The Alzheimer’s Prevention
Program: How We Can Keep
Our Brains Healthy
Gary Small, MD
University of California, Los Angeles
Division of Geriatric Psychiatry
UCLA Longevity Center
Semel Institute for Neuroscience & Human Behavior
Alzheimer’s Disease is in the News and
on our Minds
Scientists Pursue an Unusual
Tactic Against Alzheimer’s
Lifestyle Changes Can
Reduce Risk of Alzheimer's
Increased Life Expectancy and
Epidemic of Alzheimer’s

Life expectancy at birth in U.S.
 In 1900: 47 years
 Today: 78 years (men – 76; women – 80)



Age is the single greatest risk factor for Alzheimer’s
80 million Baby Boomers (born 1946 – 1964)
Every 70 seconds another American is diagnosed with
Alzheimer’s disease
What is Alzheimer’s Disease?

1906: Alois Alzheimer presented case:
confused, psychotic 51 year-old
woman who progressed rapidly until
her death 4 years later

Her autopsied brain tissue showed
waxy protein fragments/twisted fibers
that define the disease

1968: scientists discovered same
plaques/tangles caused “senility”
Plaques
Tangles
Amyloid Plaques and Tau Tangles in
Alzheimer’s Disease and Normal Aging
Plaques
Alzheimer’s
Tangles
Courtesy of Harry Vinters, MD.
Normal
PET Scanner
Plaques and Tangles Accumulate in the
Brain as Memory Worsens
More Protein
Less Protein
Memory Score
FDDNP-PET scans of 20 volunteers (8 normal, 6 MCI, 6 Alzheimer’s)
Some Definitions

Memory

 Learning
 Recall

Cognition




Memory
Attention
Visual/spatial skills
Reasoning
Dementia
 Memory loss + another
impairment
 Interferes with everyday life

Alzheimer’s disease
 Most common dementia
cause
 Gradual onset/progression
 Plaques & tangles
Example of Healthy Brain Aging
Madame Jeanne
Louise Calment
1875-1997
Cognition and Aging
Normal Aging
Mild
Cognitive
Impairment
Cognition
Alzheimer’s
Dementia
Age
The Most Common Memory
Complaints




Names and faces
Where we put things
Forgetting an appointment or plan
Forgetting a word or name we should know that is on
“the tip of your tongue”
Grandma Ollie
at 104
and me
Predicted Result of Early Treatment
Cognitive Function
Early Treatment
No Treatment
Late treatment
at time of diagnosis
using current clinical methods
Time
Brain protection more feasible short-term strategy than
brain repair
Medications for Alzheimer’s
Disease
Mild
Aricept (donepezil)
Exelon (rivastigmine)
Namenda (memantine)
Impairment
Disease modifying
Placebo
Symptomatic
Disease modifying
Severe
Start Treatment
End Treatment
Time
Ferris. Alzheimer Dis Assoc Disord. 2002;16(suppl 1):S13-S17.
Possible Anti-Plaque/Anti-Tangle
Treatments







Secretase inhibitors
Vaccines
Monoclonal antibodies
Anti-inflammatory drugs
Statins
Intranasal insulin spray
Lithium
Small. Br Med J. 2002;324:1502-1505; Peila et al. Stroke. 2001;32:2882-2889;
Craft, et al. Arch Neurol. 2011 Sept 12 [Epub ahead of print].
Anti-Inflammatory Treatment Increased
Cognition and Brain Function in Normal Aging



Mean age: 59 years
18-month placebo controlled trial
Cognition improved
 Executive function (p=.03)
 Semantic memory (p=.02)

Brain function (PET scanning)
 6% increase in prefrontal cortex
(p=.003)
Small GW, et al. Am J Geriatr Psychiatry 2008;16:999-1009.
Supported by NIMH.
MacArthur Study of Successful Aging
Genetics (what we inherit from our parents) contributes
only 1/3 of success
Brain Healthy Lifestyle Strategies
Associated with a Lower Risk for
Dementia
 Physical conditioning
 Mental challenge/cognitive training
 Stress reduction
 Healthy diet
Small GW. What we need to know about age related memory loss. Br Med J 2002;324:1205-5.
Physical Exercise

Active laboratory animals
 larger brains
 better memory

Human studies
 Cardiovascular conditioning
 larger brain size (parietal,
temporal, frontal areas)
 Physically active adults
 lower Alzheimer’s risk
 Brisk walking
 improves cognition (vs.
stretching/toning)
Gage. J Neurosci. 2002;22:612-613; Freidland et al. Proc Natl Acad Sci U S A. 2001;98:3440-3445; Colcombe et al. J
Gerontol 2003;58:176-180; Larson EB, et al. Ann Int Med. 2006;144:73-81.
Mental Exercise Builds Brain Muscle
 Mental stimulation
 activates neural circuits
 associated with lower Alzheimer’s
risk

Educational achievement,
bilingualism, doing puzzles
 Lower dementia risk

Memory training can improve
memory ability quickly and can
maintain higher performance for 5 or
more years
Ball et al. JAMA 2002;288:2271-81; Willis et al. JAMA. 2006;296:2805-14; Craik FI, et al.
Neurology. 2010;75:1726-9.
Your Brain on Google
UCLA Study of the Effects of Internet
Searching on Neural Circuitry
Small, Moody, Siddarth,
Bookheimer. Am. J. Geriatr.
Psychiatry. 2009;17:116-26.
Funded by the Parvin
Foundation
Study Methods
 Recruit middle-aged and older people with
minimal Internet experience
Functional MRI
Stimulation Tasks During fMRI
Reading a text page
Searching the Internet
Your Brain on Google
Net Naive
Net Savvy
Text
Internet
Your Brain on Google
Net Savyy Group
Neural Network Responses to Mental
Challenge
Brain Activation
Task strategy
engagement
Cognitive
efficiency with
task repetition
Unfamiliar
task
Time
Calisthenics for the Older Mind
UCLA Longevity Center
Memory Training
•
•
•
•
Four-week course taught by volunteer trainers
with monthly follow-up booster sessions
Mean student age, 70 years; range, 14-93
~20,000 participants have completed the course
Currently available in California, Arizona,
Florida, Illinois, Iowa, Maryland, and
Pennsylvania
LOOK, SNAP, CONNECT
 Look
 Actively observe what you want to learn
 Snap
 Create a vivid mental snapshot or memorable image
 Connect
 Visualize a link to associate images
Do you remember this face? Do you
remember her name?
Names and Faces
Chelsea
Notice her
cheeks and see
a Cheshire cat
smile
Names and Faces
Sue Bangel
She’s an
attorney
with bangs
Memory Word List
 Beach
 Professor
 Horse
 Teddy bear
 Cigar
 Nun
 Palm tree
 Pasta
Stress and Risk for Alzheimer’s Disease

Animal studies:
 Chronic stress

 smaller brains
 impaired memory
Human studies:
 Chronic stress
 can cause depression and increase dementia risk
 People prone to stress
 two-fold greater Alzheimer’s risk
 Cortisol injections
 temporarily impair memory
Sapolsky. Exp Gerontol. 1999;34:721-732; Newcomer et al. Arch Gen Psychiatry. 1999;56:527-533;
Köhler et al. Am J Geriatr Psychiatry. 2011;19:902-5; Wilson et al. Neurology. 2003;61:1479-85.
Stress Reduction and Brain Health
Effect of meditation vs.
relaxation on brain activity:
Meditation > Relaxation
Right frontal cortex
Right inferior
temporal gyrus
Left
Thalamus
3.0 > Z > 1.6
 Managing stress
Int J Geriatr Psychiatry 2012 Mar 11.
Relaxation > Meditation
Nutrition and Dementia Risk
 Midlife obesity
 Increases late-life dementia risk
 Omega-3 fats
 From fish, nuts, supplements
 Lower risk for AD
 Anti-oxidant fruits & vegetables
 Lowers AD risk
 Adherence to Mediterranean diet
 Fruits, vegetables, legumes, cereals, and fish with
minimal meat and dairy products
 Lowers AD risk
Xu WL, et al. Neurology. 2011;76:1568-74; Devore EE, et al. Ann Neurol. 2012. 2012 Apr 26. doi: 10.1002/ana.23594
Van Praag. Nat Rev Neurosci. 2001;1:191-8; Gu Y, et al. J Alzheimers Dis. 2010 ; 22(2): 483–492. doi:10.3233/JAD2010-100897.; Xu WL et al, Neurology. 2011;76:1568-74; Gunstad et al. Surg Obesity Related Diseases. 2011;7:465-72.
Obesity Worsens Memory While Weight
Loss Improves Memory
 Obese people have a 4-fold increased risk for
dementia

Obese patients who had weight-loss surgery →
 After 12 weeks, they showed significant improvements
in memory compared with controls
Xu WL et al, Neurology. 2011;76:1568-74; Gunstad et al. Surg Obesity Related
Diseases. 2011;7:465-72.
Brain Protective Drinks

Red wine (resveratrol)
 Anti-oxidant, “anti-aging”

Any alcohol in moderation

Caffeine
 Associated with lower risk for Alzheimer’s &
Parkinson’s disease
Ekselinen, Kivipelto. J Alzheimers Dis. 2010;20(Suppl 1):S167-7; Neafsey, Collins. Neuropsychiatr Dis
Treat. 2011;7:465-84.
New Research on Nutrition

Double-blind placebo controlled trials in people with
normal aging and mild cognitive impairment
 Curcumin: anti-oxidant, anti-inflammatory and antiamyloid properties
 18-month study
 Outcome measures: neuropsychological testing and
FDDNP-PET scans of plaques and tangles
 Pomegranate extract
 Anti-oxidant polyphenols
 12-month study
 Outcome measures: neuropsychological testing
Other Lifestyle Strategies Associated with
Lowering Risk for Alzheimer’s Disease
 Avoid head trauma
 If you smoke, stop
 Keep a positive outlook
 Treat hypertension and high cholesterol
Small G, Vorgan G. The Alzheimer’s Prevention Program. Workman, New York, 2012.
Can We Prevent Alzheimer’s Disease?

To definitively prove effectiveness of prevention
strategies:
 Double-blind studies on 1000’s of people followed for decades

But compelling epidemiological and short-term clinical
trials:
 Already indicate what we can do now to possibly delay
symptom onset

Physical exercise and healthy diet can prevent or delay
the onset of diabetes.
 Since having diabetes increases probability of developing
Alzheimer’s, then these strategies should indirectly prevent
Alzheimer’s as well
Saaristo T, et al. Diabetes Care. 2010;33:2146-51; Ohara T, et al. Neurology. 2011;77:1126-34.
Case Example: Jack W.


62-year-old executive
Minimal physical exercise
 computer during day
 TV at night

Diet
 snacks on chips
 rarely eats fruits, vegetables, or fish

After learning about potential brain health benefits of
exercise

starts walking 30 minutes/day
Physical Exercise: Estimated 2-Year Delay
in Onset of Jack’s Symptoms
Memory Ability
Daily Brisk Walks
Sedentary Lifestyle
68
69
Age (years)
70
71
72
73
Dementia-free gain
74
Jack’s Walking Program Motivates Him



Becomes more socially engaged
Starts losing weight from walking
Improves diet
 Quits chips
 Adds daily fruits and vegetables
 Fish twice a week

Practices mental aerobics
 Crosswords (even Friday puzzles—in pen!)
Estimated 4-Year Delay in Symptom Onset
From Alzheimer’s Prevention Strategies
Memory Ability
Alzheimer’s Prevention
Program
Sedentary Lifestyle
68
69
70
Age (years)
71
72
73
74
Dementia-free gain
75
76
The Projected Effect of Risk Factor Reduction
on Alzheimer’s Disease Prevalence
 Estimated number of Alzheimer’s patients
 34 million worldwide
 5 million in U.S.
 Modifiable risk factors:
 Low education, smoking, physical inactivity, depression,
hypertension, diabetes, obesity
 Projected effect of 25% risk factor reduction (# of
fewer cases):
 Worldwide: 17 million
 U.S.: 3 million
Barnes DE, Yaffe K. Lancet Neurol. 2011;10:819-28.
How Can We Help People to Change
 Educate
 connection between lifestyle and disease prevention
 Fun and easy program
 See quick results
 motivates to continue healthy behaviors so they
become habits
Names and Faces
Chelsea
What’s her
name?
Names and Faces
Sue Bangel
Do you
remember
the lawyer?
Memory Word List
ANY VOLUNTEERS?
Memory Word List
 Beach
 Professor
 Horse
 Teddy bear
 Cigar
 Nun
 Palm tree
 Pasta
Conclusions

Drug and biomarker development is key to future
Alzheimer’s prevention treatments

As we wait for results from long-term studies, the
scientific evidence points to brain healthy behaviors to:
 improve quality of life today
 possibly stave off Alzheimer’s symptoms in the future
FOR MORE INFORMATION
www.DrGarySmall.com