detection of preclinical alzheimer’s diseas for the ... · center for development of advanced...

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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