Transcript Preclinical Alzheimer Disease

THE AGING BRAIN
and the
ELIMINATION OF ALZHEIMER’S
DISEASE
Clinical and Research Update
David B. Carr, M.D
Professor of Medicine and Neurology
The Charles F and Joanne Knight
Alzheimer’s Disease Research Center
Department of Neurology
Knight ADRC
DISCUSSION OBJECTIVES
• Know the difference between memory change from
normal aging and memory loss due to dementia and
Alzheimer disease
• Know how to recognize common types and causes of
dementia and community resources available for our
patients and families, along with the latest diagnostic
tests and treatments for the disease and difficult
behaviors
• Know the type of research that is currently being
conducted at the Washington University Knight
Alzheimer’s Disease Research Center (ADRC) and
consider partnering with us to eliminate this disease
Department of Neurology
Knight ADRC
Epidemiology
16
5 Million AD Cases Today—
Over 14 Million Projected Within a Generation
14.3
14
11.3
12
10
8.7
8
6
4
5.8
6.8
4
2
0
2000
2010
2020
2030
Year
2040
2050
Affects > 5 million people in the U.S. (20 million world-wide)
Results in > 100,000 deaths per year/Costs > $100 billion annually
Department of Neurology
Knight ADRC
Forecast of Prevalence in U.S.
2000
2030
4.5 Million (est)
7.7 Million (est)
65-74 Years
75-84 Years
2050
13.2 Million (est)
85+ Years
Source: Hebert LE, et al. Arch Neurol. 2003;60:1119-1122.
Department of Neurology
Knight ADRC
http://www.alz.org/boomers/
Department of Neurology
Knight ADRC
Why is More Funding Needed?
"We spend $100 billion a year on a disease no one in his right
mind would want, but fight that with only $650 million and
declining," said Dr. David A. Bennett, director of the Rush
Alzheimer's Disease Center at Rush University Medical Center in
Chicago. "It just makes no sense."
http://mednews.wustl.edu/news/page
/normal/7360.html
Department of Neurology
Knight ADRC
Department of Neurology
Knight ADRC
National Initiatives: Funding Pending
• National Alzheimer’s Project: • Brain Initiative: 2013
2011
• New initiative to map the
• President Barack Obama
individual cells and
signed into law the National
circuits that make up the
Alzheimer’s Project Act
human brain
(NAPA), to:
• This project will give
• Create and maintain an
scientists a better
integrated national plan to
understanding of how the
overcome Alzheimer’s
brain works
disease.
Department of Neurology
Knight ADRC
The Changing Definitions of
Cognitive Impairment and Dementia
Normal
Cognition
Brain Aging
Prodromal
Dementia
Mild Cognitive
Impairment
Dementia
Stable or
Reversible
Impairment
Alzheimer’s
disease
Other
dementias
Mixed
Vascular
Dementia
Mixed
From Golomb, Kluger, Ferris NeuroScience News, 2000
Department of Neurology
Knight ADRC
•
•
•
•
•
•
•
•
Potential Reversible Causes of
Cognitive Decline
D: Drugs
E: Emotional disorders
M: Metabolic disorders
E: Eye/ear impairment
N: Nutritional deficiencies
T: Tumor, trauma
I: Infection
A: Atherosclerotic complications
Department of Neurology
Knight ADRC
There is a need to consider other
diagnoses!
• Etiologic category
• Examples
• Endocrine/metabolic*
• Autoimmune/inflamm
atory
• Infectious
• Neoplastic**
• Toxic*
• Sleep disorder**
• Vascular
• Traumatic
• Depression
TSH/B12/renal/liver*
Vasculitis/SLE/sarcoid/HIV
Syphilis/lyme/encephalitis
Paraneoplastic
Hashimoto’s Encephalitis
Menigioma/tumors
Drugs/heavy metals
OSA/CSA/PLMD
Hypertensive
encephalopathy
• Mild traumatic brain injury
• Subdural/NPH
•
•
•
•
•
•
•
•
•
Department of Neurology
Knight ADRC
CLUES TO SPECIFIC
NEURODEGENERATIVE DISEASES
Alzheimer’s
Disease
Rapidly
evolving
dementias
Frontotemporal
dementias
Vascular
dementia
Lewy body
dementia
Department of Neurology
Knight ADRC
2004 MCI Classification Process
Experience revealed that multiple cognitive domains frequently were impaired in
MCI (Grundman M et al, Arch Neurol 2004;61:59-66)
MCI criteria thus were broadened in 2004 to include multiple domain MCI, leaving
only “essentially normal functional activities” to distinguish from dementia
Petersen RC, J Int Med 2004; 256:183-194; Winblad B et al., J Int Med 2004; 256:240-246
Slide Courtesy of Dr. John Morris
Department of Neurology
Knight ADRC
Recommendations from the NIA-Alz Assn
Workgroups on Diagnostic Guidelines for AD
Criteria for Dementia is dx when cognitive and/or behavioral sx;
1. Interfere with the ability to function at work or at usual activities; and
2. Represent a decline from previous levels of functioning and performing; and
3. Are not explained by delirium or major psychiatric disorder;
4. Cognitive impairment is detected and diagnosed through a combination of;
a) history-taking from the patient and a knowledgeable informant and
b) an objective cognitive assessment, either a “bedside” mental status
examination or neuropsychological testing.
5) Cognitive or behavioral impairment involves two or more domains;
memory, reasoning or judgment, visuospatial abilities, language, personality
NOTE: MCI rests on the determination of whether or not there is significant
impairment in the ability to perform work or usual daily activities
(McKhann G et al, Alzheimer’s & Dementia 2011; 7: 263-269,
updated from McKhann G et al, Neurology 1984; 34: 939-944)
Department of Neurology
Knight ADRC
MANAGEMENT
• Nature of the illness
• Extent of Disability
• Social and psychological needs/support
services
• Future changes/prognosis
• Treatment
• Referral
• Readings: The 36-Hour Day
• Alzheimer Association
• Legal issues
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Knight ADRC
POSSIBLE TREAMENT OUTCOMES
Function
Disease Arrest
Slowed Progression
Treatment
Symptomatic Benefit
Disease Course
Without Treatment
Time
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Knight ADRC
FDA Approved Pharmacotherapy in
Alzheimer’s Disease
Cholinesterase Inhibitors
•
•
•
•
Donepezil (Aricept)
Galantamine (Razadyne)
Rivastigmine (Excelon-patch or pill)
Approved for use in mild to moderate AD
N-Methyl-D-Aspartate (NMDA)–Receptor
Antagonist
• Memantine (Namenda)
• Approved for use in moderate to severe AD
Department of Neurology
Knight ADRC
Cholinesterase inhibitors (ChEIs)

Issues
• Early vs. Late Stage
• Relative stabilization of cognitive abilities
• Behavioral pathology develops less often
• Neuropsychiatric symptoms may be responsive
• Side Effects
–
–
–
–
–
–
GI
Urinary
Muscle
Sleep
Bradycardia
Oral
Arch Intern Med. 2009 May 11;169(9):867-73.
Syncope and its consequences in patients with
dementia receiving cholinesterase inhibitors: a
population-based cohort study.
Memantine (Namenda)
Mechanism: NMDA receptor
antagonist, reduces calcium
efflux into cells and is
thought to be neuroprotective
Dose: 5m po qd and titrate up
weekly until 10 mg bid.
However, reduce dosage for
renal failure.
Benefits: similar to Ach-,
Side effects: constipation,
benefits are probably realized headache, dizziness, and
through relative cognitive
confusion
stability, moderate dementia,
dual therapy
CAPRYLIC TRIGLYCERIDE (AXONA)
• Theory: AD is characterized by early and region
specific declines in cerebral glucose metabolism
• Axona is metabolized in the liver to a ketone body
providing neurons with an alternative fuel (BHB)
• A medical food, supplied in powder
• MMSE 14-24
• N=152 with AD
• ApoE4- group showed changes
• No Clear Evidence of Efficacy
Henderson ST,Vogel JL, Barr LJ, et al.
Nutrition and Metabolism 2009; 6:31, epub
Department of Neurology
Knight ADRC
Community Collaborations
• Alzheimer’s
Association
• Diversity
• Early Stage
• Respite
Assistance
• Adult Day Services
• Level of Care:
Assisted
Living/Long Term
Care
• Chore Workers
•
•
•
•
•
•
•
•
•
Professionals
Difficult Behaviors
Driving
Education
Hospice
Legal
Research
Support Groups
Long Term Care
Docs
St. Louis Chapter Alzheimer’s Association: 314-432-3422
Department of Neurology
Knight ADRC
Dementia and Driving: When is it
time to hang up the keys?
• Green Light (Mild)
• No red flags
• Monitor at intervals
• Yellow Light (Moderate)
• Red flags
• Refer for driving
1. Know how to evaluate
evaluation
2. Know how to refer
• Red light (Severe)
3. Know legal/ethical issues
• Driving Retirement
Department of Neurology
Knight ADRC
Alzheimer Pathology
• 51 female with strange behaviors, loss
of short-term memory, suspicions died 5
years later
Mrs. Auguste D
•Dr. Alzheimer diagnosed plaques but no
neurofibrillary tangles”.
•Neuropathology includes;
•Amyloid plaques
•Neurofibrillary tangles
•Synaptic dysfunction
•Cell Death
•Inflammation
Dr. Alois Alzheimer
Department of Neurology
Knight ADRC
Model of Alzheimer’s brain pathology
Holtzman DM, Morris JC, Goate AM (2011) Science Translational Medicine Vol 3, Issue 77
Department of Neurology
Knight ADRC
In vivo Amyloid Imaging
Pittsburgh Compound B (PIB)
(Klunk et al, Ann Neurol 2004)
H 3C
6
1
S
N+
N
CH 3
CH 3
CH
Amyloid Plaques
Histology - Thioflavin T
PET Imaging [11C]6-OH-BTA-1 (PIB)
HO
S
NH11CH3
N
Courtesy of William Jagust
Department of Neurology
Knight ADRC
Presymptomatic Detection of AD:
Biomarkers (PIB Imaging)
Amyloid –
Amyloid +
Cognitively
normal
Alzheimer
dementia
Courtesy of Mark A. Mintun and John C. Morris.
Reprinted with permission.
Copyright 2010 Washington University, St. Louis Missouri.
All Rights Reserved
Amyloid +
Cognitively
normal
3 years later,
Alzheimer dementia
Department of Neurology
Knight ADRC
Avid Radiopharmaceuticals: Amyvid Scan
• Amyvid is a radioactive diagnostic agent for PET
imaging of the brain to estimate B-amyloid plaque
density in adult patients with cognitive impairment
who are being evaluated for AD
• A negative scan indicates sparse to no neuritic plaques
and is inconsistent with a neuropath dx of AD
• A positive scan indicates moderate to frequent amyloid
neuritic plaques
NOTE:
A positive scan can occur in the presence of other neurological disorders and
in cognitively intact older adults.
In addition, a negative scan in a patient with dementia does not rule out the
presence of neurodegenerative diseases from other protein pathologies.
Department of Neurology
Knight ADRC
Avid Radiopharmaceuticals: Amyvid Scan
• Image interpretation is based upon the distribution of the
radioactive signal within the brain; images are designated as
positive or negative by comparing the radioactivity in cortical gray
matter with activity in the adjacent white matter.
A (-) scan shows more
radioactivity
in white matter than
gray matter,
creating clear gray-white
contrast
A (+) scan show
cortical areas with
reduction or loss
of the normal
gray-white
contrast.
Department of Neurology
Knight ADRC
plaques
tangles
Established CSF
Biomarkers of AD
Tau
Ab42
Tau
Ab42
CTL
AD
CTL
AD
Sunderland et al., 2003, JAMA 289:2094-103
Next 7 slides on biomarkers courtesy of Dr. Anne Fagan and colleagues
Department of Neurology
Knight ADRC
Hypothetical model of dynamic biomarkers
Of AD with emphasis on the preclinical period
MRI
Amyloid
CSF/PET
FDG PET/
fMRI
Cog
Tau
Clinical
Function
Sperling et al., 2011, Alzheimers Dement 7:280-92
(Modified from Jack et al., 2009, Brain 132:1355-65)
Department of Neurology
Knight ADRC
Receiver Operating Characteristic curves for clinical
Diagnosis (DAT vs. cognitively normal controls) in ADNI
p-tau181p tau/Aβ1–42
0.753
0.917
p-tau181/
Aβ1–42
0.856
LRTAA
Model
0.942
Parameters
ROC AUC
tau
0.831
Aβ1–42
0.913
Threshold
value
Sensitivity
(%)
Specificity
(%)
93pg/ml
192pg/ml
23pg/ml
0.39
0.10
0.34
69.6
96.4
67.9
85.7
91.1
98.2
92.3
76.9
73.1
84.6
71.2
79.5
Test
accuracy
(%)
Positive
predictive
value (%)
80.6
87.0
70.4
85.2
81.5
89.9
90.7
81.8
73.1
85.7
77.3
85.7
Negative
predictive
value (%)
73.8
95.2
67.9
84.6
88.1
97.2
Shaw et al., 2009, Ann Neurol 65:403-13
Department of Neurology
Knight ADRC
Case Presentation
•
•
•
•
61 YO retired female; completed HS, community college
Husband and daughter reported ~3 years of memory decline.
Her father had onset of memory changes in his 60s, died in 70s.
Always “ditzy” but increased repeating, forgets she walks the dog,
impaired recall of events and conversations. Deficits vary
significantly day to day. No language problems.
• Some trouble with time relationships and might get lost in less
familiar areas. Got lost in neighborhood x 1.
• Never good at calculations, checkbook and bills. No major
changes. Problem solving OK. Socially appropriate.
Case Courtesy of Dr. Joy Snider
Department of Neurology
Knight ADRC
Case cont.
• Difficulty shopping even with a list and recently received a traffic
ticket for risky driving.
• Needs assistance with laundry
• Might not shower for a week, less meticulous about appearance
• Endorsed some depressive symptoms- felt sad, decreased appetite
and weight, feeling tired.
• MMSE 24, logical memory 4 (>1 SD below mean), missed 2/5 John
Brown, 2/3 MMSE; largely incorrect on personal autobiographical
events
• MRI of the brain and labs unrevealing
• Family very resistant to the diagnosis of Alzheimer’s vs. normal
aging
Department of Neurology
Knight ADRC
CASE
• Rated CDR 1(SB=4.5), diagnosis DAT with relatively early
onset (@ age 61).
• Recommended she continue taking Aricept.
• Athena biomarkers ordered.
• CSF BIOMARKERS DONE 16 days later:
• CSF Aβ42
• pTau 181
• Total Tau
N
CSF Aβ42
pTau-181
Total Tau
395 pg/ml
71.3 pg/ml
893 pg/ml
Consistent with DAT
Normal
cognition
90
DAT CDR 0.5
567.0 ± 207.0
434.1 ± 211.5 399.8 ± 144.0
240-709
62 ± 26
342 ± 175.0
85.9 ± 45.4
78.7 ± 40.7
564.9 ± 302.5 496.9 ± 287.5
25-192
156-1200
49
Pathological
AD
18
Pathological
AD (range)
Department of Neurology
Knight ADRC
Imaging Dementia—Evidence for
Amyloid Scanning (IDEAS) Study
A Coverage with Evidence Development Longitudinal
Cohort Study
• National, open-label study on utility of amyloid PET in ~18,500
Medicare beneficiaries meeting Appropriate Use Criteria for Aβ
imaging (Johnson et al. 2013)
•
Eligible patients referred for PET by dementia experts
•
Scans covered by CMS, performed and interpreted locally
• Aim 1: Impact of scan on management plan at 3 months
• Aim 2: Impact of scan on major medical outcomes at 12 months
• The primary hypothesis is that, in diagnostically uncertain cases,
amyloid PET will lead to significant changes in patient
management, and this will translate into improved medical
outcomes
Department of Neurology
Knight ADRC
IDEAS: Imaging Dementia –
Evidence for Amyloid Scanning
• An open-label, longitudinal cohort study
under CED to assess the impact of amyloid
PET on patient-oriented outcomes in
individuals meeting Appropriate Use Criteria
for amyloid PET (Johnson et al. 2013)
• The primary hypothesis is that, in
diagnostically uncertain cases,
knowledge of amyloid PET status will
lead to significant changes in patient
management, and this will translate into
improved medical outcomes
Department of Neurology
Knight ADRC
Aim 1 Primary Objective
• Test whether amyloid PET imaging will lead to a
≥ 30% change between pre-PET and post-PET
patient management within ~90 days in a
composite measure of at least one of the
following:
• AD drug therapy;
• Other drug therapy; and
• Counseling about safety and future planning
• The hypothesis will be tested separately for MCI
and dementia.
Department of Neurology
Knight ADRC
IDEAS Aim 1
• To assess the impact of amyloid PET on patient
management at 90 days
• Referring dementia expert completes CRFs:
•
•
•
Pre-PET: intended management assuming
no access to amyloid PET
Post-PET: actual management at 90 days
post-scan, incorporating amyloid PET results
Also leading diagnosis, differential diagnosis,
diagnostic confidence pre- and post-PET
Department of Neurology
Knight ADRC
IDEAS Aim 2
• To assess the impact of brain amyloid PET
on hospital admissions and emergency room
visits in study patients (amyloid PET-known)
compared to matched patients not in the
study (amyloid PET-naïve) over 12 months
• CMS claims data will be collected for all
study participants and from concurrent
controls matched according to a validated
algorithm
Department of Neurology
Knight ADRC
Aim 2 Primary Objective
Determine if amyloid PET is
associated with ≥ 10% relative
reduction in study patients
compared to matched controls:
• Inpatient hospital admissions
over 12 months
• Emergency room visits over 12
months
Department of Neurology
Knight ADRC
RESULTS REFERRAL FOR IDEAS STUDY
• CASE #1: 79 year old male with MCI-Amnestic/Executive
dysfunction with inconsistent impairments in higher order
IADL’s. Amyvid Pet Scan negative and donepezil stopped
• CASE #2: 71 year old male with MCI-Amnestic and on
cusp of IADL impairment. Amyvid PET Scan positive and
the patient was started on donepezil.
• CASE #3: 70 year old female with history of lung cancer,
depression and diagnosed with MCI-amnestic. Amyvid Pet
Scan was positive and she was placed on donepezil.
Department of Neurology
Knight ADRC
NATURE VS NURTURE
Factors: nutritional, medical conditions, medications, social, economic,
behaviorlal, toxic, genetic, etc
Department of Neurology
Knight ADRC
Physical Activity and Incident Cognitive
Impairment in Elderly Persons: The
Invade Study
Community based cohort study in Bavaria, Germany
3903 participants over 55 years enrolled 2001-3
Followed activity level over two years
Reduced risk of cognitive impairment with
moderate activity (<3x week, OR=.57, CI, .37-.87) or
high physical activity (> 3x week, OR=.54, CI, .35-.83)
• Strength of this study; excluded for dementia and functional
impairment (reverse causality), dealt with confounding
variables
• Physical Activity Defined as # of days per week performed
strenuous activities; walking, hiking, bicycling, swimming,
gardening, or other exercise).
•
•
•
•
Etgen T, et al. Arch Intern Med 2010; 170: 186-193
Department of Neurology
Knight ADRC
Physical Activity/Exercise
Barnes, DE. Whitmer RA, and Yaffe K.
Physical Activity and Dementia: The need for prevention trials.
Exercise and Sport Sciences Review. 2007; 35(1) 24-29.
Department of Neurology
Knight ADRC
Exercise Engagement as a Moderator of
the Effects of APOE Genotype on
Amyloid Deposition
• 201 Cognitively normal adults aged 45-88 were recruited from
the Knight Alzheimer’s Disease Research Center.
• APOE genotyping data and answers to a questionnaire on
physical exercise engagement over the last decade were
obtained.
• CSF Studies and amyloid imaging with PIB were obtained in
this sample.
• The studied noted that there were higher PIB binding for for
carriers of e4 with a sedentary lifestyle
• Cognitively normal sedentary APOE e4 individuals
at augmented risk for cerebral amyloid deposition.
Etgen T, et al. Arch Intern Med 2010; 170: 186-193
Department of Neurology
Knight ADRC
FOOD COMBINATION AND ALZHEIMER”S
DISEASE RISK
• Participants: 2148 Community-Based Older Adults New York
• Main Outcome Measure: Incident AD risk.
• Results: 253 subjects developed AD during a follow-up of 3.9 yrs.
We identified a Dietary Pattern (DP) strongly associated with lower
AD risk: compared with subjects in the lowest tertile of adherence
to this pattern, the AD hazard ratio (95% confidence interval) for
subjects in the highest DP tertile was 0.62 (0.43-0.89) after
multivariable adjustment (P for trend = .01).
• This DP was characterized by higher intakes of salad
dressing, nuts, fish, tomatoes, poultry, cruciferous
vegetables, fruits, and dark and green leafy vegetables and
a lower intake of high-fat dairy products, red meat, organ meat,
and butter.
• Conclusion: AD-related nutrients and multiple food groups can aid
in identifying
combinations
are associated
with AD risk.
Yian
Gu, PhD; Jerifood
W. Nieves,
PhD; et al. that
Arch Neurol.
2010;67(6):699-706.
Department of Neurology
Knight ADRC
MEDITERRANEAN DIET
Solfrizi V, Panza F, Frisardi V, et al
Diet and Alzheimer’s Disease Risk Factors or Prevention: Current Evidence
Expert Rev Neurother. 2011; 11: 677-708.
Department of Neurology
Knight ADRC
Alcohol and Dementia
• Methods: to evaluate the evidence for any relationship between
incident cognitive decline or dementia in the elderly and alcohol
consumption, a systematic review and meta-analyses were
carried out.
• Results: 23 studies were identified (20 epidemiological cohort,
three retrospective matched case-control nested in a cohort).
Meta-analyses suggest that small amounts of alcohol may be
protective against dementia (random effects model, risk ratio
[RR] 0.63; 95% CI 0.53–0.75) and Alzheimer's disease (RR 0.57;
0.44–0.74) but not for vascular dementia (RR 0.82; 0.50–1.35)
or cognitive decline (RR 0.89; 0.67–1.17)
• Conclusions: because of the heterogeneity in the data these
findings should be interpreted with caution.
Peters R, et al.
Alcohol, dementia and cognitive decline in the elderly:
a systematic review
Age and Ageing 2008; 37; 505-512
Department of Neurology
Knight ADRC
Alcohol: Why it might help the Brain
•
•
•
•
•
•
•
•
Why would it help?
Increase insulin sensitivity
Increase HDL levels
Lowers blood pressure
Decreases fibrinogen levels
Enhance NO activity
Decreasing platelet aggregation
Resveratrol from grapes
Department of Neurology
Knight ADRC
IT TAKES A VILLAGE….
Exhaustive Literature Review, Type of Study, Quality of Study
Department of Neurology
Knight ADRC
Observational Studies and AD Risk
*Indicates studies support similar risk direction for future cognitive decline
Department of Neurology
Knight ADRC
RISK FACTORS FOR SPORADIC AD
• Robust risk factors • Putative risk factors
•
•
•
•
Advanced age
Family history of AD
Down’s syndrome
ApoeE genotype 4
•
•
•
•
•
•
Systolic hypertension
Hypercholesterolemia
Diabetes mellitus
BMI
Depression
Smoking
• Putative protective factors
•
•
•
•
•
Exercise
Nutrition
Cognitive Stimulation
Education
Socialization
Department of Neurology
Knight ADRC
RANDOMIZED CONTROLLED TRIALS
to DELAY ONSET OF AD/MCI
• Challenges are many
• What has not worked…
• Vitamin E, Gingko, BP meds, Cholinesterace -,
NSAI’s*, estrogen, estrogen with progestin*,
statins
• What has been promising…
• Cognitive Training
• What we need….(some NIA pending)
• Med Diet, B vitamin supplementation,
exercise, social engagement, etc
Department of Neurology
Knight ADRC
IN SUMMARY…
• We do know a healthy lifestyle that includes
proper diet, physical activity, appropriate
weight, no smoking can lower risk for heart
disease and diabetes
• There is no definitive evidence yet about
what can prevent Alzheimer’s disease or
age-related cognitive decline
• If you decide to take a supplement, please
check with your doctor and pharmacist
• REMEMBER: it is important to consider
whether data is supported by a doubleblind, placebo controlled trial!
Department of Neurology
Knight ADRC
If AN APPLE A DAY KEEPS The DOC AWAY
HOW ABOUT ALZHEIMER DISEASE?
For Now, the 4 Legs of the Table MAY Hold You Up!!
1. Cognitive/Social Stimulation
2. Proper Nutrition
3. Exercise
4. Treat Risk Factors for Vascular Dx
And reduce stress!!!!
Department of Neurology
Knight ADRC
Failure of AD Candidate Therapeutics
Agent
Target/Mechanism
Outcome
Atorvastatin; Simvastatin
Cholesterol (HMG CoA reductase
Negative
NSAIDs
Inflammation
Negative
Rosiglitazone
Insulin (PPAR gamma agonist)
Negative
Latrepirdine
Mitochondrial function
Negative
AN1792
Amyloid immunoRx
Negative (AEs)
Tramiprosate
Amyloid aggregation
Negative
Tarenflurbil
Gamma secretase
Negative
Semagacestat; Avagacestat
Gamma secretase
Negative
Bapineuzumab
Amyloid immunoRx
Negative
Solanezumab
Amyloid immunoRx
Negative (+/-)
Crenezumab
Amyloid immunoRx
Negative
IVIG
Nonselective immunoRx
Negative
LY2886721
Beta secretase
AEs
ACC-001
Amyloid immunoRx
Negative
Non-Aβ
inhibitor)
Aβ
Department of Neurology
Knight ADRC
Conclusions for Early Detection
and Intervention in AD

Once symptoms occur, even in prodromal/MCI stage,
the brain already has been irreversibly damaged by AD

Symptomatic AD may benefit from combination
therapies

AD biomarkers may be useful to support clinical
diagnoses and now allow in vivo detection before
symptoms occur

Interventions (amyloid monotherapies) have begun in
asymptomatic persons at great risk of symptomatic AD,
but much work (timing, outcomes, etc.) remains
Department of Neurology
Knight ADRC
DIAN and the Secondary
Prevention of AD
Department of Neurology
Knight ADRC
The Dominantly Inherited
Alzheimer Network (DIAN)
• Established by a cooperative agreement (U19
AG032438; 9/08 – 12/14; JC Morris, PI) from
the National Institute on Aging
• Washington University in St Louis is the DIAN
Coordinating Center
• Designed primarily as a preclinical AD
biomarker study, and also provides the
infrastructure for prevention drug trials
Department of Neurology
Knight ADRC
DIAN AIMS
• Determine WHEN the pathobiology of AD begins in
presymptomatic mutation carriers in relation to
parental age of onset of dementia
• Determine the SEQUENCE and RATE of the
pathobiological changes
• Compare the clinical and pathological phenotypes of
dominantly inherited AD with late onset AD
• Enroll and study longitudinally with a uniform protocol
400 persons (~200 MCs, ~200 NCs) from families
with a known pathogenic mutation for AD
• Enroll affected participants in DIAN-TU trials
Department of Neurology
Knight ADRC
Preclinical Alzheimer Disease

~30% of cognitively normal older adults have biomarker
evidence of preclinical AD

Biomarker-positive CN persons are at increased risk of
developing symptomatic AD compared with biomarkernegative CN older adults

However, individual level prediction not currently possible
– Is symptomatic AD inevitable?
– If so, when will it develop?

Asymptomatic AD mutation carriers are destined to
develop symptomatic AD, and at about the same age as
their affected parent
Next 12 slides courtesy of Dr. John Morris/Dr. Joy Snider
Secondary Prevention Trials

DIAN-TU (Dominantly Inherited Alzheimer Network Trials
Unit); R Bateman
– 210 individuals at risk for autosomal dominant AD (MC and NC)
– Solanezumab (Lilly), IV infusion, and Gantenerumab (Roche),
subcutaneous

Alzheimer Prevention Initiative; E Reiman, P Tariot
– Colombian PSEN1 E280A family, 200 MC and 100 NC
– Crenezumab (Genentech), subcutaneous

TOMMORROW; Takeda and Zinfandel Pharmaceuticals
– 5800 cognitively normal persons at increased AD risk based on
APOE and TOMM40 genotypes, age 65-83 y worldwide
– Pioglitazone (AD-4833, PPAR-γ), oral

A4 (Anti-Amyloid in Asymptomatic AD); R Sperling, ADCS
– Clinically normal persons 65-85 y with elevated brain amyloid (PIB),
500 individuals per treatment arm
– Solanezumab (Eli Lilly), IV infusion
Prevention studies are here: the
A4 Study

A4 = Anti-Amyloid Treatment in Asymptomatic Alzheimer’s

To determine whether we can prevent memory loss in
people who may be at a higher risk for developing AD
before they show symptoms.

Testing whether a new investigational treatment, an antiamyloid antibody, can prevent memory loss associated
with AD
Cognitively normal older adults with elevated brain amyloid
as shown by an Amyvid scan are eligible; individuals will
learn their Amyvid results

– 550 people will be randomized to active treatment (antibody)
– 550 people will be randomized to placebo
A4 Fast Facts

Participants
–
–
–
–
Aged 65 – 85 years old
Normal thinking and memory abilities
Have a study partner
Willing and able to participate in all required procedures (brain
MRI, brain Amyvid scan, optional LP)

3.5 years with required monthly visits for antibody infusion

Focus on diversity: many groups and individuals at higher
risk for AD, but we don’t know why. Particular need for:

– African Americans and Hispanic/Latino Americans
– People over 75
– People with a family history of AD
Enrollment is at about the halfway mark nationwide; Washington
University ADRC will complete our enrollment very soon
Other Trials Starting soon:

Prevention trials (in cognitively normal older adults)
– A5, similar to A4 but with an oral agent, may start later this year
TRIALS IN PEOPLE WITH AD SYMPTOMS:
 Phase 3 Study of Aducanumab in Early Alzheimer's
Disease (EMERGE)
–
–
–
–
Aducanumab is an antibody that binds to beta amyloid
1350 participants worldwide (goal of 10 at Wash U)
Aged 50 to 85 with mild AD (CDR 0.5, MMSE 24-30)
Includes Amyloid PET screening- only continue to treatment if
positive
– Randomized to active drug or placebo for 18 months (2:1 active to
placebo; 2 doses of active drug) followed by 24 months where all
on active drug
Other Trials Starting soon:

Effect of LY3202626 on Alzheimer’s Disease
Progression as Measured by Tau-PET in Mild
Alzheimer’s Disease Dementia
– LY3202626 is an oral agent that may reduce the amount of beta
amyloid made in the body
– 1000 participants screened worldwide
– Aged 55-85 years with mild symptomatic AD
– MMSE 20-26
– Includes Amyloid PET screening- only continue to treatment if
positive
– One year treatment
– Main outcome is tau imaging, a marker of damage to the brain
Other Trials – Future



Almost 200 active intervention trials now in the US!
New preclinical studies planned including A5 and an
additional drug arm for DIAN-TU
Emphasis on biomarkers to confirm presence of AD
changes in the brain in studies in both the
asymptomatic phase and in those with symptoms

Allows enrollment of cognitively normal people with
preclinical AD for prevention trials

Allows confirmation that symptomatic people
enrolled in trials truly have AD (not a mimic)
Contact Us: A4 Study at Knight ADRC

Website: www.A4Study.org

Phone: Erin Cattoor; 314-286-2303

Email: [email protected]

Knight ADRC: 314-286-2881;
http://alzheimer.wustl.edu