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

• 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.

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

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.

Midlife Cardiovascular Risk Factors

Increase Risk of Dementia

Whitmer…Yaffe, Neurology, 2004.

• 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

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.

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.

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

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

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

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.

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.

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.

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.

Traumatic Brain Injury:

60% Increased Risk of Dementia with TBI

Adjusted HR:1.57; 95% CI (1.35–1.83)

Barnes…Yaffe, Neurology, 2014.

Comorbidities Have an Additive Effect

with TBI on Dementia RiskDepression PTSD

Cardiovascular Disease

Barnes…Yaffe, Neurology, 2014.

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.

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

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

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

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

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.

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.

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

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