BB30044: Pathophysiology of Alzheimer’s disease (RW)
WHAT IS ALZHEIMER’S DISEASE?
A progressive brain disorder and the leading cause of dementia
(dementia and ad not synonymous – other forms of dementia that
are not caused by ad e.g. vascular, frontotemporal)
associated with symptoms of memory loss and difficulties with
thinking, problem-solving and language (cognitive issues)
Precise, predictable progression: disease starts in the lateral
entorhinal cortex and spreads to other cortical regions such as the
parietal cortex
Projected rise from 44 million (2013) to 135 million affected
individuals by 2050 – affects 20% >80 year olds (source:
Alzheimer’s disease international)
However, rate of ad rise in the uk has slowed – likely due to better
management of risk factors by lifestyle changes (e.g. blood
pressure, cholesterol)
DEGENERATION IN AD BRAIN:
Early stages of ad involve loss of dendritic spines, synaptic terminals
and then neurons. This means dysfunction in synaptic signalling
occurs long before loss of functional neuronal units
Late stages of ad show extensive brain atrophy (reduced brain
volume with large ventricles) as brain neurons and tissues are lost.
Pet scans measure glucose utilisation to reveal reduced metabolic
activity in the late ad brain compared to normal brain
perhaps a more feasible therapeutic intervention to block
spine/terminal loss rather than neuronal/tissue loss.
PATHOLOGICAL FEATURES OF AD:
PLAQUES of β-amyloid peptide
deposited extracellularly
NEUROFIBRILLARY TANGLES of tau
form intracellularly
INFLAMMATION composed of reactive glia (microglia)
AGEs composed of advanced glycation end products
BOTH PLAQUES AND TANGLES required for post-mortem diagnosis
of ad
HYPOTHETICAL MODEL FOR AD DEVELOPMENT:
Advances in imaging and biomarker analysis (mri, pet scans,
markers in csf and blood) allow temporal mapping of ad.
, Discovery that the molecular changes defining ad occur ~20 years
before symptoms (e.g. cognitive deficits) manifest. Challenging for
drug development – therapeutic window is pre-diagnosis.
Model of ad maps changes in proteins, pathologies and symptoms
with
clinical disease development. Current dogma:
amyloid-b accumulation occurs first due to metabolic changes.
Synaptic dysfunction occurs with disease progression through the
preclinical stage
In the late preclinical stage, tau accumulation emerges, mediating
neuronal injury. Tau pathology correlates closely with symptom
development – maps onto symptoms much better than amyloid-b
pathology.
Gross anatomical changes in brain structure (e.g. volume, atrophy)
and cognition then occur in mci stage (mild cognitive impairment).
Majority of clinical trials are performed with mci populations.
Progression into dementia stage follows
SPORADIC & GENETIC LINKS TO PLAQUE FORMATION
98% of ad cases are sporadic, with age of onset over 65 years. Risk
of developing sporadic ad increases with age, but there is no known
defining cause.
Gwas (genome wide association studies) have identified genes that
may increase risk:
clusterin, picalm, trem2 (20 risk loci), apoe4 allele (one copy
increases risk x 4)
1-2% of cases are early onset (25-61 years) – familial/inherited
WHAT IS ALZHEIMER’S DISEASE?
A progressive brain disorder and the leading cause of dementia
(dementia and ad not synonymous – other forms of dementia that
are not caused by ad e.g. vascular, frontotemporal)
associated with symptoms of memory loss and difficulties with
thinking, problem-solving and language (cognitive issues)
Precise, predictable progression: disease starts in the lateral
entorhinal cortex and spreads to other cortical regions such as the
parietal cortex
Projected rise from 44 million (2013) to 135 million affected
individuals by 2050 – affects 20% >80 year olds (source:
Alzheimer’s disease international)
However, rate of ad rise in the uk has slowed – likely due to better
management of risk factors by lifestyle changes (e.g. blood
pressure, cholesterol)
DEGENERATION IN AD BRAIN:
Early stages of ad involve loss of dendritic spines, synaptic terminals
and then neurons. This means dysfunction in synaptic signalling
occurs long before loss of functional neuronal units
Late stages of ad show extensive brain atrophy (reduced brain
volume with large ventricles) as brain neurons and tissues are lost.
Pet scans measure glucose utilisation to reveal reduced metabolic
activity in the late ad brain compared to normal brain
perhaps a more feasible therapeutic intervention to block
spine/terminal loss rather than neuronal/tissue loss.
PATHOLOGICAL FEATURES OF AD:
PLAQUES of β-amyloid peptide
deposited extracellularly
NEUROFIBRILLARY TANGLES of tau
form intracellularly
INFLAMMATION composed of reactive glia (microglia)
AGEs composed of advanced glycation end products
BOTH PLAQUES AND TANGLES required for post-mortem diagnosis
of ad
HYPOTHETICAL MODEL FOR AD DEVELOPMENT:
Advances in imaging and biomarker analysis (mri, pet scans,
markers in csf and blood) allow temporal mapping of ad.
, Discovery that the molecular changes defining ad occur ~20 years
before symptoms (e.g. cognitive deficits) manifest. Challenging for
drug development – therapeutic window is pre-diagnosis.
Model of ad maps changes in proteins, pathologies and symptoms
with
clinical disease development. Current dogma:
amyloid-b accumulation occurs first due to metabolic changes.
Synaptic dysfunction occurs with disease progression through the
preclinical stage
In the late preclinical stage, tau accumulation emerges, mediating
neuronal injury. Tau pathology correlates closely with symptom
development – maps onto symptoms much better than amyloid-b
pathology.
Gross anatomical changes in brain structure (e.g. volume, atrophy)
and cognition then occur in mci stage (mild cognitive impairment).
Majority of clinical trials are performed with mci populations.
Progression into dementia stage follows
SPORADIC & GENETIC LINKS TO PLAQUE FORMATION
98% of ad cases are sporadic, with age of onset over 65 years. Risk
of developing sporadic ad increases with age, but there is no known
defining cause.
Gwas (genome wide association studies) have identified genes that
may increase risk:
clusterin, picalm, trem2 (20 risk loci), apoe4 allele (one copy
increases risk x 4)
1-2% of cases are early onset (25-61 years) – familial/inherited
