1. Alzheimer’s disease: Interventions and New Findings
Szofia S Bullain, MD
Geriatric Neurologist
Assistant Professor of Neurology
February 10, 2017

2. Disclosure
The author has NO affiliation with any corporate organization that may constitute a conflict of interest with this presentation
Neurology ‖ October 7, 2016

3. 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

4. Cognitive changes over time
Gain
Cognition
Time
Aging

5. Spectrum of cognitive impairment
Preclinical Phase
~20 yrs
Mild Cognitive Impairment
~5 yrs
Dementia
-Mild
-Moderate
-Severe
~10 yrs

6. 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

7. 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)

8. Alzheimer’s Disease Auguste Deter Alois Alzheimer 1850-1906 1864-1915
November 1902
Alois Alzheimer
Auguste Deter

9. Neurofibrillary Tangles
Neuropathology
Neuritic Plaques
Neurofibrillary Tangles
Extracellular deposits
of beta-amyloid
Intracellular deposits of hyperphosphorylated tau

10. 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

11. Hypothetical model of AD biomarkers
The current hypothesis is that these clinical changes correspond underlying neuropathplogical changes that we can detect by the use biomarkers
CR Jack, et al., Lancet Neurol. 2010

12. Preclinical Mild Cognitive Impairment Dementia
In order to incorporate our current knowledge and the availability of biomarkers in 2011 the NIA AA work group came out with new diagnostic guidelines for the preclinical stage of AD, MCI and AD.
Alzheimer’s & Dementia, May 2011

13. Diagnosis

14. Bedside instruments to test cognition

15. 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)

16. 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

17. Positron Emission Tomography (PET)
Fluorodeoxyglucose PET: AD vs FTD
Florbetapir PET:

18. 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

19. Epidemiology

20. Epidemiology Incidence Prevalence
CX Qiu et al.Dialogues Clin Neurosci June; 11(2): 111–128.

21. Projected prevalence of AD
L. E. Hebert et a. Arch. Neurol. 2003

22. Public health impact of AD
Alzheimer’s Association 2015 facts and figures:
Alzheimer's & Dementia: The Journal of the Alzheimer's Association  ,

23. 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
Vascular
Hypertension, obesity, diabetes,
cerebrovascular disease, smoking
Alcohol intake, antihypertensive therapy
Nutritional and Dietary
Deficiency in folate, vitamin B12, antioxidants
Omega-3-fatty acids, fruit, and vegetable intake
Limited or Mixed
Others
Head injury, occupational exposures
Hormone therapy, anti-inflammatory drugs
C Qiu et al. Dialogues in Clin Neurosci. 2009

24. 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
Vascular
Hypertension, obesity, diabetes,
cerebrovascular disease, smoking
Alcohol intake, antihypertensive therapy
Nutritional and Dietary
Deficiency in folate, vitamin B12, antioxidants
Omega-3-fatty acids, fruit, and vegetable intake
Limited or Mixed
Others
Head injury, occupational exposures
Hormone therapy, anti-inflammatory drugs
C Qiu et al. Dialogues in Clin Neurosci. 2009

25. 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

26. APOE Gene Dose and AD Risk
More copies of APOE e4 allele = Lower age of onset
Median onset!
EH Corder et al. Science.1993

27. Family History of Dementia
EURODEM pooled analyses
CM Van Duijn et al. Int J Epidemiol.1991

28. 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
Vascular
Hypertension, obesity, diabetes,
cerebrovascular disease, smoking
Alcohol intake, antihypertensive therapy
Nutritional and Dietary
Deficiency in folate, vitamin B12, antioxidants
Omega-3-fatty acids, fruit, and vegetable intake
Limited or Mixed
Others
Head injury, occupational exposures
Hormone therapy, anti-inflammatory drugs
C Qiu et al. Dialogues in Clin Neurosci. 2009

29. Education and Dementia
Consistently shown in most epidemiological studies
Higher cognitive reserve
education could stimulate compensatory mechanisms of cognitive function
higher reserve need more Alzheimer-type lesions or cerebrovascular changes than those with lower reserve to express a dementia syndrome
indicator for better health care
indicator of higher SES
indicator of cognitive stimulation
indicator of early life circumstances
people with low education more likely to be clinically diagnosed as having dementia at an earlier neuropathological stage
<7 yrs
8-11 yrs
>12 yrs
EURODEM pooled analyses
L. Letenneur. Am J Epidemiol. 2000

30. 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

31. 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
Vascular
Hypertension, obesity, diabetes,
cerebrovascular disease, smoking
Alcohol intake, antihypertensive therapy
Nutritional and Dietary
Deficiency in folate, vitamin B12, antioxidants
Omega-3-fatty acids, fruit, and vegetable intake
Limited or Mixed
Others
Head injury, occupational exposures
Hormone therapy, anti-inflammatory drugs
C Qiu et al. Dialogues in Clin Neurosci. 2009

32. Midlife Cardiovascular Risk Factors & Risk of Dementia
Results of studies of midlife risk factors and risk of dementia are fairly consistent
Effect of cardiovascular risk factors may change with age, E.g. HTN appears protective against dementia at later ages
Choles-
terol
Cardiovascular
Composite Score
Individual Risk Factors
RA Whitmer et al. Neurology. 2005

33. Treatment options

34. 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

35. Currently approved treatment options
MODERATE TO SEVERE ALZHEIMER’S DISEASE
Mean Scores on the Standardized Mini–Mental State Examination (SMMSE) and the Bristol Activities of Daily Living Scale (BADLS) according to Visit Week and Treatment Group.
Scores on the SMMSE range from 0 to 30, with higher scores indicating better cognitive function; scores on the BADLS range from 0 to 60, with higher scores indicating greater impairment. Shown are raw estimates of the mean score at each visit. I bars denote the standard error.
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:

36. Non-pharmacological treatment options
Diet - Mediterranean diet
Exercise - cardiovascular and strength training
Socialization
Cognitive Stimulation

37. 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

38. Prevention & Intervention
What can be done to prevent the disease or delay the onset of suffering, or otherwise to reduce the burden of affected cases, their families, and society in general?

39. Potential Impact: Interventions Delaying the Onset of AD
Delay (years) .5 1 2 5 8 6 4 2
Number of people with AD (millions)
Describe graph first.
Year
Adapted from R Brookmeyer et al. Am J Pub Health.1998

40. Primary Prevention Studies
Randomized placebo controlled
Cognitively intact people
Require thousands of subjects
Long follow-up
Labor intensive
Expensive

41. 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
All based on numerous and consistent observational data showing decreased risk.

42. Prevention Trials

43. Primary Prevention

44. Alzheimer’s Prevention Initiative
Genetic mutation carriers (PSEN1 E280A )
Extended Colombian family
Onset ~age 45, dementia ~age 51
Study participants: y.o. MMSE ≥ 26
Anti-amyloid drug
Crenezumab SQ Q2wks
Three arms
Drug asymptomatic mutation carriers
Placebo asymptomatic mutation carriers
Placebo relatives non-mutation carriers

45. 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

46. 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

47. MMSE 25-30 / 30, CDR 0, NO dx of MCI/AD
Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study
Participants:
65 to 85 years old
MMSE / 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

48. Hope for the future
The A4 Study and the API opens new frontier for primary prevention

49. Thank you for your attention!