Aging versus Dementia due to Alzheimers Disease

R. Scott Turner, MD, PhD

Director, Memory Disorders Program Professor, Department of Neurology Georgetown University Washington, DC memory.georgetown.edu rst36@georgetown.edu

Case 1
A 64 year old judge was referred by her PCP for evaluation of memory loss. Her husband reports memory loss and repeating questions for about 18 months. Her colleagues and law clerks have expressed concerns due to several small mistakes. She reports that she has fallen a little behind at work, and is planning to retire in 1 month because she has lost the trust and confidence of her colleagues

Case 1
She has a history of well-controlled hypertension and takes only an antihypertensive medication. She has no other medical or psychiatric history. There is no history of stroke, TIA, alcohol abuse, gait disorder, falls, or head trauma. Her parents died in their 60s of old age. She works as a judge and lives with her husband. She states that at one time her IQ was 170.

Risk factors for AD

Age Family history/genetics ApoE polymorphism Minority (African-American, Hispanic) Downs syndrome Traumatic brain injury with loss of consciousness Smoking Diabetes Stroke Low education, occupational level

NIH conference April 2010

Factors that may affect risk of both AD & cognitive decline with aging (ARHQ publication 10-E005; Plassman et al., Annals of
Internal Medicine; Archives of Neurology, 2011)

Increase risk ApoE4, diabetes, current smoking, depression Decrease risk Physical activity, Mediterranean diet/vegetable intake, cognitive training/cognitively engaging activities
5

10 Signs of Alzheimers
Memory loss that disrupts daily life (amnesia) Challenges in planning or solving problems (executive dysfunction) Difficulty completing familiar tasks at home, at work, or at leisure (executive dysfunction) Confusion with time or place (disorientation) Trouble understanding visual images and spatial relationships (visual agnosias)

10 Signs of Alzheimers
New problems with words in speaking or writing (dysnomia, anomia) Misplacing things and losing the ability to retrace steps (amnesia) Decreased or poor judgment (executive dysfunction) Withdrawal from work or social activities (apathy) Changes in mood and personality (depression, anxiety)

Normal aging Cant find your keys Search for casual names and words Briefly forget conversation details Cant find a recipe Forget to enter a check Cancel a date with friends Miss an occasional turn

Early Alzheimers disease Routinely place important items in odd places Forget names of family and common objects Frequently forget entire conversations Cant follow recipe directions Can no longer manage checkbook Withdraw from usual interests Get lost in familiar places

ADLs
Complex
Working, living alone, driving, keeping appointments, handling finances, daily medications

Basic
Dressing, bathing, grooming, toileting, walking, transfers, eating

MMSE is Alzheimers diseasecentric

Case 1
Pleasant, cooperative, and wellappearing elderly woman. Vital signs normal, as is the general medical examination. Mental status examination reveals good attention with deficits in memory, orientation, language, and visuospatial skills. The MMSE score is 25/30, with points off for orientation and memory, consistent with a mild dementia.

Case 1
The remainder of the neurological examination reveals normal eye movements, strength, tone, sensation and coordination. There are no signs of parkinsonism. Reflexes are 2+ and symmetric. Gait is normal. There are no asymmetric features.

Case 1
A CBC, chemistry panel, thyroid function tests, and B12 were all normal. A test for syphilis was negative. A head MRI revealed cortical atrophy and periventricular white matter changes (small vessel ischemic changes). No tumor, hemorrhage, subdural hematoma, or large cerebral infarct. Neuropsychologic evaluation confirmed mild dementia, with deficits in memory, language, visuospatial skills, and frontal/executive function, and a lower than expected IQ.

Case 1
has multiple cognitive deficits which impair her functional abilities and represent a cognitive decline. There is no evidence for delirium or depression by history, examination, or laboratory evaluation. Diagnosed with mild dementia due to probable Alzheimers disease.

Case 1
prescribed a cholinesterase inhibitor; effects and side-effects of the drug were discussed. advised to continue treatment for hypertension with her primary care physician. discussed prognosis, advance directives, and limitations concerning complex ADLs, including driving, handling finances, taking medications... recommended ad libitum physical activity, social activity, and mental activity. Qualified and interested, thus offered enrollment in a 12 month clinical trial of drug x (add-on to current drug therapy).

March 2011
US life expectancy hits new record more than 78 years old (75.5 for men, 80.5 for women)

Social Sec. 1935

19

October 2011
World population reaches 7 billion, and graying rapidly
(Washington Post)

20

21 September 2009
World Alzheimer Day; World Alzheimer Report released www.actionalz.org/about_wad.asp

AD Facts and Figures 2011 (Alz. Assoc.)

Diagnostic criteria
A. Dementia Interferes with ability to function at work or at usual activities A decline from a previous level of functioning Not delirium or psychiatric disorder Diagnosed by history, examination Involves at least 2 cognitive domains: Memory Reasoning and judgment Visuospatial Language Personality, behavior, comportment

Alzheimers and Dementia, April 2011

Diagnostic criteria
A. Probable AD Dementia Insidious onset Worsening of cognition over time Amnestic vs. non-amnestic presentation Not due to another dementia diagnosis

B. Probable AD with evidence of AD pathophysiology Ab (CSF or amyloid PET) Neuronal injury (CSF tau, FDG-PET, structural MRI)

Alzheimers and Dementia, April 2011

Neuropathology of AD

Cruz et al, PNAS 1997

Kretzschmar, 2009

Reagan Pathologic Criteria for AD

Likelihood
Neuritic plaques and neurofibrillary tangles CERAD plaque score Braak and Braak staging

Low
A more limited distribution or severity

Intermediate
Limbic regions

High
Neocortex

infrequent
I/II

moderate
III/IV

frequent
V/VI

Neurobiology of Aging 18, S1-S2, 1997

Amyloid Precursor Protein (APP) catabolism

NH2 Ab

COOH

a-secretase

b-secretase (BACE-1)

g-secretase (presenilin)

g-secretase Ab

p3

Genetics of sporadic AD
Apolipoprotein E (ApoE)

Strittmatter et al, Science 1993

The amyloid cascade

Downs APP----->soluble Ab--->insoluble Ab-->neuronal-->neuronal amyloid morbidity mortality diffuse plaque, NP NFT, ghost tangles APP, PS-1, loss of synapses, enzymes and PS-2 ApoE4 loss of neurotransmitters mutations ? excitotoxicity inflammatory responses apoptosis? Age mitochondrial & oxidative injury

Normal cognition--------->memory loss-->dementia-->death (mild, moderate, severe)

Turner, Seminars in Neurology 2006

The amyloid cascade

Ab immunization? APP----->soluble Ab--->insoluble Ab-->neuronal-->neuronal amyloid morbidity mortality diffuse plaque, NP NFT, ghost tangles b- or gloss of synapses, enzymes secretase loss of neurotransmitters inhibitors? excitotoxicity inflammatory responses apoptosis? mitochondrial & oxidative injury

Normal cognition--------->memory loss--->dementia-->death (mild, moderate, severe)

Turner, Seminars in Neurology 2006

The amyloid cascade

APP----->soluble Ab--->insoluble Ab-->neuronal-->neuronal amyloid morbidity mortality diffuse plaque, NP NFT, ghost tangles loss of synapses, enzymes loss of neurotransmitters cholinesterase inflammatory responses inhibitors excitotoxicity memantine apoptosis? mitochondrial & oxidative injury Normal cognition--------->memory loss--->dementia-->death (mild, moderate, severe)
Turner, Seminars in Neurology 2006

FDA-approved drugs for dementia due to AD

Donepezil (Aricept) tablet, orally-disintegrating tablet
5 mg daily, increase to 10 mg daily after 4-6 weeks; then 23 mg daily after 3 months (optional)

Rivastagmine (Exelon) capsule, transdermal patch, liquid

1.5 mg twice daily, increase to 3, 4.5, and 6 mg twice daily in 2 week intervals 1 patch daily (4.6 mg daily, increase to 9.5 mg daily after 4 weeks)

Galantamine (Razadyne, Razadyne ER) tablet, ER capsule, liquid

4 mg twice daily, increase to 8 and 12 mg twice daily in 4 week intervals for ER, 8 mg daily, increase to 16 and 24 mg daily in 4 week intervals

Memantine (Namenda, Ebixa) tablet, liquid

Start 5 mg daily, increasing in 1 week intervals up to 10 mg twice daily

Donepezil (Aricept)

Rogers et al, Neurology 1998

18F-AV45

Distinguishes Patients with AD from Cognitively Normal Controls

Avid 18F-PET A-Amyloid Imaging

AD 77 F MMSE 24

Healthy 74 F MMSE 30
Confidential

Tau

CSF biomarkers
AD

Normal

Shaw et al, Annals Neurology 2009 Ab42

FDGPET: AD

MCI
Langbaum et al, Neuroimage 2009

AD brains reveal atrophy -particularly in regions mediating higher cognitive functions

MRI atrophy in MCI & AD

McDonald et al, Neurology 2009

MCI Progression

Petersen et al, Archives Neurology 2009

Phase II Bapinezumab with PIB-PET

Rinee et al, Lancet Neurology, March 2010

Summary
We are witnessing a growing epidemic of dementia in the US and the world, most of which is AD The amyloid hypothesis is alive and well, and does not exclude other important and essential pathologic processes The genetics of familial AD provides the strongest evidence for the amyloid hypothesis Despite recent high-profile failures, many active trials target Ab/amyloid generation or clearance Other AD trials target other essential pathologic processes, with the probable result of a therapeutic cocktail (as now)

Summary
Current (FDA-approved) therapies for AD provide consistent yet modest, temporary, and palliative benefits We are searching for disease-modifying treatments to halt dementia progression, or prevent dementia onset We are in need of validated biomarkers for: screening, diagnostic accuracy, evidence of efficacy, reduction of the cost of clinical trials (decreased numbers of participants) Treatments and prevention will increasingly target subjects with MCI, then healthy high-risk individuals Future treatments will be tailored to ApoE genotype (pharmacogenomics, personalized medicine)

memory.georgetown.edu

Aging versus Dementia due to Alzheimers Disease

R. Scott Turner, MD, PhD
Director, Memory Disorders Program Professor, Department of Neurology Georgetown University Washington, DC memory.georgetown.edu rst36@georgetown.edu