diagnosing Alzheimer’s Disease
Diagnosis of Alzheimer’s disease is based on clinical assessment combined with biomarkers, which change gradually as the
disease progresses. => a process often visualized through different colored curves (Different colors are the different markers).
â Functional decline (brown curve) -> reflect loss of independence in daily activities.
Ê These changes are present in all patients with dementia.
â Neuropsychological examination (purple curve = diagnostic cornerstone): trained neuropsychologist assesses multiple
cognitive domains using standardized tests.
Ê Through this assessment, patients can be classified as having normal cognition, MCI, or dementia.
Preclinical phase: pathology
is already ongoing !!!
Research indicates that people with abnormal biomarkers in the preclinical stage will likely develop symptoms if they live
long enough. Therefore, early recognition, particularly during MCI (the therapeutic window), is essential for disease-modifying
treatments.
Ê Thus: Biomarkers allow accurate diagnosis of AD, also in the predementia stage.
3.1 Neuropsychological Examination
A neuropsychological assessment is an essential step in diagnosing cognitive disorders, including Alzheimer’s disease.
â Requires neuropsychologist
â Time-consuming: 2h of testing, 1h of data analysis and writing report
â Reimbursed once in a life-time, and only partially (± 50% of total cost)
Thus:
- Neuropsychology = required!
- Neuropsychology = major obstacle in diagnostic work-up given number of neuropsychologists and reimbursement.
3.2 MRI in AD: Hippocampal Atrophy
The hippocampal atrophy can sometimes be very hard to visualize on a brain MRI, especially in the early stages.
,3.3 CSF Biomarkers
Cerebrospinal fluid (CSF) biomarkers are a key diagnostic tool for AD and reflect early pathological changes in the brain.
Ê Why CSF biomarkers?
- Alzheimer pathology begins with amyloid accumulation (first pathological event).
- Amyloid can be visualized with a PET scan.
9 But due to cost, tracer-dependence, and limited reimbursement/availability in Belgium, PET is rarely routine.
- Therefore, clinicians more commonly perform a lumbar puncture to analyze CSF, which contains important proteins
and biomarkers that can indicate abnormal amyloid or tau processing, in a less costly and more accessible way.
Tau biomarkers:
- Phosphorylated tau (P-tau): = increased in Alzheimer’s disease.
- Total tau: represents both normal tau and hyperphosphorylated tau.
9 Total tau can also increase in other neurodegenerative conditions,
such as stroke, making it less specific for AD.
Amyloid-beta (Aβ) biomarkers:
- CSF Aβ1-42: Levels are lower in AD.
- Specificity can be improved by calculating the Aβ1-42 / Aβ1-40 ratio.
Diagnostic criteria using CSF biomarkers:
P Low amyloid marker (Aβ1-42 or ratio) + elevated tau (especially P-tau)
CSF biomarkers vs amyloid PET
CSF PET
Invasive (LP) Not invasive
Accessibility Limited accessibility
Cheap (€145) Expensive (>€1000)
Not reimbursed Not reimbursed
Info about tau-pathology and Topographical information
neurodegeneration
Can detect very early changes Can detect early changes
Analysis of AD CSF Biomarkers
• Requires lumbar puncture -> relatively invasive
• Generally well-tolerated with minimal side effects
• Provides a relatively low-cost method for assessing AD pathology
• Offers a comprehensive overview of AD-related changes
• High diagnostic yield; widely used in routine clinical practice for AD diagnosis
3.4 Blood Biomarkers
Phosphorylated tau 217 (pTau217) is a blood-based biomarker that strongly correlates with tau pathology in the brain, a
hallmark of AD.
Ê It provides a minimally invasive, low-cost alternative to CSF analysis and PET imaging.
Ê Levels become abnormal before clinical symptoms appear, making it suitable for very early detection.
Clinical relevance of pTau217:
• Distinguishes AD from other causes of dementias with high accuracy.
• Detects AD pathology in pre-symptomatic individuals.
• Is used in clinical trials for (pre)screening purposes.
• Start to be used in tertiary memory clinics under controlled circumstances / well-defined clinical indications.
• Potential to transform screening and diagnosis in primary care settings.
, 4. Treatment of AD: Current Situation
Current treatment of AD focuses on maintaining quality of life (QoL) for as long as possible:
• Individualised guidance
• Individualised treatment
• Focus on independency
• Delay of nursing home placement
Ê !!! Stop symptomatic treatment when side effects reduce quality of life more than they help.
Current Treatment Options in Alzheimer’s Disease
1. Psychoeducation and Cognitive Rehabilitation -> helps patients adapt daily routines.
2. Symptomatic Pharmacological Treatments
• Cholinesterase inhibitors and memantine
• Provide modest, temporary improvements in cognition and daily functioning
• Do not modify disease progression
3. Behavioral and Psychological Symptoms of Dementia (BPSD) treatment
• Non-pharmacological strategies first: structured routines, environmental adjustments, caregiver support
• Pharmacological treatments only if symptoms are severe or distressing
4. Other Supportive Measures
• Control cardiovascular risk factors (hypertension, diabetes)
• Encourage cognitive and physical activity
• Promote healthy lifestyle: moderate alcohol, social engagement
5. Disease-Modifying Treatment (DMT): Anti-Amyloid Monoclonal Antibodies
Anti-amyloid monoclonal antibodies are the first therapies aimed at modifying the underlying Alzheimer’s pathology rather
than just relieving symptoms.
Mechanism of Action
Anti-amyloid monoclonal antibodies target amyloid-β (Aβ) plaques in the brain.
Ê They promote microglial activation, leading to phagocytosis and clearance of
fibrillar amyloid, followed by degradation in the endosomal–lysosomal system.
Ê The aim is to reduce amyloid burden and potentially slow disease progression.
Side Effects: Amyloid-Related Imaging Abnormalities (ARIA)
A major safety concern associated with these therapies is ARIA, which includes:
• ARIA-E: Cerebral edema, often asymptomatic.
• ARIA-H: Microhemorrhages, can occasionally lead to larger brain bleeds.
Although ARIA can also occur spontaneously in untreated individuals, it is much more frequent and severe in treated patients.
Therefore, regular MRI monitoring is required, and treatment may be paused or discontinued if ARIA develops.
Anti-Amyloid Antibodies
• Aducanumab: first approved, clears amyloid, modest benefit.
• Lecanemab: slows cognitive decline ~30%, better if started early.
• Donanemab: similar to lecanemab, modest effect, FDA & EMA approved but costly.
Sebastiaan Engelborghs
Contents
• Dementia and Alzheimer's disease (AD): epidemiology
• How is AD diagnosed?
• How is AD treated?
o Present
o Future?
• Can we prevent AD and dementia?
1. Dementia: Epidemiology
Since 2023, dementia has become the leading cause of death in Belgium, and approximately 1 in 5 people will develop it
during their lifetime. Since aging is the strongest risk factor, the number of cases is expected to almost double by 2070,
making dementia a rapidly growing medical health issue.
Dementia is not a single disease, but an umbrella term for a group of symptoms including memory loss, personality changes,
spatial impairment, lack of insight, and loss of independence.
Ê It is defined by 3 key domains: cognitive decline, behavioral changes, and functional impairment in daily activities.
Main causes of dementia:
- Alzheimer’s disease (most common – 60–75%)
- Vascular dementia (20–30%)
- Lewy body dementia (10–25%)
- Frontotemporal lobar degeneration (10–15%)
- Other, less frequent causes
2. AD - Amyloid Cascade Hypothesis
New disease-modifying treatments for Alzheimer’s are built on the amyloid cascade hypothesis, which suggests that abnormal
amyloid accumulation triggers the entire disease process.
(1) Amyloid pathology: the amyloid precursor protein (APP) is normally processed in the brain, but in Alzheimer’s a toxic Aβ42
fragment accumulates and aggregates, forming insoluble amyloid plaques between neurons.
(2) Tau pathology: Tau protein normally stabilizes neuronal microtubules. In Alzheimer’s, Tau becomes (hyper)phosphorylated
which causes it to lose its normal function and to form aggregates and deposits inside neurons, known as neurofibrillary
tangles.
(3) Neuronal degeneration: these amyloid and tau changes lead to synaptic loss and neuronal death, causing cognitive decline.
(4) Brain atrophy: These pathological changes start years before clinical symptoms appear. Brain volume decreases,
with maximal atrophy in the temporal lobe, especially in the hippocampus, explaining early recent-memory failure and
repeated questioning.
Ê Therapeutic implications: If the formation of amyloid plaques can be prevented or cleared, disease progression can
be partially slowed, but not fully stopped.
2.1 Sequence of spread of neurofibrillary tangles
The progression of Alzheimer’s disease follows a predictable spread of neurofibrillary tangles, and this pattern reflects the
gradual transition from subtle memory problems to full dementia.
1) Mild Cognitive Impairment (MCI): MCI is the first symptomatic stage of Alzheimer’s, despite the fact that the disease
process has already been ongoing for 10–20 years before symptoms appear.
Ê Patients show mild recent-memory problems, but daily functioning is largely preserved and behavior remains unchanged.
They do not yet meet the criteria for dementia -> only for very mild cognitive decline, making this stage a key target for
early intervention and prevention.
2) Dementia (early stage): when dementia develops -> long-standing and progressive accumulation of neurofibrillary tangles.
,2.2 The Alzheimer Continuum
Alzheimer’s disease unfolds gradually over a long continuum, beginning many
years before symptoms become clinically visible. AD exist of 3 phases:
1) Preclinical Stage – pathology without symptoms
Most of the course of Alzheimer’s disease occurs during the preclinical
stage, when no symptoms are yet visible. Despite the absence of
symptoms, pathological changes in the brain are already ongoing.
2) Mild Cognitive Impairment (MCI) – first clinical signs
MCI is the first symptomatic stage of Alzheimer’s. Patients show mild recent-memory problems, but daily functioning is
largely preserved and behavior remains unchanged. They do not yet meet the criteria for dementia -> only for very mild
cognitive decline. Because the brain is not yet severely damaged, this stage is considered the key therapeutic window.
Ê Therapeutic relevance: new disease-modifying treatments mainly target MCI, aiming to slow disease progression
before irreversible damage occurs.
3) Dementia -> long-standing and progressive accumulation of neurofibrillary tangles.
3. Diagnosing Alzheimer’s Disease
Diagnosis of Alzheimer’s disease is based on clinical assessment combined with biomarkers, which change gradually as the
disease progresses. => a process often visualized through different colored curves (Different colors are the different markers).
â Functional decline (brown curve) -> reflect loss of independence in daily activities.
Ê These changes are present in all patients with dementia.
â Neuropsychological examination (purple curve = diagnostic cornerstone): trained neuropsychologist assesses multiple
cognitive domains using standardized tests.
Ê Through this assessment, patients can be classified as having normal cognition, MCI, or dementia.
Preclinical phase: pathology
is already ongoing !!!
Research indicates that people with abnormal biomarkers in the preclinical stage will likely develop symptoms if they live
long enough. Therefore, early recognition, particularly during MCI (the therapeutic window), is essential for disease-modifying
treatments.
Ê Thus: Biomarkers allow accurate diagnosis of AD, also in the predementia stage.
3.1 Neuropsychological Examination
A neuropsychological assessment is an essential step in diagnosing cognitive disorders, including Alzheimer’s disease.
â Requires neuropsychologist
â Time-consuming: 2h of testing, 1h of data analysis and writing report
â Reimbursed once in a life-time, and only partially (± 50% of total cost)
Thus:
- Neuropsychology = required!
- Neuropsychology = major obstacle in diagnostic work-up given number of neuropsychologists and reimbursement.
3.2 MRI in AD: Hippocampal Atrophy
The hippocampal atrophy can sometimes be very hard to visualize on a brain MRI, especially in the early stages.
,3.3 CSF Biomarkers
Cerebrospinal fluid (CSF) biomarkers are a key diagnostic tool for AD and reflect early pathological changes in the brain.
Ê Why CSF biomarkers?
- Alzheimer pathology begins with amyloid accumulation (first pathological event).
- Amyloid can be visualized with a PET scan.
9 But due to cost, tracer-dependence, and limited reimbursement/availability in Belgium, PET is rarely routine.
- Therefore, clinicians more commonly perform a lumbar puncture to analyze CSF, which contains important proteins
and biomarkers that can indicate abnormal amyloid or tau processing, in a less costly and more accessible way.
Tau biomarkers:
- Phosphorylated tau (P-tau): = increased in Alzheimer’s disease.
- Total tau: represents both normal tau and hyperphosphorylated tau.
9 Total tau can also increase in other neurodegenerative conditions,
such as stroke, making it less specific for AD.
Amyloid-beta (Aβ) biomarkers:
- CSF Aβ1-42: Levels are lower in AD.
- Specificity can be improved by calculating the Aβ1-42 / Aβ1-40 ratio.
Diagnostic criteria using CSF biomarkers:
P Low amyloid marker (Aβ1-42 or ratio) + elevated tau (especially P-tau)
CSF biomarkers vs amyloid PET
CSF PET
Invasive (LP) Not invasive
Accessibility Limited accessibility
Cheap (€145) Expensive (>€1000)
Not reimbursed Not reimbursed
Info about tau-pathology and Topographical information
neurodegeneration
Can detect very early changes Can detect early changes
Analysis of AD CSF Biomarkers
• Requires lumbar puncture -> relatively invasive
• Generally well-tolerated with minimal side effects
• Provides a relatively low-cost method for assessing AD pathology
• Offers a comprehensive overview of AD-related changes
• High diagnostic yield; widely used in routine clinical practice for AD diagnosis
3.4 Blood Biomarkers
Phosphorylated tau 217 (pTau217) is a blood-based biomarker that strongly correlates with tau pathology in the brain, a
hallmark of AD.
Ê It provides a minimally invasive, low-cost alternative to CSF analysis and PET imaging.
Ê Levels become abnormal before clinical symptoms appear, making it suitable for very early detection.
Clinical relevance of pTau217:
• Distinguishes AD from other causes of dementias with high accuracy.
• Detects AD pathology in pre-symptomatic individuals.
• Is used in clinical trials for (pre)screening purposes.
• Start to be used in tertiary memory clinics under controlled circumstances / well-defined clinical indications.
• Potential to transform screening and diagnosis in primary care settings.
, 4. Treatment of AD: Current Situation
Current treatment of AD focuses on maintaining quality of life (QoL) for as long as possible:
• Individualised guidance
• Individualised treatment
• Focus on independency
• Delay of nursing home placement
Ê !!! Stop symptomatic treatment when side effects reduce quality of life more than they help.
Current Treatment Options in Alzheimer’s Disease
1. Psychoeducation and Cognitive Rehabilitation -> helps patients adapt daily routines.
2. Symptomatic Pharmacological Treatments
• Cholinesterase inhibitors and memantine
• Provide modest, temporary improvements in cognition and daily functioning
• Do not modify disease progression
3. Behavioral and Psychological Symptoms of Dementia (BPSD) treatment
• Non-pharmacological strategies first: structured routines, environmental adjustments, caregiver support
• Pharmacological treatments only if symptoms are severe or distressing
4. Other Supportive Measures
• Control cardiovascular risk factors (hypertension, diabetes)
• Encourage cognitive and physical activity
• Promote healthy lifestyle: moderate alcohol, social engagement
5. Disease-Modifying Treatment (DMT): Anti-Amyloid Monoclonal Antibodies
Anti-amyloid monoclonal antibodies are the first therapies aimed at modifying the underlying Alzheimer’s pathology rather
than just relieving symptoms.
Mechanism of Action
Anti-amyloid monoclonal antibodies target amyloid-β (Aβ) plaques in the brain.
Ê They promote microglial activation, leading to phagocytosis and clearance of
fibrillar amyloid, followed by degradation in the endosomal–lysosomal system.
Ê The aim is to reduce amyloid burden and potentially slow disease progression.
Side Effects: Amyloid-Related Imaging Abnormalities (ARIA)
A major safety concern associated with these therapies is ARIA, which includes:
• ARIA-E: Cerebral edema, often asymptomatic.
• ARIA-H: Microhemorrhages, can occasionally lead to larger brain bleeds.
Although ARIA can also occur spontaneously in untreated individuals, it is much more frequent and severe in treated patients.
Therefore, regular MRI monitoring is required, and treatment may be paused or discontinued if ARIA develops.
Anti-Amyloid Antibodies
• Aducanumab: first approved, clears amyloid, modest benefit.
• Lecanemab: slows cognitive decline ~30%, better if started early.
• Donanemab: similar to lecanemab, modest effect, FDA & EMA approved but costly.
