1. Aging & Alzheimer’s Disease
Definitions
Differentiating dementia from normal aging
Prevalence
Common causes of dementia

2. Broad, Practical Definition of Dementia
A primary and progressive decline of intellect due to structural brain disease to the point that customary social, professional, and recreational activities of daily living become compromised.

3. Major neurocognitive disorder DSM- V
A. Evidence of significant cognitive decline in >=1 cognitive domain
Concern of the individual, informant or clinician
Impairment in cognitive performance, preferably documented by standardized neuropsychological testing
B. The cognitive deficits interfere with independence in everyday activities.
C. The cognitive deficits do not occur exclusively in the context of a delirium.
D. The cognitive deficits are not better explained by another mental disorder.

4. Major neurocognitive disorder DSM- V Domains
Complex attention
Executive function
Learning and memory
Language
Perceptual – Motor
Social cognition

5. Intellectual Dysfunction
Acquired
Developmental
Autism
Pervasive Devel. D/O
Mental Retardation
Reversible
Heavy Metal/Organic
poisoning
Hyperthyroidism
Hypothyroidism
Hypernatremia
Hyponatremia
Hydrocephalus
Tumor
Respiratory diseases
Kidney diseases
Vitamin Deficiencies
(B12, folate) etc.
Irreversible
Idiopathic
Parkinson’s (PD)
Huntington’s (HD)
Dementia w/ Lewy Bodies (DLB)
Multiple System Atrophy (MSA)
Alzheimer’s (AD)
Prog.Supranuclear Palsy (PSP)
Corticobasal Degeneration (CBD)
Fronto-Temporal Dementias (FTD)
Posterior Cortical Atrophy (PCA)
Amyotrophic Lateral Sclerosis (ALS)
Symptomatic
Vascular Dementia
Multiple Sclerosis
Epilepsy
CNS Lupus
Traumatic Brain Injury
Infectious (HIV, Herpes,
CJD, BSE)

6. Scope of Problem

7. We are an aging society
Age 65+ = 40 million
Age 65+ = 87 million

8. Risk of Dementia Increases with Age
AD accounts for between 60% and 80% of all cases of dementia

9. Projected prevalence of AD
Alzheimer’s Association, (2013) Alz & Dementia

10. Projected prevalence and cost of AD
Alzheimer’s Study Group (2010) Alzheimer’s Association

11. Defusing the Bomb Early, accurate diagnosis Modify disease course
Ameliorate symptoms
Address patient safety and vulnerability
Make important decisions when competent
Adjustment and planning for the family

12. Cognition and aging
Cognitive abilities generally peak in 3rd or 4th decade of life
Relative stability through 5th and 6th decade, with some decline common in the 7th decade
Declines commonly found in
Processing speed
Focusing of attention
Reduced mental flexibility and working memory
Reduced learning efficiency and free recall
Individual trajectories

13. Age-related cognitive trajectories
AAMI
MCI
Cognitive Performance AD
Age

14. Age-associated memory impairment (AAMI)
The patient is at least 50 years old
The patient has noticed a decline in memory performance.
The patient performs below "normal" levels on a standard test of memory.
All other obvious causes of memory decline, except normal aging, have been ruled out.
Adapted from Blackford and La Rue, Dev. Neuropsychol. 1989

15. Mild Cognitive Impairment (MCI)
‘Petersen’ criteria
Memory complaint, preferably corroborated by an informant
Objective memory impairment (1.5 SD below mean)
Normal general cognitive function
No impairment in functioning/not demented
Amnestic & Non-amnestic subtypes
5 -16 % of amnestic MCI convert to AD per year
44 % of MCI in population revert to ‘normal’ per year

16. Which Population Does the Patient Belong to?
Memory Score
SD units
0.5
Range of
Scores d/t
Imperfect
Reliability
Normal,
Age-Associated
Memory
Decline ??
0.5
Observed
Score 2
1.0
Observed
Score 1
Mild
Cognitive
Impairment (MCI)
1.5
2.0 ??
Dementia
2.5
Time 1
Test
Time 2
Test

17. Behavioral heterogeneity of MCI
Profile
Etiology M C I
Amnestic
Alzheimer’s Disease
Alzheimer’s Disease
Vascular Dementia
Normal Aging
Multiple Domain
Mild Impairment
Frontal Temporal Dementia
Primary Progressive Aphasia
Dementia with Lewy Bodies
Alzheimer’s Disease
Non-mnemonic
Adapted from Neurodegenerative Diseases Beal, Lang, Rudolph eds, Cambridge Univ Press, 2005

18. Useful Classification of Dementias
Cortical vs subcortical vs mixed
Cortical: Alzheimer's Disease
Subcortical: Multiple sclerosis
Mixed: Dementia with Lewy bodies
Static vs Progressive
Static: neurotoxic exposure, infection
Progressive: disease process (AD, Pick’s, HD)
Reversible vs Irreversible
Reversible: B12 deficiency
Irreversible: Alzheimer's disease

19. Cortical Dementias In The Elderly
Alzheimer's Disease (~70%)
Dementia with Lewy bodies (~10%)
Pick's Disease/Fronto-temporal dementia (~10%)
Focal atrophy w/out distinctive histology (~10%)

20. Alzheimer’s Disease

21. NIA/AA Criteria Probable AD dementia: Possible AD dementia:
Meets the criteria for dementia
Insidious onset
Clear-cut history of worsening of cognition
Amnestic (memory +1) or nonamnestic presentations (language, visuospatial or executive +1)
Absence of other diseases capable of producing a dementia syndrome
Possible AD dementia:
Dementia but atypical course
Dementia but etiologically mixed presentation
Probably or possible AD dementia with evidence of the AD pathophysiological process:
Probable AD on clinical criteria
Biomarkers of brain amyloid-beta or downstream neuronal degeneration or injury
2011

23. Plaques and Tangles
Alzheimer’s Brain

24. A precursor molecule is abnormally cleaved…
…beginning a cascade of reactions…
…resulting in plaques & tangles…
…leading to decreased Ach in “memory centers.”
Cummings, N Engl J Med 2004; 351:56-67

25. Early AD pathology is not global
Plaques most prevalent in temporal and posterior association cortex
Primary sensory cortex largely spared
Eventually, plaques distributed in frontal cortex
Adapted from Cummings, JAMA, 2002

26. Early cognitive impairments are not global
Memory deficits tend to be prominent early.
But many present with progressive cognitive symptoms other than memory including language, mood, visuospatial, and executive abilities
Eventually, most AD patients follow a common pathway which includes memory and other cognitive deficits.

27. Memory Decline in Dementia
Age (yrs)
Heaton, 2004

28. Gross Cortical Changes
Normal Brain
Alzheimer's Brain

29. Alzheimer’s causes changes in brain structure and function

30. Genetic Risk Factors Early-onset FAD Late-onset AD Chromosome 21 (APP)
Chromosome 14 (Presenilin 1)
Chromosome 1 (Presenilin 2)
Late-onset AD
Chromosome 19 (APOE ε4 allele)

31. Testing for Susceptibility AD Gene Risk in a Community-Based Sample
Myers, 1996

32. AD Tx: Cholinesterase inhibitors
Mechanism: slows the breakdown of acetylcholine by blocking the activity of acetylcholinesterase
Doesn’t address the underlying cause of the degeneration of cholinergic neurons
Efficacy: modest benefit on measures of cognitive function and ADLs
Slower declines compared to placebo
Alleviates noncognitive manifestations (agitation, wandering, inappropriate behavior)
Adverse effects - nausea, vomiting, diarrhea, and dizziness.

33. AD Tx: NMDA receptor antagonist
Mechanism: binds to NMDA receptor and prevents excessive excitation by glutamate
Efficacy: moderate decrease in clinical deterioration, small positive effect on cognition, mood, behavior, and the ability to perform ADLS in moderate to severe AD, No sig benefit in mild disease
Adverse effects: confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations
(N-methyl-D-aspartate)

34. Where are we now? We have no cure for Alzheimer’s disease
We have no disease modifying therapies for Alzheimer’s disease
We have only minimally effective symptomatic treatments for Alzheimer’s disease

35. Cognitive trajectories Sperling et al. (2011) Alzheimer’s & Dementia.
Timing is everything
Cognitive trajectories
Asymptomatic
Symptomatic
Responsive substrate?
Unresponsive substrate
Sperling et al. (2011) Alzheimer’s & Dementia.