Alzheimers Flashcards
Is there a genetic cause to AD?
form of AD known as ‘familial Alzheimer’s disease’
Very rare but more common in early onset cases.
The effects on the brain are almost indistinguishable from ‘normal’ AD - tangles and beta amyloid plaque
Changes happen rapidly, show signs in 40s-50s
What causes AD? - genetics
Mutations occur when a gene is copied incorrectly. If the mutant gene is dominant, its effects will be seen in the organism (‘phenotype’).
If the gene is recessive, its effects will only be seen in a person who inherits two copies of the faulty gene, one from each parent. People with one copy are healthy “carriers”
Familial AD inheritance
The genes responsible for familial AD are found on 3 different chromosomes.
Each of these mutations causes a build-up of amyloid plaques in the brains of affected individuals.
Genetic testing can identify whether an individual is carrying a mutant form of one of the genes responsible for familial AD (and will therefore develop AD).
An individual carrying a mutation knows that if they have children, each child has a 50% chance of inheriting familial AD.
Some evidence that late onset AD is inherited - APOE4
Having other family members with AD increases the probability of developing the disease, but only by a small amount.
One copy of APOE4 increases the risk of late onset AD by about 4 times.
Two copies increase the risk about 10-20 times.
But many people with even 2 copies of APOE4 do not develop AD.
Only 35% of people with AD have the APOE4 gene
Hoe diet can act as a protective factor to AD
60000+ people in UK Biobank over 9 years, large sample size
Scored for adherence to “Mediterranean diet”, higher in chicken, fish, salad, nuts, pulses, olive oil, fruits and vegetables, lower in red meat, high fat dairy and added sugar.
Highest adherence had 23% lower risk of developing dementia, compared with lowest adherence.
Many confounds, these foods are more expensive so may have a higher income, may be younger or more educated, many variables which may have caused results
Other environmental factors that may increase risk of developing AD
Smoking may increase the risk in carriers of APOE4.
Bad gut microbes (high fat and sugar diet) can trigger a systemic inflammatory response – inflammatory markers which can cause brain inflammation, may be a risk factor for dementia
Modifiable risk factors to reduce chances of developing AD
45% of cases of dementia are potentially preventable by addressing 14 modifiable risk factors during the life course.
These are lower levels of education in early life (5%); hearing impairment (7%), high levels of LDL cholesterol (7%), depression (3%), traumatic brain injury (3%), physical inactivity, diabetes, smoking, high blood pressure, obesity, and excessive alcohol consumption in midlife; social isolation (5%), air pollution (3%) and vision loss in later life.
How early can AD be detected and what are the warning signs?
Dementia has an insidious onset – hardly noticed at first
MCI can be a sign of early dementia
What are the symptoms of mild cognitive impairment (MCI)?
Forgetting appointments and recent events
Losing train of thought or thread of conversations
Misplacing everyday items, or putting them in strange places
Failing to recognise familiar people and places
Problems with ‘word finding’ (e.g., remembering the names of people or things)
Problems with planning complex tasks like making meals
Impaired judgement and decision making
What is needed for an AD diagnosis?
Increasing deficits in at least two areas of cognitive function (e.g. memory and language)
Severe problems that interfere with everyday activities
MCI figures
May reflect the earliest stages of dementia
Could also be due to depression, bereavement, side-effects of medications can produce reversible MCI
Repeated testing every 6 months to identify dementia
Only 12% of people with MCI aged 65+ develop AD every year
50% after 5 years
Not a solid prediction of AD
Brain imaging in people with MCI
Show degeneration of hippocampus and other memory structures in MCI patients 3 years before diagnosis of AD.
Temporal lobes and ventral surface lost the most mass in people with AD
Same pattern in MCI but less extreme
Benefits of cognitive reserve
High levels of intelligence and education may allow a person to continue to function relatively normally through the early stages of AD.
The nun study - how cognitive reserve helps to prevent symptoms of AD
Analysed their autobiographies for grammatical complexity and density of ideas.
Nuns who had developed dementia by the mid 1990s showed lower scores in their early autobiographies than nuns who had not developed dementia.
Education may be a protective factor against AD - they were teachers who had been educated
At post moretom it was revealed that many nuns had alzheimer’s pathology but were still functioning normally
May be due to brain activity daily, puzzles, reading, community
How do education levels impact a persons likelihood of being diagnosed with AD?
No effect of years of education on signs of AD pathology in brain (e.g. plaques, tangles)
But more educated participants were less likely to have been diagnosed with AD – they could still function adequately despite pathology.
What are the treatments for AD?
Cognitive stimulation (‘brain training’), exercise and improved nutrition can boost performance (in short-term) and improve mood.
‘Reminiscence therapy’ may allow patients to make the best use of early memories and knowledge and promote social interaction and well-being.
No evidence that these change progression of disease.
Which drugs are used for mild to moderate AD and why are they used?
‘Cholinesterase inhibitors’
Drugs which boost acetylcholine levels by inhibiting enzymes which break it down.
About half of AD patients show benefits for a limited time.
Which drugs are used for severe AD and why are they used?
‘NMDA inhibitors’
Drugs which block glutamate. This is released in large quantities by damaged cells and is toxic to surrounding cells.
Main excitatory neurotransmitter in the brain
Help sufferers to function at a better level
Are drugs used to treat AD cost effective?
No
Anti-Alzheimer drugs do not stop the progression of AD
They only work for some patients
Expensive
Have significant side-effects
Why could immunotherapy be useful for treating AD?
Using the immune system to reduce amyloid plaques
New drugs involve monoclonal antibodies that target beta amyloid
How effective was Immunotherapy when used to treat AD?
Treated with anti-amyloid antibody
Infusions twice a week over 18 months vs. placebo.
Reduced amyloid plaques supports “amyloid hypothesis”
Cognition declined 27% slower in participants taking drug than in placebo
Only delaying progression by 6 months - is it worthwhile?
Very serious side effects in 3% - brain swelling and small brain bleeds. Requires expensive monitoring.
Need for regular infusions is unpleasant and expensive.
Eligibility for the drug requires levels of amyloid in the brain to be measured – involves PET scan or lumbar puncture which only 2% of Alzheimer’s patients have currently.
Drug is not prescribed by NHS
Which areas of the brain are responsible for each aspect of AD?
- episodic memory and language
- controlling thoughts and behavior
- memory and navigation
Episodic memory (remembering recent events) - Atrophy in medial temporal lobe
Semantic memory and language (understanding and producing words) - Atrophy in anterior temporal and inferior frontal cortex
Controlling thought and behaviour - Atrophy in frontal cortex
Memory and navigation skills reduce- Hippocampus starts to deteriorate
Where is the hippocampus found?
embedded within the temporal lobes, one in each hemisphere
WHat causes memory issues in AD?
Recall - you have to find a way of accessing the relevant memory traces
Recognition - seeing the item again acts as a potential cue
Deficit for both recall and recognition in early AD
AD damages formation of memory traces themselves; it is not just a problem with retrieval
