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 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 Gain Cognition Time Aging

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

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 Auguste Deter Alois Alzheimer 1850-1906 1864-1915 November 1902 Alois Alzheimer 1864-1915 Auguste Deter 1850-1906

Neurofibrillary Tangles Neuropathology Neuritic Plaques Neurofibrillary Tangles Extracellular deposits of beta-amyloid 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 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

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

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 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

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

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 Median onset! EH Corder et al. Science.1993

Family History of 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 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

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

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 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

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

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 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;366:893-903

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 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?

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

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

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

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 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!