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8/3/2019 Cotman - Ppt
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Exercise induces BDNF,
improves learning and reduces
-amyloid
Carl W. Cotman
Institute for Brain AgingUniversity of California, Irvine
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Behavioral Interventions:
The New Direction
Exercise
MentalActivity
Diet
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Outline
Part 1. Can exercise induce neurotrophic
factors and improve learning?Part 2. Can exercise reduce pathology in a
AD transgenic mouse and improvelearning?
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BDNF (Brain Derived Neurotrophic
Factor) is a Synaptic Modulator:
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BDNF Brain Derived
Neurotrophic Factor Necessary for learning and long term
synaptic change Stimulates synaptic growth and
neurogenesis Protects neurons from injury
How to get more? Simple - exercise
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Is BDNF increased by
exercise in the brain ?
Where? And how fast and long
lasting?
How much exercise?
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Exercise increases BDNF mRNAHIPPOCAMPUS:
Rats: 1 week exercise (male sprague-dawley, 3 months)
Berchtold et al., 2002
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Time course of BDNF Protein
Induction
0
2550
75
100
125150
175
200
225
250
0
2550
75
100
125
150
175
200
225
250
20 4 7 14 28 72
DAILY EXERCISE
***
***
***
0 7 14 28
*
**
ALTERNATING DAYS
BDNFProtein
(%S
eden
tary)
Days Days
Berchtold, et al., submitted
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So..what is the functional
significance?
Learning?
Stress Relief?
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Exercise Enhances
Learning in the Morris Water Maze
0
20
40
60
80
100
120
Timetoreachplatform(
sec
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
Days of training
Sedentary
Exercising
* p < 0.05*
*
*
*
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Blocking BDNF action (anti-TrkB) during the exercise period on
memory retention using the probe trial on the Morris Water Maze task(Vaynman, et al., 2004)
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Can exercise prevent the stress
induced reduction in BDNF? Animals given 3 wks. of voluntary running
Subjected to acute immobilization stress Circulating corticosterone and brain BDNF
measured
Hypothesis: Exercise will offset the effect of
acute stress, possibly via a reduction inlevels of circulating corticosterone.
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At 10 hours post-stress, BDNF is decreased in stressed animals,
but remains elevated in animals that had prior exercise
0
20
40
60
80
100
120
140
160
180
200
Normalisedlevel
ofBDNFprot
ein(%o
f
sedentary)standarderrorattenhours
ControlSedentary
ControlExercising
StressedSedentary
StressedExercising
*
*
*
* Significantly different (p
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Many plasticity genes are regulated
by BDNF,e.g., Synapsin: Regulates presynaptic vesicle availability
Modulates neurotransmitter release into synapse Block TrkB in vivo suppresses exercise-induction of synapsin mRNA (Gomez-Pinilla,
2003)
CREB: Transcription factor, drives downstream gene expressionImportant in LTP, learning and memory
Block TrkB in vivo suppresses exercise-induction of CREB (Gomez-Pinilla, 2003)
NR2b: subunit of glutamate receptor (NMDA)Overexpression enhances LTP and improves learning Slice culture: BDNF increases NR2b protein
NARP: Trafficking/insertion of glutamate receptors in PSD,critical to LTP and learning Slice culture: BDNF increases NARP protein
COX-2: traditionally known for immune functionRole in plasticity: localized to dendrites
Slice culture: BDNF increases COX-2 protein
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Practical Questions
How long lasting is the increase after
stopping exercise? How frequent is necessary
Can the increase be recoveredrapidly if exercise is stopped for a
peroid?
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Is there a molecular memory
for exercise?
Many of the gene changes including CREB arelinked to learning and memory
Is the experience of exercise encoded so toallow the brain to learn to respond?
Thus, if so exercise may prime the brain to
respond to experiences, and induce a state ofreadiness.
How Often to Exercise?: Is there a
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How Often to Exercise?: Is there a
Molecular Memory Exercise
Paradigm:
14 days of exercise:
- Daily (during 2 weeks)- Alternating (during 4 weeks)
Wheels locked:
- 1 week, 2 weeks
Second short run period (2 days)
Note: 2 days exercise alone isnot sufficient to increase BDNF
0
2550
75
100
125
150
175
200
1 wk delay2 wk delay
Daily Alternating DaysSED
*** *** ******
roten
(%s
edentary)
Prior Exercise Primes subsequent BDNFResponsiveness
Priming effect endures at least 2 weeks
Equivalent Secondary Responsiveness if prior
exercise is Daily Regime or Alternating Days ofExercise
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HIPPOCAMPUSGenomic regulationStructural change
- vascular- neuronal- neurogenesis
Increased neuronal health
EXERCISE
PeripheralFactors
Blood Brain Barrier
EstrogenIGF-1
Raphe (5-HT)Locus coeruleus (NE)
BDNF
Glucocorticoids
Medial Septum
other plasticity genes
(ACh/GABA)
Cotman & BerchtoldCotman & Berchtold
20022002
E t d i ti d b li
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Estrogen-deprivation reduces baseline
BDNF gene expression (Berchtold, etal., E.J.of Neurosc., 2001)
Intact
OVX-3
OVX-7
100
125
150
DG hilus CA3 CA1
0
25
50
75
***
*
*T*
*T
B
DNFmRNAex
pression
(%I
ntact)
* p
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xerc se- n uceincrease is lost after 7 weeks of
estrogen deprivation
0
25
50
75
100
125
150
175INTACT OVX-3 wk OVX-7 wk
BDNFm
RNAexpress
ion
(%s
ed
entaryIntact)
***
***
SedentaryExercise
*** significantly different from sedentary p
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Estrogen-replacement
increases BDNF mRNA level
B
DNFmRNAexp
ression
(%s
edentaryIn
tact)
200
0
25
50
75
100
125
150
175
225
DG hilus CA3 CA1
OVX-7
OVX-7/E
T
***
***
*** p
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Exercise Further Increases
BDNF, Specifically in the DG
DG hilus CA3 CA1
0
50
100
150
200
**T
SED
EX
BDNFmRNAexpression
(
%s
edentaryInta
ct)
** p
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ormone rep acemen(17-beta Estradiol)
Restores Running Behavior
0
500
1000
1500
2000
2500
3000
3500
1 2 3 4 5
OVX
OVX/Ebeta
INTACT
*
**
**
*
T
Days
nigh
tlyrunningdist
ance
(meters)
* p
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ESTROGENPHYSICALACTIVITY
BDNF
I i ff ti i AD
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Is exercise effective in AD
transgenic models ?
Will voluntary running improve learningand memory?
Stimulate neurogenesis? Reduce -amyloid in the brain?
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Animal model
Widespread plaque deposition, including the hippocampus and
cortex
Chishti et al., JBC 276: 21562-21570, 2001.
V l t E i P di
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Voluntary Exercise Paradigm(Adlard, etal., 2005)
Utilized TgCRND8 mouse model
Voluntary access to running wheels (animals run ~3 miles/day)
Short-term running
- start at 6 weeks of age
- sacrifice four weeks later
Long-term running
- start at 6 weeks of age- sacrifice 5 months later
E i i h f f
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Exercise improves the performance of
TgCRND8 animals in the Morris water maze
0
5
10
15
20
25
30
35
40
45
50
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6Averageescapelatency(seconds)
standard
er
ror
Sedentary
Exercise
*
*
*
* p
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Long-term running reduces -amyloid
load in TgCRND8 animals(by immunohistochemistry)
Long-term running reduces -amyloid
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Long term running reduces amyloid
load in TgCRND8 animals(by ELISA)
0
20
40
60
80
100
120
140
A1-40 A1-42Formic-acidextractablecor
ticalamyloid
(%
ofsedentary
)
SedentaryExercise
* *
L t i h
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Long-term running enhances
neurogenesis in TgCRND8 animals
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Mechanism: Long-term running had -
no effect on steady-state levels of the amyloidprecursor protein, APP
no effect on secretase activity levels (, , )
Does short term running affect APP
processing?
Short-term running mediates APP
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Short term running mediates APP
processing
0
20
40
60
80
100
120
A1-40 A1-42
P
ercentage
of
sedent
ary
Sedentary
Exercise
0
20
40
60
80
100
120
alpha-CTF beta-CTF
P
ercentage
of
sedent
ary
Sedentary
Exercise
no effect on total APP
no effect on secretase activity (, , )
no effect on neprilysin or IDE
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Summary
BDNF increases with exercise in the
hippocampus within a few days and lasts BDNF induction can be rapidly restored bya brief period of exercise even after
exercise is stopped for weeks Exercise improves the rate of learning
Exercise reduces -amyloid in thehippocampus and cortex
Exercise alters APP processing
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Summary Part 2
Exercise in a transgenic AD mouse
improves learning Exercise reduces -amyloid in the
hippocampus and cortex
Exercise alters APP processing
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Diet? What effect
does an antioxidant
diet have on
cognition?
Can antioxidants and/or
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Exercise/Environmental Enrichment
Delay the Development of Age
Dependent Cognitive Dysfunction
and Neuropathology in Canines?
Canine Antioxidant
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Canine Antioxidant
Diet Antioxidants
dl-alpha tocopherol acetate-1050 ppm (20 mg/kg - 800IU
Stay-C (ascorbyl
monophosphate)-100 ppm Spinach, carrot granules,
tomato pomace, citrus pulp,grape pomace - 1% each in
exchange for corn(Increased ORAC by 50%)
Mitochondrial cofactors
dl-Lipoic acid - 135 ppm (2.7mg/kg)
l-carnitine,Acetyl-car-300
ppm (6 mg/kg)
ROS
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Enrichment Protocol
Play toys kennelmate
3x20 min walks additional cognitive
experience
Controls
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6 months
Learning Is Impaired in Old
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Oddity Discrimination Learning as a Function of Age
Task
Oddity -1 Oddity -2 Oddity -3 Oddity -4
ErrorstoCriterion(Mean)
0
20
40
60
80
100
120
140
Young Dogs
Old Dogs
Aged dogs make
more mistakes astask complexity
increases .
Canines
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E ffec t o f d ie t on od d i ty d isc r im ina tion in a ge d b ea g les
O dd ity task
0 1 2 3 4 5
Errorstocriterion
0
5 0
1 0 0
1 5 0
2 0 0C o n t r o lA n t i o x i d a n t
*
*
Diet fortified animals make few mistakes as task difficulty increases
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Is the intervention able to
reverse age relatedcognitive dysfunction?
Spatial Memory and
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p y
TreatmentP
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What effect, if any, do thetreatments have on brain
pathology?
Effect of Antioxidant Diet on
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Total Amyloid Load (6E10)By Brain Region
Brain Region
Prefrontal Entohrinal Parietal Occipital
AmyloidLoad(%
)
0
2
4
6
8
Control Diet
Antioxidant Diet
Entorhinal
Conclusion
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Conclusion
A growing clinical literature suggests that
exercise and diet can delay the onset ofcognitive decline and AD
Animal models show that exercise induces
BDNF, a key plasticity and neuroprotecive
factor
Animal models show that exercise and dietcan reduce -amyloid levels
Summary Part 3
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Summary Part 3
A diet enriched in mitochondrialantioxidants improves learning in aged
dogs Reduces -amyloid accumulation
Diet plus environmental enrichment is
better than either alone
Reduced reactive oxygen species(ROS) production by mitochondria in
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(ROS) production by mitochondria in
treated aged dogs
Time5 min 10 min 15 min
%I
ncreaseinReactiveOxygenSp
eciesProduction
0
200
400
600
800
1000
1200
1400YoungOld Control
Old Antioxidant
ROS
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Long-term running enhances
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g g
neurogenesis in TgCRND8 animals
Is there a molecular memory for
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exercise? Exercise may prime the brain for learning
and induces a state of readiness?
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exercise seems to prime the brain to respond to
experiences, induce a state of readiness.
Is there a molecular memory for
exercise?
BDNF is a Synaptic
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BDNF is a Synaptic
Modulator
Is BDNF induced by exerciseand where in brain?
How much exercise?
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Exercise increases BDNF mRNAHIPPOCAMPUS:
Rats: 1 week exercise (male sprague-dawley, 3 months)
Berchtold et al., 2002
Exercise increases BDNF protein
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Exercise increases BDNF protein
Distance (meters/night)
500040003000200010000
60
120
180
240300
360
BDNF(pg/ml)
R2 = 0.771
D.
EX SED0
100
200
300
BDNF(pg/ml)
*C.
Group
Many plasticity genes are regulated
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by BDNF,e.g., Synapsin: Regulates presynaptic vesicle availability
Modulates neurotransmitter release into synapse
Block TrkB in vivo suppresses exercise-induction of synapsin mRNA (Gomez-Pinilla,2003)
CREB: Transcription factor, drives downstream gene expressionImportant in LTP, learning and memory
Block TrkB in vivo suppresses exercise-induction of CREB (Gomez-Pinilla, 2003)
NR2b: subunit of glutamate receptor (NMDA)Overexpression enhances LTP and improves learning Slice culture: BDNF increases NR2b protein
NARP: Trafficking/insertion of glutamate receptors in PSD,
critical to LTP and learning Slice culture: BDNF increases NARP protein
COX-2: traditionally known for immune functionRole in plasticity: localized to dendrites Slice culture: BDNF increases COX-2 protein
Exercise restores some of theage-related losses in synaptic
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age related losses in synaptic
proteins
50
75
100
125
150
PSD-95 VESL/homer COX-2 Synapsin
%
YoungSe
dentary
CNS and Peripheral FactorsInteract with Exercise to Regulate
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Interact with Exercise to Regulate
BDNF
Exercise Hippocampus DownstreamfunctionalchangesBDNF
Medial Septum(ACh/GABA)
Locus Coeruleus (NE)
Raphe (5-HT)
Peripheral Factors
Blood-Brain Barrier
IGF-1EstrogenGlucocorticoids
Cotman and Berchtold (2002), TINS
Practical Questions
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Practical Questions
How long lasting is the increase after
stopping exercise? How frequent is necessary
Can the increase be recoveredrapidly if exercise is stopped for a
peroid?
BDNF Protein Stability
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After Exercise Ends
Berchtold, et al., submitted
0
20
40
60
80
100
120
140
160
180
SED
BDNFprotein(%s
edentary)
0 1 3 7 14
Days after end of exercise(4 weeks Daily Exercise)
*** ***
* *Paradigm: 4 weeks daily voluntaryexercise
Day 0 - end of exercise
period,- wheels locked
Sacrifice on days 0,1,3,7,14
after end of exercise
Protein levels assessed
Time course of BDNF Protein
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Induction
0
25
50
75
100
125
150
175
200
225
250
0
25
50
75
100
125
150
175
200
225
250
20 4 7 14 28 72
DAILY EXERCISE
***
***
***
0 7 14 28
*
**
ALTERNATING DAYS
BDNFP
rotein
(%S
edentary)
Days Days
Berchtold, et al., submitted
Is there a molecular memory
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for exercise?
Many of the gene changes including CREB arelinked to learning and memory
Is the experience of exercise encoded so to
allow the brain to learn to respond?
Thus, if so exercise may prime the brain to
respond to experiences, and induce a state ofreadiness.
Once exercise stops is the induction stored in
molecular memory?!
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molecular memory?!
0
25
50
75
100
125
150
175
200
1 wk delay2 wk delay
Daily Alternating DaysSED
*** *** *** ***
roten
(%s
edentary)
Paradigm:
14 days of exercise:- Daily (during 2 weeks)
- Alternating (during 4 weeks)
Wheels locked:- 1 week, 2 weeks
Second short run period (2 days)
Note: 2 days exercise alone isnot sufficient to increase BDNF
Prior Exercise Primes subsequent BDNFResponsiveness
Priming effect endures at least 2 weeks
Equivalent Secondary Responsiveness ifprior exercise is Daily Regime or
Alternating Days of Exercise
So What is the
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functional significance
of brain changes
induced by exercise? Learning? Stress relief?
Exercise Enhances
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Learning in the Morris Water Maze
0
20
40
60
80
100
120
Timetoreachplatform(
sec
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
Days of training
Sedentary
Exercising
* p < 0.05*
*
**
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Is exercise an effective intervention
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in AD transgenic models ?
Will voluntary running improve learningand memory?
Reduce -amyloid in the brain?
Stimulate neurogenesis?
Voluntary Exercise Paradigm
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Utilized TgCRND8 mouse model
Voluntary access to running wheels (animals run ~3 miles/day)
Short-term running
- start at 6 weeks of age
- sacrifice four weeks later
Long-term running
- start at 6 weeks of age- sacrifice 5 months later
Long-term running enhances the rate
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of learning in TgCRND8 animals
Long-term running reduces -amyloid
load in TgCRND8 animals
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g(by immunohistochemistry)
Short-term running mediates APP
processing
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0
20
40
60
80
100
120
A1-40 A1-42
P
ercentage
of
seden
tary
Sedentary
Exercise
0
20
40
60
80
100
120
alpha-CTF beta-CTF
P
ercentage
of
sede
ntary
Sedentary
Exercise
no effect on total APP
no effect on secretase activity (, , )
no effect on neprilysin or IDE
Why is learning and memory
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improved?
Hypothesis Neurogenesis? Hypothesis A may impair CREB and
Elk transcriptional activity essential forlearning and memory, e.g., induced by
BDNF
Long-term running enhances
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neurogenesis in TgCRND8 animals
Recent clinical/ epidemiological
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findings Exercise and intellectual activities in mid life delay ADonset (Friedland, 2001)
TV is associated with an increased risk of AD, 1.3Xrisk/hr of TV/day (Friedland, 2005)
Exercise increases brain volume in select areas andlarger brains are associated with those most fit (Kramer,2004,2005)
Women who get the most exercise show less cognitivedecline (Yaffe, 2005;Grodstein, 2004)
Those engaged in 4 or more physical activities have halfthe risk for AD, but mainly for ApoE4 carriers (Lyketsos,2005)
Exercise
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Functional changes:
Exercise
? -Increase BDNF-synaptic plasticity
-Increased neuron
number
-Improve learning