Whitney Wharton, PhD Cognitive Neuroscientist Assistant Professor Department of Neurology Emory University

Learning Objectives Alzheimer’s Defined Social and Economic Impact Risk Factors Neuropathology and Disease Trajectory AD Diagnosis, Treatment and Management Healthy Brain Tips

Social and Economic Costs of AD AD is the 6th leading cause of death among CCs and the 4th among AAs, in the US.1 Annual cost in US is $226 billion in healthcare costs + the equivalent of $217 billion in unpaid caregiving.1 Annual costs for health care, long-term care, and hospice care for patients with AD and other dementias are expected to increase to more than $1 trillion in 2050.1 Total annual per-person healthcare and long-term care payments in the US in 2014 were $47,752 for patients with AD, which is more than three times the costs for someone without AD.1 AD is the most costly illness in the United States, more so than cancer and stroke and heart disease combined.2 Alzheimer’s Association, 2015 (www.alz.org/facts/downloads/facts_figures_2015.pdf). 2. Hurd MD et al. N Engl J Med. 2013;368:1326-1334.

Dementia Dementia: A group of symptoms affecting thinking and social abilities severely enough to interfere with daily functioning. The difference depends the cause and location of the brain damage. Alzheimer's Disease (AD): a specific neurodegenerative disease and is the most common cause of dementia in older individuals.

What is ‘Probable AD’? An acquired condition Persistent symptoms Decline from normal baseline Persistent symptoms Not temporary confusion Severe Interfere with normal social or occupational function Affects ≥2 areas of higher brain functions Memory Language Learned motor skills Visuospatial abilities “Executive” functions Judgment and problem solving abilities Personality and behavioral changes

What is Mild Cognitive Impairment (MCI)? An acquired condition Decline from normal baseline Persistent symptoms Not temporary confusion Symptoms are mild Does not interfere with normal activities May affect only one area of higher brain function, most often: Memory Language “Executive” functions Earliest detectable stage of illness High risk of progression to dementia

AD Symptoms Executive Dysfunction Memory Loss Repetition of words, stories, phrases Personality Changes- belligerent, apathy, withdrawal Psychoses- paranoia Gait instability- falls Inability to independently dress, groom, or manage finances or meals Loss of bowel and bladder function

Alternative Causes Other neurodegenerative disease Medications Stroke (Vad) Medications Chemotherapy Depression Fever / Infection / HIV Nutritional deficit TBI Alcoholism

Why the Need to Correctly Diagnose? Different projected path Different Medications Family Planning / Caregiving

AD Risk Factors Age Gender Race Genetics (AopE 4) Parental History Stress / inflammation Midlife Hypertension Midlife Hypercholesterolemia Obesity Diabetes Sleep disturbances Healthcare neglect (nutrition, exercise, Dr.)

AD Neuropathology Normal AD

Atrophy of the hippocampus in normal aging, MCI, and AD Normal Brain MCI Moderate AD

AD Disease Progression Cognitive Function Pathologic Load Mild Cognitive Impairment Normal AD CSF biomarkers Neuroimaging Cognitive measures

Clinical Evaluation MCI or Dementia Cognitive Impairment History from informant exam, mental status MCI or Dementia Delirium Depression Vascular dementia Hydrocephalus Tumor Subdural MS B12 or folate Thyroid Organ failure Neurosyphilis HIV Blood tests Imaging Degenerative Dementias Alzheimer’s disease Dementia with Lewy Bodies Frontotemporal dementias PD, PSP, CBGD, HD, CJD Clinical features CSF, genetics

Treatment There is no known cure for AD Medications prescribed are used to treat symptoms

AD Management Caregiver support Education and training Planning Respite care Support groups Hope and encouragement The promise of new and more effective treatments Access to cutting edge clinical trials Reduced risk for family members Cholinesterase inhibitors Aricept –donepezil Razadyne (galantamine) Exelon(rivastigmine) NMDA Antagonists Namenda- Memantine Antidepressants to manage mood/sleep Zoloft, Citalopram, Lexapro, Trazodone, Mirtazepine Antipsychotics to manage psychosis

Experimental Agents Mechanism Agent Outcome β-secretase inhibition LY2886721 E2609 MK-8931 RG7129 HPP854 Phase 2 ongoing Phase 1 complete Phase 1 ongoing -secretase inhibition Semagacestat Avagacestat NIC5-15 X (decline) X (nonsignificant) -secretase modulation Tarenflurbil Fibrillogenesis inhibition Tramiprosate Chelation to prevent metal-based oligomers Clioquinol, PBT2 Ongoing trials 5HT6 antagonism RVT 101, Idalopirdine Cerebral glucose metabolism Caprylindene Cerebral insulin resistance Rosiglitazone, T3D959, Pioglitazone RAGE antagonism Azeliragon Ongoing trial Melatonin receptor antagonism Piromelatine Protein kinase C activator Bryostatin

Prevention Research Increasing Age Worse Cognitive Abilities  better Normal Cognition Worse Cognitive Abilities  better MCI Mild AD Moderate AD Severe AD Increasing Age

Prevention Research Increasing Age Start Treatment HERE Normal Cognition Worse Cognitive Abilities  better MCI Mild AD Start Treatment HERE Moderate AD Severe AD Increasing Age

Prevention Research MCI Mild AD Moderate AD Severe AD Increasing Age Normal Cognition MCI Worse Cognitive Abilities  better Mild AD Moderate AD Start Treatment HERE Severe AD 95 Years Increasing Age

How do we clinically shift the curve??? What factors do we know that…. Are linked to cognitive decline and AD symptomatology Are linked to the pathological hallmarks of AD (plaques and tangles) Occur during Midlife TREATABLE / REVERSIBLE

Vascular Risk Factors and Alzheimer’s disease AD has been associated with: Increased cholesterol levels in midlife Elevated blood pressure in midlife Increased levels of inflammation Obesity Diabetes Physical inactivity What are the environmental risk factors?

Vascular Risk Factors: Cognitive Onset and Progression Cognitive Functioning 20 30 40 50 60 70 72 74 76 78 80 Age Normal Aging Hypertension Plus Diabetes Vascular Risks Plus Hyperlipidemia

The Brain-Body Connection The brain needs a healthy blood supply 25 % of the blood from every heartbeat goes to the brain The brain depends on oxygen from this blood flow to work well

Maintain Blood Flow

Blood Pressure Meds and AD Certain meds = reduced risk (55%), progression and conversion from MCI to AD. ACE-Is and ARBs Not commonly prescribed to African Americans

Strategy Be Aware. Pubmed, Medscape, Google Scholar Start EARLY Ensure good control is achieved Only 36% of adults taking antihypertensive medication had good BP control (less than 140/90 mm Hg)

                   

Strategy Reduce risks Reduce Stress (depression, caregiver resources) Exercise!! Physical activity increases the number of connections between brains cells as well as maintains the old connections. 30 minutes moderate aerobic activity 5 days/week 20 minutes vigorous activity 3 days/week Reduce Stress (depression, caregiver resources) Ask for help

Diet Moderate alcohol intake DASH diet Columbia University examined the relationship between diet and development of Alzheimer’s disease. Analyses from 2,000 dementia-free adults ages 65 and older Persons who consumed a Mediterranean-type diet regularly were 38% less likely to develop Alzheimer’s disease over a four year follow-up

Mediterranean Diet Fruits Vegetables Beans Moderate amounts of fish Low to moderate dairy Very limited red meat Olive oil instead of butter or margarine Tree Nuts such as walnuts or pecans Red Wine in Moderation

What else?? Stay cognitively active Get involved in RESEARCH!! See your Dr. (Take notes, go with questions Correct meds Diagnose and prevent sleep disturbances. Nighttime BP patterns Supplements (fish oil, glucosamine, daily vitamin, ensure) But buyer beware Stay cognitively active Get involved in RESEARCH!!

Summary AD is not a normal part of aging Medications, in use, treat symptoms only Vascular risk factors are linked to AD risk Slowing disease progression will significantly improve quality of life for patients and caregivers Prevention studies, in conjunction with treatment studies, are needed to help better define the disease process and find effective treatments

Thank You! 404.712.7085 w.wharton@emory.edu