Low prevalence of CCR5-Δ32, CCR2-64I and SDF1-3′A alleles in ...
OUTLOOKALZHEIMER’S DISEASE AN AGE-OLD STORY A GLOBAL … · 2020-04-08 · ages, the number...
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AN AGE-OLD STORY DISEASE OF DECLINE Subtle losses of memory or changes in behaviour are the first outward signs of Alzheimer’s disease. Slowly but relentlessly, cognition declines, language is disrupted and behavioural changes accumulate, diminishing a person’s independence. These changes are underpinned by both structural and microscopic changes in the brain. A SLOW MARCH By the time that a person begins to experience the symptoms of Alzheimer’s disease, the condition is already well-established in the brain. The accumulation of amyloid-β, generally thought to be the first step in disease progression, could precede symptoms by 10–15 years. Tau accumulation occurs later, much closer to the onset of neurodegeneration. 10–15% of people with mild cognitive impairment* go on to develop dementia each year. *Mild cognitive impairment is an abnormal decline in cognition that, unlike Alzheimer’s disease, does not affect daily living. It is considered to be a precursor to the condition. Amyloid-β plaques Tau-mediated neuron injury and dysfunction Brain structural changes Memory impairment Functional deficits Dementia Mild cognitive impairment Disease progression Disease hallmark Normal cognition Alzheimer’s disease is a progressive neurodegenerative condition of the brain that is responsible for around two-thirds of dementia cases. Despite much effort, the condition’s cause remains uncertain and no effective treatment yet exists. By Liam Drew; infographic by Mohamed Ashour. Alzheimer’s disease is a progressive neurodegenerative condition of the brain that is responsible for around two-thirds of dementia cases. Despite much effort, the condition’s cause remains uncertain and no effective treatment yet exists. By Liam Drew; infographic by Mohamed Ashour. STRUCTURAL CHANGES Alzheimer’s disease spreads through the brain, causing a progressive loss of the connections between neurons (synapses), and then neurons themselves. In the later stages of the condition, the brain is noticeably shrunken — the cerebral cortex appears shrivelled and the fluid-filled ventricles are expanded. 8–10 YEARS The average time for which a person with Alzheimer’s disease lives after diagnosis. MICROSCOPIC CHANGES Two hallmarks of Alzheimer’s disease are visible only under the microscope. Accumulations of the peptide amyloid-β, known as plaques, form between neurons. Microtubule- associated protein tau aggregates into neurofibrillary tangles inside neurons, and these structures persist after neurons have died. NORMAL BRAIN Fluid-filled ventricles Cerebral cortex Hippocampus The hippocampus, an area of the brain that is crucial for memory formation, is one of the first areas to be affected. Tissue loss is severe. ALZHEIMER’S DISEASE Amyloid-β plaque Neurofibrillary tangle Neuron ADAPTED FROM ILLUSTRATION BY STACY JANNIS/ALZHEIMER'S ASSOCIATION ADAPTED FROM REF. 1 S2 | NATURE | VOL 559 | 26 JULY 2018 ALZHEIMER’S DISEASE OUTLOOK ©2018SpringerNatureLimited.Allrightsreserved.
Transcript of OUTLOOKALZHEIMER’S DISEASE AN AGE-OLD STORY A GLOBAL … · 2020-04-08 · ages, the number...
Neuron
AD
AP
TED
FR
OM
REF
. 5
Nucleus
AN AGE-OLD STORY
G E N E T I C SAround 1% of cases of
Alzheimer’s disease are caused by mutations in the genes APP, PSEN1 or PSEN2, which a�ect amyloid-β processing. Certain mutations in APOE and TREM2
can increase the risk of developing the more common sporadic form of the condition.
S E XThe overall incidence of
Alzheimer’s disease in women is up to twice that of men4. This di�erence cannot be explained
by women’s greater life expectancy — but hormones
and lifestyle might play a part.
L I F E S T Y L EA raft of potentially modi�able
risk factors for Alzheimer’s disease have been identi�ed.
These include diabetes, obesity, depression, smoking and low
educational attainment.
A G E I N G A N D G R O W I N GIn 2015, almost 50 million people worldwide had dementia2. As the population grows and ages, the number a�ected is expected to surpass 130 million people by 2050.
L O C A L L E S S O N SThe prevalence of Alzheimer’s disease (left) in people aged 60 or above is highest in north Africa and the Middle East, and the condition is least common in central Europe2. In a�uent countries in the West, such as the United Kingdom, a decline in the prevalence of Alzheimer’s disease in the elderly has been observed (right)3. This suggests that concurrent changes in lifestyle might have provided some protection from dementia (see page S18).
1990–93 2008–11
D I S E A S E O F D E C L I N ESubtle losses of memory or changes in behaviour are the �rst outward signs of Alzheimer’s disease. Slowly but relentlessly, cognition declines, language is disrupted and behavioural changes accumulate, diminishing a person’s independence. These changes are underpinned by both structural and microscopic changes in the brain.
A S L O W M A R C H By the time that a person begins to experience the symptoms of Alzheimer’s disease, the condition is already well-established in the brain. The accumulation of amyloid-β, generally thought to be the �rst step in disease progression, could precede symptoms by 10–15 years. Tau accumulation occurs later, much closer to the onset of neurodegeneration.
A G L O B A L P R O B L E M
R I S K FA C T O R S
10–15% of people with mild
cognitive impairment* go on to develop
dementia each year.
*Mild cognitive impairment is an abnormal decline in cognition that, unlike Alzheimer’s disease, does not
a�ect daily living. It is considered to be a precursor to the condition.
Sources: 1. Jack. C. R. Jr et al. Lancet Neurol. 12, 207–216 (2013); 2. Alzheimer’s Disease International. World Alzheimer Report 2015: The Global Impact of Dementia (Alzheimer’s Disease International, 2015); 3. Matthews, F. E. et al. Lancet 382, 1405–1412 (2013); 4. Chêne, G. et al. Alzheimers Dement. 11, 310–320 (2015); 5. L. Mucke. Nature 461, 895–897 (2009).
Amyloid-β plaques
Tau-mediated neuroninjury and dysfunction
Brain structural changes
Memory impairment
Functional de�cits
Dementia
Mild cognitive impairment
Disease progression
Dis
ease
hal
lmar
k
Normal cognition
Peo
ple
wor
ldw
ide
with
dem
entia
(m
illio
ns)
Standardized prevalence in those aged ≥60 Age2015 2050
Alzheimer’s disease is a progressive neurodegenerative condition of the brain that is responsible for around two-thirds of dementia cases. Despite much effort, the condition’s cause remains uncertain and no effective treatment yet exists. By Liam Drew; infographic by Mohamed Ashour.
Alzheimer’s disease is a progressive neurodegenerative condition of the brain that is responsible for around two-thirds of dementia cases. Despite much effort, the condition’s cause remains uncertain and no effective treatment yet exists. By Liam Drew; infographic by Mohamed Ashour.
30
60
90
120
150
Estim
ated
pre
vale
nce
(%
)
40
30
20
10
0S T R U C T U R A L C H A N G E SAlzheimer’s disease spreads through the brain, causing a progressive loss of the connections between neurons (synapses), and then neurons themselves. In the later stages of the condition, the brain is noticeably shrunken — the cerebral cortex appears shrivelled and the �uid-�lled ventricles are expanded.
0 65–69 70–74 75–79 80–84 85–89 ≥902 4 6 8
Europe
Asia andAustralasia
Americas
Africa andMiddle East
T R E AT M E N TS T H R O U G H U N D E R S TA N D I N GThe amyloid hypothesis is the most widely accepted mechanism to account for Alzheimer’s disease. It posits that the condition is driven by aggregation of amyloid-β. The proposed sequence of events presents several opportunities for intervention, but so far no drug has been shown to reverse, stop or even slow the condition’s advance.
8–10 YEARSThe average time for which a person with Alzheimer’s
disease lives after diagnosis.
M I C R O S C O P I C C H A N G E STwo hallmarks of Alzheimer’s disease are visible only under the microscope.
Accumulations of the peptide amyloid-β, known as plaques, form between neurons. Microtubule-associated protein tau aggregates into neuro�brillary tangles inside neurons, and these structures persist after neurons have died.
NORMAL BRAIN
Fluid-�lled ventricles
Cerebral cortex
Hippocampus
The hippocampus, an area of the brain that is crucial for memory formation, is one of the �rst areas to be a�ected. Tissue loss is severe.
ALZHEIMER’S DISEASE
Amyloid-β plaque
Neuro�brillary tangle
Amyloid-β is produced by the cleavage of amyloid precursor protein in the membrane of neurons.
In the space between neurons, amyloid-β forms oligomers that are thought to disrupt the function of synapses.
Fibrils of amyloid-β oligomers aggregate into plaques, which interfere with the function of neurons.
Amyloid-β deposits outside cells and in blood vessels of the brain activate immune cells called microglial cells that congregate around a�ected neurons. This triggers the release of in�ammatory mediators and might contribute to synapse loss.
Misfolded tau aggregates into neuro�brillary tangles inside neurons, displacing intracellular organelles.
Misfolded tau can pass through synapses to other neurons, where it catalyses further misfolding of tau.
1
2
3
4
5
6
A
B
C
O P P O R T U N I T I E S F O R I N T E R V E N T I O N Amyloid-β
plaque Amyloid-β
Neuro�brillarytangle
Tau
Mitochondrion
Synapse
Oligomer
Microglialcell
1
2
A
B
C
3
4
5
6
Neuron
In�ammatory mediators
Amyloid-βaccumulation
Blood vessel
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Inhibitors of the enzymes that cut amyloid precursor protein and antibodies that bind to various forms of amyloid-β have been tested without success (see page S4).
Immunotherapies and small molecules that inhibit the aggregation and spread of tau are also under development.
If in�ammation is shown to contribute to Alzheimer’s disease, anti-in�ammatory drugs could provide bene�ts to those a�ected.
S 2 | N A T U R E | V O L 5 5 9 | 2 6 J U L Y 2 0 1 8
ALZHEIMER’S DISEASEOUTLOOK
© 2018
Springer
Nature
Limited.
All
rights
reserved. ©
2018
Springer
Nature
Limited.
All
rights
reserved.
Neuron
AD
AP
TED
FR
OM
REF
. 5
Nucleus
AN AGE-OLD STORY
G E N E T I C SAround 1% of cases of
Alzheimer’s disease are caused by mutations in the genes APP, PSEN1 or PSEN2, which a�ect amyloid-β processing. Certain mutations in APOE and TREM2
can increase the risk of developing the more common sporadic form of the condition.
S E XThe overall incidence of
Alzheimer’s disease in women is up to twice that of men4. This di�erence cannot be explained
by women’s greater life expectancy — but hormones
and lifestyle might play a part.
L I F E S T Y L EA raft of potentially modi�able
risk factors for Alzheimer’s disease have been identi�ed.
These include diabetes, obesity, depression, smoking and low
educational attainment.
A G E I N G A N D G R O W I N GIn 2015, almost 50 million people worldwide had dementia2. As the population grows and ages, the number a�ected is expected to surpass 130 million people by 2050.
L O C A L L E S S O N SThe prevalence of Alzheimer’s disease (left) in people aged 60 or above is highest in north Africa and the Middle East, and the condition is least common in central Europe2. In a�uent countries in the West, such as the United Kingdom, a decline in the prevalence of Alzheimer’s disease in the elderly has been observed (right)3. This suggests that concurrent changes in lifestyle might have provided some protection from dementia (see page S18).
1990–93 2008–11
D I S E A S E O F D E C L I N ESubtle losses of memory or changes in behaviour are the �rst outward signs of Alzheimer’s disease. Slowly but relentlessly, cognition declines, language is disrupted and behavioural changes accumulate, diminishing a person’s independence. These changes are underpinned by both structural and microscopic changes in the brain.
A S L O W M A R C H By the time that a person begins to experience the symptoms of Alzheimer’s disease, the condition is already well-established in the brain. The accumulation of amyloid-β, generally thought to be the �rst step in disease progression, could precede symptoms by 10–15 years. Tau accumulation occurs later, much closer to the onset of neurodegeneration.
A G L O B A L P R O B L E M
R I S K FA C T O R S
10–15% of people with mild
cognitive impairment* go on to develop
dementia each year.
*Mild cognitive impairment is an abnormal decline in cognition that, unlike Alzheimer’s disease, does not
a�ect daily living. It is considered to be a precursor to the condition.
Sources: 1. Jack. C. R. Jr et al. Lancet Neurol. 12, 207–216 (2013); 2. Alzheimer’s Disease International. World Alzheimer Report 2015: The Global Impact of Dementia (Alzheimer’s Disease International, 2015); 3. Matthews, F. E. et al. Lancet 382, 1405–1412 (2013); 4. Chêne, G. et al. Alzheimers Dement. 11, 310–320 (2015); 5. L. Mucke. Nature 461, 895–897 (2009).
Amyloid-β plaques
Tau-mediated neuroninjury and dysfunction
Brain structural changes
Memory impairment
Functional de�cits
Dementia
Mild cognitive impairment
Disease progression
Dis
ease
hal
lmar
k
Normal cognition
Peo
ple
wor
ldw
ide
with
dem
entia
(m
illio
ns)
Standardized prevalence in those aged ≥60 Age2015 2050
Alzheimer’s disease is a progressive neurodegenerative condition of the brain that is responsible for around two-thirds of dementia cases. Despite much effort, the condition’s cause remains uncertain and no effective treatment yet exists. By Liam Drew; infographic by Mohamed Ashour.
Alzheimer’s disease is a progressive neurodegenerative condition of the brain that is responsible for around two-thirds of dementia cases. Despite much effort, the condition’s cause remains uncertain and no effective treatment yet exists. By Liam Drew; infographic by Mohamed Ashour.
30
60
90
120
150
Estim
ated
pre
vale
nce
(%
)
40
30
20
10
0S T R U C T U R A L C H A N G E SAlzheimer’s disease spreads through the brain, causing a progressive loss of the connections between neurons (synapses), and then neurons themselves. In the later stages of the condition, the brain is noticeably shrunken — the cerebral cortex appears shrivelled and the �uid-�lled ventricles are expanded.
0 65–69 70–74 75–79 80–84 85–89 ≥902 4 6 8
Europe
Asia andAustralasia
Americas
Africa andMiddle East
T R E AT M E N TS T H R O U G H U N D E R S TA N D I N GThe amyloid hypothesis is the most widely accepted mechanism to account for Alzheimer’s disease. It posits that the condition is driven by aggregation of amyloid-β. The proposed sequence of events presents several opportunities for intervention, but so far no drug has been shown to reverse, stop or even slow the condition’s advance.
8–10 YEARSThe average time for which a person with Alzheimer’s
disease lives after diagnosis.
M I C R O S C O P I C C H A N G E STwo hallmarks of Alzheimer’s disease are visible only under the microscope.
Accumulations of the peptide amyloid-β, known as plaques, form between neurons. Microtubule-associated protein tau aggregates into neuro�brillary tangles inside neurons, and these structures persist after neurons have died.
NORMAL BRAIN
Fluid-�lled ventricles
Cerebral cortex
Hippocampus
The hippocampus, an area of the brain that is crucial for memory formation, is one of the �rst areas to be a�ected. Tissue loss is severe.
ALZHEIMER’S DISEASE
Amyloid-β plaque
Neuro�brillary tangle
Amyloid-β is produced by the cleavage of amyloid precursor protein in the membrane of neurons.
In the space between neurons, amyloid-β forms oligomers that are thought to disrupt the function of synapses.
Fibrils of amyloid-β oligomers aggregate into plaques, which interfere with the function of neurons.
Amyloid-β deposits outside cells and in blood vessels of the brain activate immune cells called microglial cells that congregate around a�ected neurons. This triggers the release of in�ammatory mediators and might contribute to synapse loss.
Misfolded tau aggregates into neuro�brillary tangles inside neurons, displacing intracellular organelles.
Misfolded tau can pass through synapses to other neurons, where it catalyses further misfolding of tau.
1
2
3
4
5
6
A
B
C
O P P O R T U N I T I E S F O R I N T E R V E N T I O N Amyloid-β
plaque Amyloid-β
Neuro�brillarytangle
Tau
Mitochondrion
Synapse
Oligomer
Microglialcell
1
2
A
B
C
3
4
5
6
Neuron
In�ammatory mediators
Amyloid-βaccumulation
Blood vessel
AD
AP
TED
FR
OM
ILLU
STR
ATIO
N B
Y ST
AC
Y JA
NN
IS/A
LZH
EIM
ER'S
AS
SO
CIA
TIO
N
AD
AP
TED
FR
OM
REF
. 1
Inhibitors of the enzymes that cut amyloid precursor protein and antibodies that bind to various forms of amyloid-β have been tested without success (see page S4).
Immunotherapies and small molecules that inhibit the aggregation and spread of tau are also under development.
If in�ammation is shown to contribute to Alzheimer’s disease, anti-in�ammatory drugs could provide bene�ts to those a�ected.
ALZHEIMER’S DISEASE OUTLOOK
© 2018
Springer
Nature
Limited.
All
rights
reserved. ©
2018
Springer
Nature
Limited.
All
rights
reserved.
