AGEING, MEMORY LOSS AND ALZHEIMER’S

DISEASE?

Dr JANE HECKERDept Internal Medicine, Royal Adelaide

HospitalCollege Grove Hospital

MEMORY• Age• health (chronic pain, exercise, diet,

alcohol,)• attitudes(anxiety, poor self-confidence)• lifestyle (participation in cognitive

activities)• lifestyle (stress, workload, fatigue,

relationship problems)

DIFFERENTIAL DIAGNOSISDEMENTIA

• Depression• Delirium• Drugs• Decline in memory

DEMENTIA

• Alzheimer’s disease 60%• Vascular dementia 20%• Dementia with Lewy bodies 10-15%• Fronto-temporal dementia 10%• Dementia associated with other neurological

conditions e.g. Parkinson’s disease • Mixed dementia

Prevalence of Alzheimer’s disease

Kurz A. Eur J Neurol 1998; 5(Suppl 4): S1-8Wimo A et al. Int J Geriatr Psychiatry 1997; 12: 841-56

0

10

20

30

40

50

60

60-64 65-69 70-74 75-79 80-84 85+ 95+

Age (years)

Pre

vale

nce

(%)

1% 2% 4%8%

16%

30%

50%

Ref: Doraiswamy et al, 1998.

Advantages of an early diagnosis of AD

– Enables early treatment - cognitive enhancers

– Future planning for patient and caregiver– Early provision of community support

and healthcare resources can decrease stress

– May provide cost savings and delay institutionalisation

HISTORICAL POINTERS• Forgetting recent events despite prompting• Failure to attend appointments• Frequent repetition of statements, stories or

questions• Frequent lost or misplaced items• Losing track in conversation, word-finding

difficulty• Difficulty understanding conversation or

following the story in a book or on TV• Confusion with time eg. day, date, time of day• Becoming lost, unable to find the way

HISTORICAL POINTERS

• Difficulty handling money or paying bills• Difficulty working gadgets, planning or preparing

meals, performing handyman tasks• Neglect of personal care, home maintenance or

nutrition• Withdrawal from previous community and social

activities (poor work performance if employed)• Difficulty coping with new events or change to

routine• Personality and behaviour change

Clinical features of AD• Loss of cognition

– short-term memory– language– visuospatial functions

• Loss of daily function– instrumental activities of daily living (ADL)– self-maintenance skills

• Behaviour and personality change

Brainatrophy

Senileplaques

Neurofibrillarytangles

Katzman, 1986; Cummings and Khachaturian, 1996

AD: a progressive CNS disorderwith a characteristic pathology

Natural history of Alzheimer’s disease

1 2 3 4 5 6 7 8 9

0

5

10

15

20

25

30

Time (years)

Symptoms

Diagnosis

Loss of functional independence

Behavioural problems

Nursing home placement

DeathMin

i-Men

tal S

tate

Exa

min

atio

n (M

MS

E) Early diagnosis Mild-to-moderate Severe

Feldman and Gracon. The Natural History of Alzheimer’s Disease. London: Martin Dunitz, 1996

Cholinergic deficit

– progressive loss of cholinergic neurones

– progressive decrease in available ACh

– impairment in ADL, behaviour and cognition Hippocampus

Cortex

N. basalis Meynert

Bartus et al., 1982; Cummings and Back, 1998, Perry et al., 1978

Cholinergic Deficit underlies clinical symptoms

Treating Alzheimer’s Disease

Post synaptic

Acetyl CoA+

Choline

Choline+

AcetateAChE

ACh

ACh

ChAT

Central Cholinergic Synapse

X

Cholinesterase Inhibitors

(-)

M2

Muscarinic 1receptor

(+)

Cholinesterase inhibitors: a rational therapeutic approach in AD

NH2

N

Mechanism: AChE/BuChE-IInhibition: reversible

Tacrine

O

OON

Mechanism: AChE-IInhibition: reversible

Donepezil

N

O

O

NN

H

Mechanism: AChE/BuChE-IInhibition: pseudo-irreversible

Physostigmine

OO

O

OHP

ClCl Cl

O

OO

O

PCl

Cl

Mechanism: AChE/BuChE-IInhibition: irreversible

Metrifonate

OO

HH

N

OH

Mechanism: AChE-IInhibition: reversible

Galantamine

O

O N

N

Mechanism: AChE/BuChE-IInhibition: pseudo-irreversible

Rivastigmine

Weinstock, 1999

CHOLINESTERASE INHIBITORS-Second Generation

• Donepezil (Aricept)

• Rivastigmine (Exelon)

• Galantamine (Reminyl)

A.D. CLINICAL TRIALS9204 patients in 21 clinical trials

modest benefit in mild-mod AD

• Donepezil :- 8 trials, 2664 patients• Rivastigmine :- 7 trials, 3370 patients• Galantamine :- 6 trials, 3170 patients

Cognition

Activi

ties o

f dail

y livi

ng

Behaviour

ABC: the key symptom domainsaffected in AD

AAN Guidelines CONCLUSIONS

• ‘Significant treatment effects have been demonstrated with several different cholinesterase inhibitors (tacrine, donepezil, rivastigmine, galantamine) indicating that the class of agents is consistently better than placebo. The disease eventually continues to progress despite treatment and the average “effect size” is modest. Global changes in cognition, behaviour, and functioning have been detected by both physicians and caregivers, indicating that even small measurable differences may be clinically significant.’

-50

-40

-30

-20

-10

0

10

20

30

Chan

ge fr

om b

asel

ine

in d

aily

tim

e sp

ent a

ssis

ting

with

ADL

(min

)

* p < 0.05 vs baseline

Placebo

Galantamine 24 mg/day

*

Mean change in daily time spent by caregiver assisting with ADL at 6 months:

GAL-INT-1

NICE RECOMMENDATIONS:COST EFFECTIVENESS

• cost savings on institutional care not

well established• quality of life (QALY) not easily

measured• Oscar Wilde “knowing the price of

everything and the value of nothing”

Therapeutic Dilemmas: Alzheimer’s Disease

• Which drug?

• Who to treat?

• When to start treatment?

• How long to treat?

• By whom?

• Whether to treat?

Memantine (Ebixa)

• NMDA receptor antagonist• trialled predominantly in moderately

severe to severe dementia• modest benefit in cognition, function,

behaviour• expensive ~ $180 per month, no PBS

subsidy

PREVENTION?

AN OUNCE OF PREVENTION IS WORTH A POUND OF CURE

Benjamin Franklin

Protective Factors?• NSAID’s (anti-inflammatories)• statins (cholesterol lowering)• moderate alcohol consumption• higher education• ongoing intellectual stimulation• physical and leisure / social activities• diet - fruit and vegetables, low in saturated

fat

The pathological cascade of ADClinical symptoms

Neurodegeneration

Neurofibrillary tangles

-amyloid

Environmental risk factors

Genetic risk factors

Apo-E

Pathogenetic mutations

APP

PS1,2

Cholinergic dysfunction

TAU hypophosphorylation

Post and Whitehouse - “Guidelines on Ethics of Care of People with Alzheimer’s Disease”

“As the 20th century draws to a close, it is the decline of the mind contained in a still viable body that raises some of the most urgent concerns for medical ethics and society. The emphasis on technical reason and productivity that characterizes our modern industrial cultures may create a bias against people with dementia. It is important to realize that emotional and relational well-being can be enhanced despite dementia and to insist that human dignity can still be respected. In severe dementia, the finest expression of this respect may be through the touch of a hand rather than through technology.”