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Alzheimer’s Disease
Susan M. Resnick, Ph.D.
Chief, Lab of Behavioral Neuroscience
NIA
Joint Effects of Aging, Vascular Changes
and AD Pathology
Aging
AD Pathology Vascular
Disease
Plaque Tangles
WMH
Increasing Focus on the Earliest Stages of AD
Alzheimer’s & Dementia ‐ (2011) 1–13
Brain Aging: BLSA Neuroimaging Study
Early Markers of Alzheimer’s Disease and Cognitive Decline
Annual/Biennial Evaluation over 23 Years
158 Men and Women (Age 55+)
Without Prior Neurologic or
Severe Cardiovascular Disease
2009 – present: > 1000 MRI participants
Baseline 1 2 3 4 5 6 7 8 9 10 11 12 … 18
Cognitively Normal (n=96) Cognitively Impaired (n=25)
SI> CN
-4 -2 2 4
Pacheco et al.
Neurobiology of Aging 2015
Imaging Amyloid Plaques in Living People
Alzheimer’s Mild Cognitive
Disease Impairment Normal
Wolk et al. Annals of Neurology 2009
Amyloid Build-Up Precedes Memory Problems
• Memory
Problems 4
Years Later
• Stable
Memory
Baltimore Longitudinal Study of Aging
Amyloid Accumulation by Age and Over Time
Updated from NeuroImage 134 (2016) 658–670
DVR Increasing Amyloid
Baltimore Longitudinal Study of Aging
Risk Factors for Amyloid Build-Up
Ɛ4‐ Ɛ4+
Genetics
APOE
Resnick, BLSA
Sleep
Duration
Spira et al. JAMA
Neurol. 2013
Baltimore Longitudinal Study of Aging
Amyloid Build‐Up Predicts Motor Decline in Aging
Greater Amyloid Burden is Associated with
Longitudinal Slowing of Walking Speed
Gait maintainers Gait decliners
0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4
Predicted gait speed, m/s
PiB+:
amyloid positivity
PiB‐:
amyloid negativity
PET Scan Imaging of Plaques and Tangles
Amyloid
PiB
Tau
AV‐1451
Normal Alzheimer’s
Cognition Disease
Sperling et al., Neuron 2014
Stay Tuned for Next
Generation Tau Tracers
AV‐1451
RO‐948
MK‐6240
PI‐2620
JNJ‐64349311
GTP‐1
THK‐5351
Hypothetical Model of Pathophysiology
Leading to Cognitive Decline and Impairment
Sperling et al., Neuron 2014
Hypothetical Model of Pathophysiology
Leading to Cognitive Decline and Impairment
?
Vascular Risk
? ?
Stress Sensorimotor
? Function
Inflammation
Questions and
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