Understanding Personalized Dementia Risk

David S. Geldmacher, MD, FANA, FACPPatsy and Charles Collat Endowed Professor of Neuroscience

Aging population = More dementia cases

Adapted from: Hebert et al. Alzheimer Dis Assoc Disord. 2001;15:169-173.

2000 2010 2020 20300

50

100

150

200

250

300

350Age 65-74 Age 75-84 Age 85+

Annu

al N

umbe

r of I

ncid

ent

Case

s (in

100

0s)

Year

And how do people respond to these numbers?What disease you fear most?

Data from YouGov survey, August 2013; US respondents over 60Graphic from 2014 Alzheimer’s Disease Facts and Figures, Alzheimer’s Association, Chicago

Memory and Aging

Memory complaints are common with aging

• About 3 of 4 people over age 65 report that“memory is somewhat of a problem”

• For those with 12 or more years of education• Complaints are more frequent with more education• Complaints are less frequent over age 75

• Memory complaints relate to memory performance• More complaints = weaker memory performance• The relationship weakens with advancing age

Fritsch T et al. J Neurodegenerative Dis DOI: http://dx.doi.org/10.1155/2014/176843

No matter how you slice it…Visual recall worsens in aging

Cross-sectional

Older people have more difficulty

Longitudinal

Individuals worsen as they age

From S. Resnick, NIH – Baltimore Longitudinal Study on Aging

It’s not just memory that changes with age

Salthouse T. Psychological Bulletin 2011 doi: 10.1037/a0023262

Over-learned skills such as vocabulary are preserved throughout the lifespan

From S. Resnick, NIH – Baltimore Longitudinal Study on Aging

You win some, you lose some…Age effects vary by mental function

WA

IS V

OC

AB

ULA

RY

The challenge of early dementia diagnosisSubtly diverging paths

Healthy Age-Related Cognitive Decline

Alzheimer’s Disease

Mem

ory

abili

ty

Time

So, what can we do to fight off the effects of aging?

Optimizing the trajectory of cognitive aging

Lindenburger U. Science 2014;346:572-578

Intervention

Delayed loss of function

Aging Brain: Aging MindFighting Back

• The brain is constantly changing• Unused connections get

pruned • Used connections get

strengthened• This process continues

throughout life

Can we harness these processes to promote better mental function in aging?

Supply and Demand ModelResponse to injury or impairment

Lindenburger, U. Science 2014;346:572-578

Lindenburger, U. Science 2014;346:572-578

Supply and Demand ModelBrain Training Model

Exercise and Problem SolvingDurability of responses

Lindenburger, U. Science 2014;346:572-578

Benefits of navigation training with exercise persist after 4 months

Exercise and Problem SolvingAnatomic Benefits

Lindenburger, U. Science 2014;346:572-578

How might exercise protect the brain?

Muscles

Insulin-Like Growth Factor

FNDC5

Irisin

Exercise

BDNFBrain Derived Neurotrophic

Factor

Multiple pathways for exercise to benefit

Image: http://yogadopa.com/wp-content/uploads/2013/11/memory-is-enhanced-by-exercise.png

Adding to exerciseThe role of “wellness”

Image: http://yogadopa.com/wp-content/uploads/2013/11/memory-is-enhanced-by-exercise.png

Wellness

WellnessWhat is it? Why should we care?

• Definitions• "...a state of complete physical, mental, and social well-

being, and not merely the absence of disease or infirmity." -World Health Organization.

• "a conscious, self-directed and evolving process of achieving full potential."

-National Wellness Institute

What wellness attributes influence dementia risk?

• Interpersonal Connections

• Marriage

• Social networks

• Motivational ability

• Mind

• Formal education

• Intellectual activities

• Midlife occupation complexity

Strout & Howard. J Holistic Nursing 2012;30:195-204

• Body

• Physical activity

• Healthy nutrition

• Spirit

• Purpose in life

• Spirituality

Wellness and cognition

• Wellness in one dimension may:• Protect cognition in aging • Enhance wellness in other dimensions• Compensate for wellness lacking in another dimension.

• Wellness in more dimensions may be more protective than wellness in one dimension

Strout & Howard. J Holistic Nursing 2012;30:195-204

“Promoting wellness may be an effective strategy to prevent cognitive impairment

and protect cognition in aging”

Prevention of Dementia

Delay AD onset Prevent AD cases

Brookmeyer et al, 1998

50% Reduction

Elias Zerhouni, M.D.Director, National Institutes of Health Congressional Testimony April 2, 2003

Lesson Learned: Prevention Research Pays Off

It is already happening!

• In the Framingham Heart study a person age 60 today has a 44% lower chance of developing dementia than a similar-aged person 30 years ago

• Dementia rates also are down in Germany

Langa KM. Alz Res Therapy 2015, 7:34 doi:10.1186/s13195-015-0118-1

Risk Factors for Alzheimer’s Disease

Known risk factors

Aging Family History Gene markers Down’s syndrome

Possible risk factors

Head trauma Depression Diabetes mellitus Hypertension Stroke Hormone therapy*

Possible protective factors Higher level of education Physical activity Anti-oxidants

curcumin Estrogen* Anti-inflammatory drug use Alcohol Cholesterol lowering drugs Mediterranean diet

How do common illnesses contribute to dementia?

High Cholesterol

Obesity

Dementia

Oxidative cell damage

Insulin resistance

Blood vessel dysfunction

Inflammation Stroke-like damage

Middleton & Jaffe, Arch Neurol 2009;66:1210-5

High Blood Pressure

Fat cell activity

Diabetes Mellitus

Lifestyle Approaches

Target Observational Studies Controlled Trials

Diet* Risk with high antioxidant and healthy fat intake

Improved cognition and lower AD risk

Cognitive activity

Dementia risk with high education and more cognitive engagement

Improved cognition and less decline

Physical* activity

AD risk with high activity in mid & late life

Improved cognition with exercise

*Middleton & Jaffe, Arch Neurol 2009;66:1210-5

• Physical exercise• Moderate intensity, e.g. walking, 150 minutes per week• Light weight lifting, too

• Healthy diet• Brightly colored fruits and vegetables (5 servings/day)• Fish (ocean, swimming) every week• Mediterranean diet, DASH diet

• Mental exercise• Creative/productive activities

• Puzzles, games, art, crafts, etc.

• Computerized Brain Games• www.aarp.org• www.lumosity.com• www.brainHQ.com

General Risk reduction recommendations

Individualizing Risk Assessment

Personalizing Dementia Risk Assessment

Characteristic Points

Age 75-79 1

80-100 2

↓ Global Cognitive Score 2

↓ Digit Symbol Substitution 2

Body Mass Index <18.5 2

APOE ε-4 positive 1

MRI: Stroke-type damage 1

MRI: Enlarged ventricles 1

Carotid thickness >2.2mm 1

History of Coronary Bypass 1

Slowed time to dress 1

Lack of clcohol consumption 1

Dementia Risk Index (age >65)

Barnes DE, et al. Neurology 2009;73:173–179;

Possible Range 0-16

Six-year Risk Prediction (Age 65 and older)

Barnes DE, et al. Neurology 2009;73:173–179

N=3375, n age =76

• Dementia risk at 6 years• All participants = 14%• Score ≤3 = 4%• Score 4-7 = 23%• Score ≥8 = 56%

N=3375, mean age =76

Possible Range 0-16

Model 1 score Model 2 score

Age

47-53 3 3

>53 4 5

Education (years)

7-9 2 3

0-6 3 4

Male Sex 1 1

Systolic BP >140 2 2

Body Mass Index >30 2 2

Low physical activity 1 1

APOE ε-4 positive n/a 2

Mid-Life Dementia Risk Score (age 45-65)

Kivipelto, M et al Lancet Neurol 2006; 5: 735–41

Model 1 (no gene tests) Model 2 (with gene test)Score Risk Score Risk

0-5 1.0% 0-5 0.3%6-7 1.9% 6-8 1.7%8-9 4.2% 9-10 4.6%

10-11 7.4% 11-12 4.4%12-15 16.4% 13-18 16.3%

Late-life dementia riskPredictions from mid-life risk scores

Kivipelto, M et al Lancet Neurol 2006; 5: 735–41

Study sample N=1409, mean age = 50

Overall 20-year dementia incidence = 4%

20 year risk predictionGene testing did not infuence predictions!

Kivipelto, M et al Lancet Neurol 2006; 5: 735–41

• 52 year old woman who complains: “Doctor, I can’t remember anything anymore. Am I getting

Alzheimer’s disease like my mom?”

• Medical History: • High Cholesterol (good control on statin treatment)• Past depression with good response to treatment

• Family history: Mother with Alzheimer’s disease• Diagnosed at age 55

• Exam: Obese, but otherwise normal • Blood Pressure 150/77• Height 5’1” Weight 173.4 lbs.: Body Mass Index 32.8

Risk Reduction: Case Study

Lifestyle Targets: BP <140; Weight 159 (15# loss!); Physical activity: exercise 2x/week

• If either BP or weight are optimized, dementia risk lowers to < 2%• If all three are optimized, predicted risk lowers to 1%

Case StudyRisk score example

Patient Risk Score

Age 54 4

Education >10 0

Gender: Female 0

SBP: 150 2

BMI: 32.8 2

Cholesterol: <250 0

Activity: low 1

TOTAL 9

Kivipelto, M et al Lancet Neurol 2006; 5: 735–41

Personalized 20 year risk: 4.2%

Conclusions

• Memory and thinking change with aging• This does not predict Alzheimer’s disease or dementia• Tasks take longer, but can still be done

• Many risk factors for AD can be modified• The glass is not “half empty”

• Simple steps like exercise, diet, brain games, and focusing on wellness can protect the brain• This is not magic• Many of the exact mechanisms are known

• Healthy lifestyle choices may already be working

The first Alzheimer’s prevention studyhttp://A4study.org

UAB is a Participating Center

Memory Disorders at UAB

• Clinical Care:• Alzheimer Risk Assessment and Intervention Clinic (205-975-7575)

• Memory Disorders Clinics (appointments: 205-801-8986)

• Research• Studies of memory and related function over time (information: 205-934-6223)

• Treatment studies• Mild and Moderate Alzheimer’s dementia

• Mild cognitive impairment

• Pre-clinical Alzheimer’s disease

205-996-3679 (99-MEMRY) memory@uab.edu www.uab.edu/memorydisorders www.facebook.com/uab.memorydisordersclinic