Alzheimer’s disease:
Interventions and New Findings
Szofia S Bullain, MD
Geriatric Neurologist
Assistant Professor of Neurology
February 10, 2017
Disclosure
The author has NO affiliation with any corporate
organization that may constitute a conflict of
interest with this presentation
2
Neurology ‖ October 7, 2016
Outline
• Cognitive impairment and dementia
• Alzheimer’s disease
• What is Alzheimer’s disease?
• Diagnosis of Alzheimer’s disease
• Epidemiology
• Pubic health impact
• Risk factors for Alzheimer’s disease
• FDA-approved treatment options
• Clinical trials
Cognitive changes over time
Cognition
Gain
Time
Aging
Spectrum of cognitive impairment
Preclinical Phase
~20 yrs
~5 yrs
Mild Cognitive
Impairment
Dementia
~10 yrs
-Mild
-Moderate
-Severe
Mild cognitive impairment (MCI)
• Complaint (by patient or other informant)
• Testing indicates deficits in one or more areas of
cognition 1.5 SD below age-adjusted norms
• Not impacting occupational or social functioning
• MCI may represent “early dementia” and may
progress with time
• Some patients with MCI remain MCI indefinitely or
return to normal
Definition of dementia
DSM-5 diagnostic criteria
Dementia = Major neurocognitive disorder
• Evidence of significant cognitive decline from a previous level of
performance in one or more cognitive domains
&
• A substantial impairment by standardized neuropsychological testing (or
if not available other quantified clinical assessment )
• The cognitive deficits interfere with independence in everyday activities
(i.e., at a minimum, requiring assistance with complex instrumental
activities of daily living such as paying bills or managing medications)
• The cognitive deficits do not occur exclusively in the context of a delirium
• The cognitive deficits not better explained by another mental disorder
(e.g., major depressive disorder, schizophrenia)
Alzheimer’s Disease
November 1902
Alois Alzheimer
1864-1915
Auguste Deter
1850-1906
Neuropathology
Neuritic Plaques
Extracellular deposits
of beta-amyloid
Neurofibrillary Tangles
Intracellular deposits of
hyperphosphorylated tau
Clinical presentation
• Gradual onset, slowly progressive
• Pronounced memory impairment
• Episodic > Semantic
• Visuospatial impairment
• Executive Dysfunction
• Language impairment
• Apraxia
• Neuropsychiatric symptoms
• Most common form of dementia after age 65
Hypothetical model of AD biomarkers
CR Jack, et al., Lancet Neurol. 2010
Preclinical
Mild Cognitive
Impairment
Dementia
Alzheimer’s & Dementia, May 2011
Diagnosis
Bedside instruments to test cognition
Routine laboratory and imaging evals
• Laboratory testing:
 CBC, CMP, TSH, B12, RPR
• Brain imaging:
 CT for patients with pacemaker, metal implants,
severe claustrophobia or if MRI is not readily
available
 MRI is more sensitive and preferred
• Other evaluations are based on the individual
case (e.g. paraneoplastic work-up)
Specialized or advanced testing
• CSF analysis – not recommended by AAN for
routine use
 decreased CSF Aβ-42 (correlates with earlier death)
 elevated tau levels (correlates with severity)
 large volume lumbar puncture may improve cognition
and gait in normal pressure hydrocephalus
 useful if chronic infection or inflammation suspected
• Sleep study
 REM sleep behavior disorder
 Obstructive sleep apnea
Positron Emission Tomography (PET)
• Fluorodeoxyglucose PET: AD vs FTD
• Florbetapir PET:
Neuropsychological testing
• Performance on standardized memory, language,
problem-solving, visuospatial tests compared to
age, education-specific norms
• Testing performed and interpreted by a
neuropsychologist
• Testing lasts 2-6 hours
• Ideal for
 highly educated patients (who have deficits that cannot
be detected on simple bedside tests)
 to distinguish pseudo-dementia (poor effort and
concentration, slowing, variable performance)
 to monitor progression
Epidemiology
Epidemiology
Incidence
Prevalence
CX Qiu et al.Dialogues Clin Neurosci. 2009 June; 11(2): 111–128.
Projected prevalence of AD
L. E. Hebert et a. Arch. Neurol. 2003
Public health impact of AD
Alzheimer’s Association 2015 facts and figures:
Alzheimer's & Dementia: The Journal of the Alzheimer's Association 2015 11, 332-384
Risk and Protective Factors
Etiologic
Hypothesis
Risk and Protective Factors
Epidemiologic
Evidence
Genetic
Susceptibility
Deterministic (APP, PS1, PS2), Susceptibility (APOE)
Family History
Strong
Psychosocial
High education, mentally stimulating activities,
enriched social network, physical activity
Moderate
Hypertension, obesity, diabetes,
cerebrovascular disease, smoking
Alcohol intake, antihypertensive therapy
Moderate
Vascular
Nutritional
and Dietary
Others
Deficiency in folate, vitamin B12, antioxidants
Omega-3-fatty acids, fruit, and vegetable intake
Limited or Mixed
Head injury, occupational exposures
Hormone therapy, anti-inflammatory drugs
Limited or Mixed
C Qiu et al. Dialogues in Clin Neurosci. 2009
Risk and Protective Factors
Etiologic
Hypothesis
Risk and Protective Factors
Epidemiologic
Evidence
Genetic
Susceptibility
Deterministic (APP, PS1, PS2), Susceptibility (APOE)
Family History
Strong
Psychosocial
High education, mentally stimulating activities,
enriched social network, physical activity
Moderate
Hypertension, obesity, diabetes,
cerebrovascular disease, smoking
Alcohol intake, antihypertensive therapy
Moderate
Vascular
Nutritional
and Dietary
Others
Deficiency in folate, vitamin B12, antioxidants
Omega-3-fatty acids, fruit, and vegetable intake
Limited or Mixed
Head injury, occupational exposures
Hormone therapy, anti-inflammatory drugs
Limited or Mixed
C Qiu et al. Dialogues in Clin Neurosci. 2009
Genetics Risk Factors
Deterministic genes (1-5% of cases)
 Amyloid Precursor Protein (ch 21)
 Presenilin 1 (ch 14)
 Presenilin 2 (ch 1)
Susceptibility genes
 Apolipoprotein E e4 allele (ch 19)
Increases the risk but does not
guaranty the development of AD
APOE Gene Dose and AD Risk
More copies of
APOE e4 allele =
Lower age of
onset
EH Corder et al. Science.1993
Relative Risk (95% CI) (log scale)
Family History of Dementia
16.0
8.0
7.5
4.0
2.6
2.0
1.0
1.0
0.5
0
1
2+
Number of 1st Degree Relatives with Dementia
EURODEM pooled analyses
CM Van Duijn et al. Int J Epidemiol.1991
Risk and Protective Factors
Etiologic
Hypothesis
Risk and Protective Factors
Epidemiologic
Evidence
Genetic
Susceptibility
Deterministic (APP, PS1, PS2), Susceptibility (APOE)
Family History
Strong
Psychosocial
High education, mentally stimulating activities,
enriched social network, physical activity
Moderate
Hypertension, obesity, diabetes,
cerebrovascular disease, smoking
Alcohol intake, antihypertensive therapy
Moderate
Vascular
Nutritional
and Dietary
Others
Deficiency in folate, vitamin B12, antioxidants
Omega-3-fatty acids, fruit, and vegetable intake
Limited or Mixed
Head injury, occupational exposures
Hormone therapy, anti-inflammatory drugs
Limited or Mixed
C Qiu et al. Dialogues in Clin Neurosci. 2009
Education and Dementia
Relative Risk (95% CI) (log scale)
4.0
Educational Level
2.0
1.8
1.3
1.0
1.0
0.5
Low
Medium
High
<7 yrs
8-11 yrs
>12 yrs
EURODEM pooled analyses
L. Letenneur. Am J Epidemiol. 2000
Physical and Intellectual Activities and
Risk of Dementia
Intellectual activity
 Observational studies protective effects
 RCT - benefits do not seem to translate to
other activities or affect day-to-day function
Physical activity
 Observational studies –
benefits even from low intensity activity
 RCT – conflicting results
Risk and Protective Factors
Etiologic
Hypothesis
Risk and Protective Factors
Epidemiologic
Evidence
Genetic
Susceptibility
Deterministic (APP, PS1, PS2), Susceptibility (APOE)
Family History
Strong
Psychosocial
High education, mentally stimulating activities,
enriched social network, physical activity
Moderate
Hypertension, obesity, diabetes,
cerebrovascular disease, smoking
Alcohol intake, antihypertensive therapy
Moderate
Vascular
Nutritional
and Dietary
Others
Deficiency in folate, vitamin B12, antioxidants
Omega-3-fatty acids, fruit, and vegetable intake
Limited or Mixed
Head injury, occupational exposures
Hormone therapy, anti-inflammatory drugs
Limited or Mixed
C Qiu et al. Dialogues in Clin Neurosci. 2009
Relative Risk (95% CI) (log scale)
Midlife Cardiovascular Risk Factors & Risk
of Dementia
4.0
2.4
2.3
2.0
1.7
1.2
1.3
1.0
1.0
0.5
1.3
1.5
1.4
No
HTN
Smoking Hyperchol.
Cholesterol
Individual Risk Factors
DM
1
2
3
4
Cardiovascular
Composite Score
RA Whitmer et al. Neurology. 2005
Treatment options
Pharmacological options
Cholinesterase inhibitors- mild to moderate AD
• Tacrine – not used in clinical practice
• Donepezil (5mg, 10mg, 23 mg PO QD) also for
severe MMSE<10 cases
• Rivastigmine (3-6mg PO BID or 4.6mg, 9.5mg/24 hr
patch QD)
• Galantamine (8-12mg PO BID)
NMDA receptor antagonist- moderate to severe AD
• Memantine XR (7mg, 14mg, 28mg PO daily)O
Currently approved treatment options
MODERATE TO SEVERE ALZHEIMER’S DISEASE
SMME: Mean Scores on the Standardized Mini–Mental State Examination (SMMSE)
BALDS: Bristol Activities of Daily Living Scale (BADLS)
Howard R et al. N Engl J Med 2012;366:893-903
Non-pharmacological treatment options
 Diet - Mediterranean diet
 Exercise - cardiovascular and strength training
 Socialization
 Cognitive Stimulation
Prognosis
 Average patients decline 3 to 3.5 points on average on
the MMSE/year
 <10 percent decline of 5 to 6 points on MMSE /year
 Mean survival: 11.8±0.6 years from onset of symptoms
 Patients generally succumb to terminal-stage
complications that relate to advanced debilitation, such
as dehydration, malnutrition, and infection
Prevention & Intervention
Potential Impact: Interventions
Delaying
the
Onset
of
AD
Delay
(years)
0
8
.5
1
6
2
4
5
2
0
2037
2017
Number of people
with AD (millions)
4
6
8
2047
2027
Year
2007
1997
Adapted from R Brookmeyer et al. Am J Pub Health.1998
Primary Prevention Studies
 Randomized placebo controlled
 Cognitively intact people
 Require thousands of subjects
 Long follow-up
 Labor intensive
 Expensive
Primary Prevention Trials
of Dementia and AD
Hormone Therapy
WHIMS - estrogen OR estrogen + progesterone
PREPARE - estrogen OR estrogen + progesterone
NSAIDs
ADAPT - Naproxen or Celecoxib
Ginkgo
GEMS - Ginkgo biloba
Antioxidants
PREADVISE - Vitamin E & Selenium
Prevention Trials
Primary Prevention
Alzheimer’s Prevention Initiative
Genetic mutation carriers (PSEN1 E280A )
• Extended Colombian family
• Onset ~age 45, dementia ~age 51
• Study participants: 30-60 y.o. MMSE ≥ 26
Anti-amyloid drug
• Crenezumab SQ Q2wks
Three arms
• Drug - 100 asymptomatic mutation carriers
• Placebo - 100 asymptomatic mutation carriers
• Placebo - 100 relatives non-mutation carriers
Alzheimer’s Prevention Initiative
Primary Outcomes
• Memory and other cognitive tests
Secondary Outcomes - Change in biomarkers
•
•
•
•
Amyloid burden - PET scans
Glucose metabolism - FDG PET
Brain volume - MRI
Amyloid & tau protein levels – CSF
Secondary Prevention Trials
Anti-amyloid antibodies
Bapinuzemab
• Vasogenic edema
• Failed in Phase III
Solanezumab
• Failed at primary endpoint in Phase III
• Some improvement in mild patients
A4 Study
Anti-Amyloid Treatment in Asymptomatic
Alzheimer’s Study
Participants:
• 65 to 85 years old
• MMSE 25-30 / 30, CDR 0, NO dx of MCI/AD
• Logical Memory II score 6–18 / 25
• Positive amyloid PET scan
Intervention:
• Solanezumab 400mg or placebo IV q4wks x 36 wks
Primary outcome:
• Cognitive performance
Hope for the future
The A4 Study and the API opens new
frontier for primary prevention
Thank you for your attention!