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National Center for Geriatrics and GerontologyCenter for Development of Advanced Medicine for Dementia
Katsuhiko Yanagisawa
Detection of preclinical Alzheimer’s diseasfor the preemptive therapy
Stop Alzheimer Disease Before It Starts !
Greg Miller, Science 337, 790-792, 2012
Mangialasche et al., Lancet Neurology, 9:702-716, 2010
Illustration by Gracia Lam
A tangled web of targetsDrugs in development for Alzheimer's disease take aim at a variety of neural mechanisms.But despite a wealth of possibilities, there have been few successes. Lauren Gravitz
Nature 475, S9, 2011
too late for therapeutic intervention
Bateman et al, New Engl J Med, 367: 795-804, 2012
Carriers
Noncarriers
Estimated Yr fromSymptom Onset -20 -10 0
PiB-amyloid imaging on PET- Study on familial Alzheimer disease -
clinical threshold
time
degr
ee
preclinicalAD
MCI AD muc
h co
gniti
ve re
serv
ele
ss c
ogni
tive
rese
rve
synapse loss
neuron loss
tangle formation
inflammation etc
Yanagisawa, Cognition and Dementia, 2012
amyloid-dependent phase
amyloid-independent phase
Alzheimer Disease
・inflammation・oxidative stress
・mitochondria injuryetc
・impairment of calcium homeostasis・energy failureetc
・disruption of neuronal network
switch
modified from Yanagisawa. Igaku-no-Ayumi 239: 379-382, 2011
amyloid-dependent phase
amyloid-independent phase
Alzheimer Disease
・inflammation・oxidative stress
・mitochondria injuryetc
・impairment of calcium homeostasis・energy failureetc
・disruption of neuronal network
anti-amyloid therapy
effective ineffective
switch
Pathological stage of Alzheimer Disease
Modified Jack et al. The Lancet Neurology, 2010
previous and current clinical trials
preemptive therapysecondary prevention
Alzheimer Disease
How should you know the pathological change before clinical onset?
Cerebrospinal fluid examination
(Yahoo Japanより取得)
Amyloid imaging on PET
Plasma!
obtained from Yahoo Japan
Rembach A et al., Alzheimer’s and Dementia,10: 53-61, 2014
Plasma amyloid ß-proteins Baseline
18-months later
**
* **
* * * * **
*
** * **
* * * *Aβ
[1-4
0]3000 3500 4000 4500 5000 5500m/z
x5 x5
n
n
nn
n
n nn n
0
20
40
60
80
100
*various Aßs and Aß-approximate peptides
Aβ[1
-42]
*
Novel procedure to detect Aß from plasma usingmass spectrometry
Kaneko et al., Proc. Jpn. Acad. Ser. B,104-117, 2014
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