Global demographic changes and
the challenge of dementia
Marc I Combrinck
Division of Neurology,
Groote Schuur Hospital &
Walter & Albertina Sisulu
Institute of Ageing,
University of Cape Town
Aspects
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•
•
•
•
•
•
world demographic trends
dementia
Alzheimer’s disease
projected prevalence rates
costs
treatment, prevention
Sub-Saharan Africa & HIV/AIDS dementia
Life Expectancy at Birth
Country
Japan
China
India
USA
Europe
France
M
F
1950
60.4
63.9
2000
78.3
85.7
2050
83.5
91
M
F
M
F
39.3
42.3
38.7
37.1
70.5
73.7
60.9
63.3
77.4
81.3
71.4
75.4
M
F
M
F
M
F
66.1
72.0
63
68
64.1
69.9
75.8
80.6
69.6
78
75.8
83.1
80.8
85.8
78.5
84.5
83.1
88.9
Medical consequences I
an increase in age-related diseases
• dementia, depression
• stroke
• chronic musculo-skeletal disorders,
arthritis, falls, hip fractures
• cardiovascular diseases
• cancers (prostate, colon)
• macular degeneration
Medical consequences II
• multi-morbidity
• polypharmacy
Dementia
• chronic progressive disorder
• deterioration in multiple aspects of
cognitive function
• associated with behavioural &
psychological symptoms
• severe impact on quality of life
• longest duration of burden on patient,
family & society
Causes of dementia
• primary neurodegenerative diseases:
Alzheimer’s, vascular disease, frontotemporal dementia, Lewy body dementia
• secondary: hypothyroidism, CNS infections,
vitamin B-12 deficiency, chronic subdural
haematoma, tumour, etc.
Alzheimer-type pathology
Silver stained
plaques and
tangles
• Thick arrow: senile
(neuritic) plaque
• Small arrow: diffuse
plaque
• Star: tangle
Amyloid hypothesis
 Secretase
APP
KPI
 Secretase
670, 671
717
N
C
Cell
proliferation
Calcium
regulation
Membrane
 Secretase
 Secretase
A
APPs
Reduced Ca++
Neuroprotection
Neuroplasticity
Aggregated
A
Increased Ca++
Neurotoxicity
Abnormal outgrowth
Pathogenesis of amyloidosis in
AD
Brain atrophy in
Alzheimer’s disease
control 
AD
Risk factors for AD
• Age
AD prevalence rates
US General Accounting Office (1998)
% prevalence rate – all severity levels
Age
65
70
75
80
85
90
95
males
0.6
1.3
2.7
5.6
11.1
20.8
35.6
females
0.8
1.7
3.5
7.1
13.8
25.2
41.5
Ferri CP et al. Lancet 2005; 366: 2112 - 2117
• In 2010, 57.7% of people with dementia
live in low and middle income countries.
By 2050, this will rise to 70.5%.
AD: risk factors I
Established
• age
• family history
• Down’s syndrome
• apolipoprotein e4 allele
• autosomal dominant mutations: amyloid
precursor protein gene (APP) chr 21,
presenilin-1 gene chr 14, presenilin-2
gene chr 1. (<2% cases)
AD risk factors II
Probable
•
•
•
•
depression
hypertension
head injury
homocysteine
AD: risk factors III
Possible
•
•
•
•
•
•
gender (F>M)
education / neuro-cognitive reserve
diabetes
smoking
cholesterol
herpes simplex virus-I?
Possible protective factors
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•
•
•
anti-inflammatory drugs
oestrogen
apolipoprotein e2 allele
high neurocognitive reserve & cognitively
stimulating activities
• cholesterol lowering drugs (statins)
• alcohol
AD & vascular disease
AD: cholinergic hypothesis
drug treatment
• centrally acting acetylcholinesterase
inhibitors e.g. donepezil, rivastigmine,
galantamine
• NMDA receptor antagonist: memantine
symptomatic treatment in early disease, only
30-40% respond
new drugs?
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•
•
•
•
-secretase inhibitors
ß-secretase inhibitors
ß-amyloid immunisation
anti- ß-amyloid monoclonal antibodies
mitochondrial stabilisers
Alzheimer’s prevention?
• treat vascular risk factors - dyslipidaemia,
hypertension, diabetes mellitus
• lifestyle changes: improve diet, lose weight,
exercise more, stop smoking
• keep mentally active
• vitamin D? anti-oxidants? statins? vitamin B
group? non steroidal anti-inflammatory drugs?
• no proven interventions in randomised control
trials
Qu ickTime™ and a
TIFF (Uncompressed) de compressor
are nee ded to see this pic ture.
Alzheimer’s disease in Africa?
Alzheimer’s disease in Africa II
• Nigeria: Ibadan vs. African Americans
in Indianapolis
• no other good studies
• few pathological reports
• clinical anecdotal evidence
Life expectancy at birth: SubSaharan Africa
2008
South Africa
F
M
Malawi
53
50
53
Mozambique
51
Zimbabwe
42
South Africa
• 65+ population: 5% (Japan 23%)
but marked socio-economic differences:
“whites”: 13% “blacks” 4%
• 80+ population: 0.7% (Japan 5%)
“whites” 2.4%, “blacks” 0.5%
HIV/AIDS South Africa
• estimated 16.6% of population infected
• = 8 out of 48 x106 people
HIV-associated dementia/neurocognitive disorders
• a subcortical dementia
• progressive cognitive & behavioural decline
memory deficits, psychomotor slowing, apathy
• slowed eye & limb movements
• hyper-reflexia, hypertonia, frontal lobe release
signs
HIV encephalopathy II
• macrophage, microglial and astrocyte
activation
• multi-nucleated giant cells
• basal ganglia, deep white matter, brainstem
especially affected
HIV encephalopathy
CT
MRI-FLAIR
HIV dementia / HIVassociated
neuro-cognitive disorders III
• prevalence? 20-30% Uganda, South Africa
• risk factors: high initial viral load, low CD4
counts, age, anaemia, systemic symptoms
• APOE ε4 allele
• anti-retroviral drug therapy   incidence
& often reverses deficits
HIV encephalopathy IV
• HAART   HIV dementia but 
minor cognitive-motor disorders
(MCMD)
• CNS sanctuary for latent or slowly
replicating virus?
• slow neurodegeneration
APOE ε4 & HIV
HIV-infected subjects with the E4 allele for APOE have
excess dementia and peripheral neuropathy
ELIZABETH H. CORDER, KEVIN ROBERTSON, LARS LANNFELT,
NENAD BOGDANOVIC, GÖSTA EGGERTSEN, JEAN WILKINS, COLIN
HALL
Nature Medicine 1998;4(10):1182-4
E4 allele accelerates AIDS progression (Burt, PNAS 2008;
105: 8718)
HIV dementia & Alzheimer’s
• common pathological mechanisms?
• activation of microglial cells  release of
inflammatory cytokines  damage to
neurones & their synaptic
connectionscognitive impairment
• -amyloid found in both
• apolipoprotein E e4 a risk factor for both?
Impact of HIV/AIDS on elderly
• Care of ill children
• Care of AIDS orphaned grand-children
Summary
• increased life expectancy in industrialised
countries and low to middle income countries of
Asia, Latin America
• increased dementia prevalence
• increased dependent elderly population
• increased stress on social welfare systems &
economies
• no good treatment available yet
• no proven preventative strategies
• additional problem of HIV dementia, especially in
southern Africa