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Military Risk Factors for
Cognitive Aging and Dementia
Kristine Yaffe, MDScola Endowed Chair & Vice Chair
Professor of Psychiatry, Neurology & Epidemiology
University of California, San Francisco
Chief of NeuroPsychiatry & Director, Memory Clinic, San Francisco VA Medical Center
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• Almost 50% of veterans are older than 65 years of age
• Veterans face a unique set of military risk factors for dementia including
PTSD and TBI
• In addition, veterans are at risk due to a similar set of risk factors as
older adults in the general population
• But the burden of these risk factors may be even greater in veterans
Veterans at Risk for Cognitive Aging & Dementia
Age of Veterans, 2014 and 2024 (Projected)
Rand Health, 2015.
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Projected Changes in Veterans by Era of Service
Pew Research Center, 2016.
In the next few decades, Gulf War veterans will comprise more than half
of the veteran population
2013
2043
5 3 32
6
29
56 25
25
13
WWII Korea Vietnam Gulf War Post-Gulf War Other
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The Importance of Modifiable Risk Factors
for Cognitive Aging and Dementia
• Identification of modifiable risk factors can help
• Understand the biological mechanisms associated with
cognitive impairment & dementia development
• Identify those at highest risk of developing dementia
• Improve prevention and treatment options
• Need to understand the role of both non-military and
military risk factors for aging veterans
Yaffe, Chronic Medical Disease and Cognitive Aging: Toward a Healthy Body and Brain, 2013.
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Midlife Cardiovascular Risk Factors
Increase Risk of Dementia
Whitmer…Yaffe, Neurology, 2004.
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• Metabolic syndrome:
↑ blood pressure
↑ cholesterol
↑ triglycerides
↑ blood sugar
↑ body weight
• Together may be greater than individual components
• Role of inflammation
• Offer strategies to modify risk factors as a group
Multiple Cardiovascular Risk Factors Together
Increase Risk of Dementia
Yes
No
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
HighLow
Metabolic Syndrome
OR
fo
r D
eclin
e
Inflammatory Markers
Yaffe et al, JAMA, 2004.
P for interaction = 0.04
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Cardiovascular Risk Factors in Early-Mid Adulthood
& Cognition at Midlife
Systolic Blood Pressure AUC
(mmHg-years)
Diastolic Blood Pressure AUC
(mmHg-years)
RAVLT
DSST
Stroop
Fasting Blood Glucose AUC (mg/dl-years) Total Cholesterol AUC (mg/dL-years)
Yaffe et al,
Circulation, 2014.
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Burden of Cardiovascular Risk Factors
in Veterans
Survey of Veteran Enrollees in VHA ≥65 years old
Hypertension 63.8%
Diabetes 27.1%
Myocardial infarction 26.8%
Stroke 15.0%
Selim et al, J Am Geriatr Soc, 2004; Yoon et al, Med Care, 2014.
Among VA patients ≥65 years old, an estimated 29.1%
have diabetes, hyperlipidemia, and hypertension.
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Mouse Model of Physical & Cognitive Activity:
Use it or Lose it?
0
1000
2000
3000
4000
Nu
mb
er
of
new
cells
Control Runner Enriched
van Praag, Nature Neuroscience, 1999.
P<0.02P<0.02
Physical activity &
mental activity
activity increase
new brain cell
development in
mice
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More blocks walked associated with less decline
Yaffe et al, Arch Intern Med, 2001.
Walking and Rate of Cognitive Decline
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
Low Second Third High
P<0.001 overall
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Exercise Improves Cognitive Function in Older
Adults with Memory Complaints
5
6
7
8
9
0 6 12 18
AD
AS
-Co
g S
co
re
(lo
wer
is b
ett
er)
Time (months)
Control
Exercise
P=0.04
Lautenschlager, JAMA, 2008.
170 adults
age ≥ 50 yrs
Better cognition in
exercise group
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Littman et al, Med Sci Sports Exerc, 2009.
Physical Activity in Veterans
Physical activity in veterans vs non-veterans,
Behavioral Risk Factor Surveillance System
Physical activity trajectories in older women
veterans vs older women non-veterans,
Women’s Health Initiative
Washington et al, Gerontologist, 2015.
Non-Veterans Veterans
Active duty members report high levels of physical activity,
but veterans do not maintain those levels.
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Sleep and Dementia Risk
Emerging evidence that
sleep disturbances and
poor sleep quality
increase risk of
developing dementia
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Poor SleepEfficiency
ShiftedCircadianRhythm
SleepDisorderd Breathing
OR
95%
CI
Diem…Yaffe et al, AJGP, 2016; Tranah…Yaffe, Annals of Neurology, 2011; Yaffe et al, JAMA, 2011.
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Sleep in Veterans
• Greater than 20% of veterans report insufficient sleep and
almost 35% report sleeping <7hrs/night
• Recent study of VHA users suggest diagnoses of sleep
disorders are increasing
• Sleep apnea and insomnia were the most common
diagnoses of sleep disorders
• Sleep disorders often comorbid with PTSD and TBI
Faestel et al, J Clinical Sleep Medicine, 2009; Alexander et al, Sleep, 2016.
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Sleep Disturbances and Increased Risk of
Dementia in Veterans
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
Sleep Disturbance Sleep Apnea Insomnia
HR
95%
CI
Yaffe et al, Am J Geriatr Psychiatry, 2015.
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Traumatic Brain Injury:
60% Increased Risk of Dementia with TBI
Adjusted HR:1.57; 95% CI (1.35–1.83)
Barnes…Yaffe, Neurology, 2014.
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Comorbidities Have an Additive Effect
with TBI on Dementia RiskDepression PTSD
Cardiovascular Disease
Barnes…Yaffe, Neurology, 2014.
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Psychiatric Risk Factors & Dementia Risk
• More and more data on depression and PTSD as risk
factors for dementia
• High burden of psychiatric diagnoses among veterans
• Odds of depression in Gulf War veterans is 2 times higher
compared to non-deployed military personnel
• Odds of PTSD in Gulf War veterans is 3 times higher
compared to non-deployed veterans
Blore et al, Pyschol Med, 2015; Stimpson et al, Br J Psychiatry, 2003.
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Greater Depressive Symptom Burden
Over Time Increases Risk of MCI/Dementia
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
Unadjusted Adjusted
Quartile of Depressive Symptom Burden (AUC)
Od
ds R
ati
o o
f M
CI/D
em
en
tia,
95
% C
I
Zeki Al Hazzouri…Yaffe, J Gerontology Med Sci, 2013.
* Adjusted for socio-demographics, health behaviors, co-morbidities, and use of anti-depressants
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Depression Increases Risk of Dementia
Among Older Veterans
Byers…Yaffe, Am J Geriatr Psychiatry, 2012.
Depression aHR: 2.18, 95% CI: 2.08-2.28
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PTSD Increases Risk of Dementia
Among Older Veterans
Yaffe et al, Arch Gen Psychiatry, 2010.Yaffe et al, Arch Gen Psychiatry, 2010.
PTSD aHR: 1.77 95% CI 1.70-1.85
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PTSD & Prevalence/Incidence of Dementia
Veterans ≥65 years old from VISN 16
PTSD+/PH- vs PTSD-/PH- 2.3 (2.0–2.7) 2.2 (1-8-2.6)
PTSD+/PH- vs PTSD-/PH+ 2.0 (1.6–2.5) 1.7 (1.4–2.2)
Qureshi et al, JAGS, 2010.
PTSD in older veterans associated with dementia prevalence and
incidence compared to those without PTSD and compared to those with
combat related trauma
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PTSD Symptoms and
Hippocampal Volume in
Vietnam Twin Pairs
Discordant for Warzone
Service
• Hippocampal volume in
non-exposed twin predicts
PTSD symptom severity
• Suggests hippocampal
volume loss is a pre-
existing vulnerability trait
Gilbertson et al, Nat Neurosci, 2002.
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National Academies Gulf War and Health :
Updates Related to Cognitive Aging
• Gulf war illness shares many similar symptoms to PTSD
and depression and affects multiple systems
• Need to investigate link between body and brain
• Limited data on risk of neurologic outcomes
• Too early for manifestation of neurodegenerative diseases
in Gulf War veterans so more follow up needed
National Academies of Sciences, Engineering, and Medicine.
Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016.
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Summary
• Evidence for TBI, PTSD, and other military exposures as risk
factors for dementia is increasing
• In addition, veterans are at risk for accelerated cognitive
aging because they have a greater burden of medical and
psychiatric risk factors
• Need continued investigation of modifiable risk factors in
veterans to understand the interplay of these associations
• Explore specific exposures of Gulf War veterans
• Develop a multi-domain framework for research, prevention,
and intervention for cognitive aging in veterans
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Acknowledgements
Funders
• NIA
• NIDDK
• NHLBI
• Department of Defense
• Veterans Administration
• Sierra-Pacific Mental Illness Research,
Education, and Clinical Center
Collaborators
• Deborah Barnes
• Amy Byers
• Raquel Gardner
• Allison Kaup
• Joel Kramer
• Carrie Peltz
• Karen Seal
USUHS
• Ramon Diaz Arrastia
• Kimbra Kenney
Chronic Effects of Neurotrauma Consortium (CENC)
• David Cifu
• Mary Jo Pugh