National Press Foundation

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 anti-
hypertensive 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 60’s 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
• Downs syndrome
• Head injury with LOC
• Smoking
• Hypertension
• 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
 ADLs
• Complex
– Working, living alone, driving, keeping
appointments, handling finances, daily
medications…
• Basic
– Dressing, bathing, grooming, toileting,
walking, transfers, eating…
 Case 1
• Pleasant, cooperative, and well-
appearing 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.
MMSE is
Alzheimer’s
disease-
centric
 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 Alzheimer’s 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).
 > 65 years old

SS established
1935
 21 September 2009
World Alzheimer Day; World Alzheimer Report released
www.actionalz.org/about_wad.asp
 Clinical Criteria for AD

• Probable AD (NINCDS-ADRDA)
– Dementia on clinical examination and
neuropsychologic testing
– Deficits in two or more areas of cognition
– Progressive worsening
– No disturbance of consciousness
– Onset 40-90, usually > 65
– All else ruled out

McKhann et al, Neurol 1984

 Clinical Criteria for AD

• Possible AD
– Dementia with atypical presentation or course
for AD
– With a second disorder which may cause
dementia
• Definite AD
– Probable AD diagnosed clinically
– Brain tissue diagnostic for AD

McKhann et al, Neurol 1984

 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

Alzheimer’s 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

• A (CSF or amyloid PET)
• Neuronal injury (CSF tau, FDG-PET, structural MRI)

Alzheimer’s and Dementia, April 2011

Neuropathology of AD

Cruz et al, PNAS 1997

Kretzschmar, 2009
 Reagan Pathologic Criteria for AD

Likelihood Low Intermediate High

Neuritic
plaques and A more limited Limbic regions Neocortex
neurofibrillary distribution or
tangles severity
CERAD plaque
score infrequent moderate frequent

Braak and
Braak staging I/II III/IV V/VI

Neurobiology of Aging 18, S1-S2, 1997

Amyloid Precursor Protein (APP) catabolism

NH2 A COOH

-secretase (BACE-1)
-secretase

-secretase (presenilin) -secretase

p3 A
Genetics of
sporadic AD

Apolipoprotein E
(ApoE)

Strittmatter et al,
Science 1993
 The amyloid cascade
Downs

APP----->soluble A--->insoluble A-->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
Age apoptosis?
mitochondrial & oxidative injury

Normal cognition--------->memory loss-->dementia-->death

(mild, moderate, severe)

Turner, Seminars in Neurology 2006

 The amyloid cascade
A immunization?

APP----->soluble A--->insoluble A-->neuronal-->neuronal

amyloid morbidity mortality
diffuse plaque, NP NFT, ghost tangles
- or -
loss 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 A--->insoluble A-->neuronal-->neuronal
amyloid morbidity mortality
diffuse plaque, NP NFT, ghost tangles
loss of synapses, enzymes
cholinesterase loss of neurotransmitters
inhibitors inflammatory responses
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

Donepezil (Aricept)

Rogers et al, Eur Neuropsychopharmacology 1998

 18
F-AV45 Distinguishes Patients with AD
from Cognitively Normal Controls

AD
77 F
Avid 18F-PET Aß-Amyloid Imaging
MMSE 24

Healthy
74 F
MMSE 30

Confidential
Tau

CSF
biomarkers
AD

Normal

Shaw et al, Annals

Neurology 2009

A42
FDG-
PET:
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
 FDG-PET

CSF Aβ42
MRI hipp

Cog

CSF tau

Fxn
Prevalence of MCI

Petersen et al, Archives of Neurology 2009

MCI: Rates of Progression to Dementia

Petersen et al, Archives of Neurology 2009

MCI Progression

Petersen et al, Archives Neurology 2009

 Goals of AD therapy

Cure
Cognition

Arrest
Progression

Symptomatic
Therapy (NOW)
Natural
Course

Time
 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
A/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