Introduction lecture
- high income countries have had a 30% drop in incidence of AD in the last 30 years
- amyloid cascade hypothesis: too limited info, mitochondrial cascades?,
metabolism pathway?, vascular hypothesis → multiscale multicausality
(more causes are found for AD, not monocausal) → there are a lot of drugs
that target amyloid aggregation but they are not used in practice yet
(there are some drugs that are close to registration)
- AD mostly of old age → only 1% of cases is familial
- 40% of dementia prevalence can be explained by modifiable lifestyle factors
Typical AD: with atrophy
- heterogeneity in different AD cases
,Prevalence of dementia over the years (by Livingston)
- early life: less education
- midlife: hearing loss, hypertension, obesity, traumatic brain injury, alcohol
- later life: smoking, depression, social isolation, physical inactivity, air pollution,
diabetes
- maybe also sleep problems but this is not included in Livingston
Prevention of dementia
- dementia is the end stage of neurodegenerative brain disease → before
you actually have dementia, there are decades of neurodegenerative
brain aging which only in the end leads to cognitive impairment
- mechanistic perspective: primary prevention = before neurodegeneration, secondary
prevention = when neurodegeneration has started
- clinical perspective: primary prevention = before disease diagnosis, secondary
prevention = after disease diagnosis
Risk factors of Dementia
- diabetes (later in life)
- hypertension (mid-life - later life)
- obesity (mid-life)
- inactivity (mid-life)
- depression (later in life)
- smoking (mid-life - later-life)
- low education (in early life)
, - age (most important risk factor)
→ these risk factors are found in 30% of people with dementia
→ risk factors are not proven to be causal of the disease (but probably are) →
reversed causality: is depression a cause of dementia or is dementia a cause of depression?
→ hearing loss might also be a risk factor (or a consequence)
→ risk factors don’t have a linear relationship (higher BMI does not necessarily
mean more dementia risk)
Timing of prevention
- the effect of intervention is highest when the intervention is done in middle age to
prevent dementia
- the incidence of dementia in middle age is low
- the incidence of dementia in old age is high but the effect of intervention is low
- the optimal window for outcome assessment (of the intervention) is in old age
→ very long research span to see if intervention during middle age helped
prevent dementia in old age (almost impossible) → thus, do not look a dementia
as treatment outcome but at other factors that can be measured in middle age
like cognitive decline
- a lot of people die with dementia but not from dementia
Targeted clinical trials: clinical trials that research people with a high risk of
dementia (because it runs in the family) → most cases of dementia are not
familial so this type of research only helps a small group of the dementia
patients which has a low impact on population level, but the risk of getting
dementia in these patients is almost 100% (if they get old enough) → abnormal
biomarkers can be measured: CSF markers, MRI markers, stroke
Pragmatic clinical trials: large population studied, so it has a high impact on society
→ however, the risk factors in this population vary so the target outcomes vary:
demographics, anthropometrics, blood pressure (BP), family history, lifestyle
→ it might be more useful to do a pragmatic clinical trial as the risk is lower in
the study population so prevention might be more useful
- there is a higher increase in dementia patients expected in low-income countries
relative to high-income countries as the low-income countries start resembling the
higher-income countries more and more which leads to less healthy food, less
physical activity and a longer life span which leads to more risk factors of dementia
- risk factors for dementia are also risk factors of other (cardiovascular) diseases so
one prevention might actually prevent multiple diseases
Intervention and outcome
- dementia risk: measured with dementia risk score
- biological parameter: for example imaging, blood pressure, CSF →
biological markers do not always actually reflect the disease (you can look
if your intervention led to a lower BP but if it did, this does not necessarily
mean that the risk of dementia is gone)
- cognitive impairment: cognitive testing (like the 15 word test)
- high income countries have had a 30% drop in incidence of AD in the last 30 years
- amyloid cascade hypothesis: too limited info, mitochondrial cascades?,
metabolism pathway?, vascular hypothesis → multiscale multicausality
(more causes are found for AD, not monocausal) → there are a lot of drugs
that target amyloid aggregation but they are not used in practice yet
(there are some drugs that are close to registration)
- AD mostly of old age → only 1% of cases is familial
- 40% of dementia prevalence can be explained by modifiable lifestyle factors
Typical AD: with atrophy
- heterogeneity in different AD cases
,Prevalence of dementia over the years (by Livingston)
- early life: less education
- midlife: hearing loss, hypertension, obesity, traumatic brain injury, alcohol
- later life: smoking, depression, social isolation, physical inactivity, air pollution,
diabetes
- maybe also sleep problems but this is not included in Livingston
Prevention of dementia
- dementia is the end stage of neurodegenerative brain disease → before
you actually have dementia, there are decades of neurodegenerative
brain aging which only in the end leads to cognitive impairment
- mechanistic perspective: primary prevention = before neurodegeneration, secondary
prevention = when neurodegeneration has started
- clinical perspective: primary prevention = before disease diagnosis, secondary
prevention = after disease diagnosis
Risk factors of Dementia
- diabetes (later in life)
- hypertension (mid-life - later life)
- obesity (mid-life)
- inactivity (mid-life)
- depression (later in life)
- smoking (mid-life - later-life)
- low education (in early life)
, - age (most important risk factor)
→ these risk factors are found in 30% of people with dementia
→ risk factors are not proven to be causal of the disease (but probably are) →
reversed causality: is depression a cause of dementia or is dementia a cause of depression?
→ hearing loss might also be a risk factor (or a consequence)
→ risk factors don’t have a linear relationship (higher BMI does not necessarily
mean more dementia risk)
Timing of prevention
- the effect of intervention is highest when the intervention is done in middle age to
prevent dementia
- the incidence of dementia in middle age is low
- the incidence of dementia in old age is high but the effect of intervention is low
- the optimal window for outcome assessment (of the intervention) is in old age
→ very long research span to see if intervention during middle age helped
prevent dementia in old age (almost impossible) → thus, do not look a dementia
as treatment outcome but at other factors that can be measured in middle age
like cognitive decline
- a lot of people die with dementia but not from dementia
Targeted clinical trials: clinical trials that research people with a high risk of
dementia (because it runs in the family) → most cases of dementia are not
familial so this type of research only helps a small group of the dementia
patients which has a low impact on population level, but the risk of getting
dementia in these patients is almost 100% (if they get old enough) → abnormal
biomarkers can be measured: CSF markers, MRI markers, stroke
Pragmatic clinical trials: large population studied, so it has a high impact on society
→ however, the risk factors in this population vary so the target outcomes vary:
demographics, anthropometrics, blood pressure (BP), family history, lifestyle
→ it might be more useful to do a pragmatic clinical trial as the risk is lower in
the study population so prevention might be more useful
- there is a higher increase in dementia patients expected in low-income countries
relative to high-income countries as the low-income countries start resembling the
higher-income countries more and more which leads to less healthy food, less
physical activity and a longer life span which leads to more risk factors of dementia
- risk factors for dementia are also risk factors of other (cardiovascular) diseases so
one prevention might actually prevent multiple diseases
Intervention and outcome
- dementia risk: measured with dementia risk score
- biological parameter: for example imaging, blood pressure, CSF →
biological markers do not always actually reflect the disease (you can look
if your intervention led to a lower BP but if it did, this does not necessarily
mean that the risk of dementia is gone)
- cognitive impairment: cognitive testing (like the 15 word test)
