Case 1

• Geneeskunde
• WO
• Studiejaar 3

Which Apolipoprotein E allele is associated with an increased risk of familial Alzheimer’s disease?

1. Apo E2
2. Apo E3
3. Apo E4

Explanation:

- Risk of late-onset AD increases with number of Apo ε4 alleles

- Apo ε2 may have protective effect

- Apo ε3 has no effect

The APP gene is associated with an increased risk of familial Alzheimer’s Disease. AD caused by this gene has a high comorbidity with which syndrome?

1. Klinefelter Syndrome
2. Down Syndrome
3. Turner Syndrome
4. Triple X Syndrome

Explanation:

The APP gene lies on chromosome 21. Down syndrome is trisomy 21, so there are 3 copies of the gene, rather than 2. This increased expression of the APP gene increases the risk of early-onset familial Alzheimer’s Disease.

What is NOT a risk factor for the development of Alzheimer’s Disease?

1. Diabetes
2. Low socioeconomic status
3. Sleep deprivation
4. Cancer

Explanation:

Diabetes: Potential mechanisms: Glucotoxicity can result in structural damage and functional impairment of brain cells and nerves, hemorrhage of cerebral blood vessels and increased accumulation of amyloid beta.

Low socioeconomic status: Insufficient access to health care?; Education could postpone the clinical expression of dementia symptoms by increasing the neocortical synaptic density (the "brain reserve" hypothesis); Higher educational and occupatioanl attainment might provide a reserve: able to better cope with advanced pathologic changes of disease more effectively by maintaining funciton longer (the "cognitive reserve" hypothesis); Detection bias: subjects with a low level of education tend to be clinically diagnosed at an earlier point in time

Sleep deprivation: causes accumulation of beta-amyloid

Cancer: there is an inverse relationship between Alzheimer’s Disease and cancer: people with cancer have a slower rate of memory decline than people without cancer

possible explanation: AD is a degenerative disease while cancer is a disease of excess growth

Age (strongest predisposing factor for regular AD)

Because: AD is a degenerative disease-> if longer time for buildup of tangles and plaques, higher chance of developing symptoms

Family history of dementia (strongest predisposing factor for early-onset AD)

If mutations in one of the genes, higher chance of developing AD

Low socioeconomic and/or education status (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311262/)

Insufficient access to health care?

Education could postpone the clinical expression of dementia symptoms by increasing the neocortical synaptic density (the "brain reserve" hypothesis)

Higher educational and occupatioanl attainment might provide a reserve: able to better cope with advanced pathologic changes of disease more effectively by maintaining funciton longer (the "cognitive reserve" hypothesis)

Detection bias: subjects with a low level of education tend to be clinically diagnosed at an earlier point in time

Diabetes (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209735/), obesity (https://theconversation.com/alzheimers-disease-obesity-may-worsen-its-effects-new-research-154214), dyslipidemia

Diabetes: Potential mechanisms: Glucotoxicity can result in structural damage and functional impairment of brain cells and nerves, hemorrhage of cerebral blood vessels and increased accumulation of amyloid beta.

Obesity: strain on cardiovascular system-> damage to endothelial walls of brain vessels-> high levels of inflammation, toxicity to brain cells and lower metabolism and blood flow in brain-> worsen mechanisms that cause Alzheimer's

Hypertension, peripheral atherosclerosis, and cerebrovascular disease

See explanations on diabetes and obesity

African American or Hispanic descent (compared to White individuals)

Lot of contradicting information, but probably

Genetic factors

Socioeconomic factors

Lack of physical activity (independent risk factor) (https://www.sciencedirect.com/science/article/pii/S2095254620300119)

Exercise modulates amyloid β turnover, inflammation, synthesis and release of neurotrophins, and cerebral blood flow

Traumatic brain injuries (https://www.alz.org/alzheimers-dementia/what-is-dementia/related_conditions/traumatic-brain-injury)

Within hours after injury, severe traumatic brain injury increases levels of beta-amyloid

Chronic Traumatic Encephalopathy (CTE) (dementia linked to repeated mild traumatic brain injury) is strongly characterized by deposists of tau protein

Environmental factors (e.g. secondhand smoke)

See explanations on diabetes and obesity (inflammation and blood vessel damage)

Sleep deprivation (https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-020-01960-9)

Sleep deprivation causes accumulation of beta-amyloid

Wakefulness increases neuronal activity-> increased production and secretion of Aβ

Reduced neuronal activity during sleep can increase clearance of Aβ and lower Aβ production

Glymphatic system (waste clearance system in brain) is more active in sleep time compared to wakefulness

Match the letter with the correct number

Ataxia

Agnosia

Anosognosia

Being unaware of your own mental health condition

Failure to recognise objects such as clothing, places and people

The ability to carry out skilled motor activities is impaired

You may ask a suspected
dementia patient to draw a clock. Why
would you do this?

1. To assess abstract thinking
2. To assess visuospatial function
3. To assess episodic memory
4. To assess for Parkinsonism

In Alzheimer’s disease, the brain shows
variable cortical atrophy. This includes
(2 possible answers)

1. Gyral narrowing
2. Gyral widening
3. Sulcal narrowing
4. Sulcal widening

There are several possible targets in the treatment of Alzheimer’s Disease. Which of the following targets is currently not yet used in practice?

1. Amyloid
2. Acetylcholine
3. Glutamate

Explanation:

Several pathways have been tried in the targeting of amyloid to treat Alzheimer’s Disease, but they all either did not work, or caused too many side-effects. Research is still being done.

Amyloid (Future treatments)

Vaccines and immunotherapy (Figure 13-14)

Immunizing the body to beta-amyloid

Nice idea, but hasn't really worked so far

Gamma-secretase inhibitors (Figuer 13-15)

Inhibit enzyme gamma-secretase-> block amyloid plaque formation

Nice idea, did reduce Abeta production, but caused worsening symptoms (probably through effect on other proteins)

Beta-secretase inhibitors (Figure 13-16)

Prevent beta-amyloid formation by blocking beta-secretase

Research is still being done

Acetylcholine (currently used)

Boosting availibility of acetylcholine

Cholinergic deficiency hypothesis of amnesia

Deficiency in cholinergic functioning is linked to a disruption in memory, particularly short-term memory

Nucleus basalis of Meynert in basal forebrain is major brain center for cholinergic neurons that project throughout the cortex-> neurons have principal role in mediating memory formation-> suspected: short-term memory disturbances of Alzheimer's patients due to degeneration of these particular cholinergic neurons

Cholinesterase inhibitors

Most successful approach to boosting cholinergic functioning in patients with Alzheimer's disease + improve memory= inhibit ACh destruction by blocking enzyme acetylcholinesterase (Figure 13-18)

-> build-up of ACh,because no longer destroyed-> enhanced availability-> impacts clinical outcome in Alzheimer's disease

* cholinergic agents require post-synaptic cholinergic receptors to mediate beneftis of enhanced cholinergic input-> most effective in early stages of disease, while postsynaptic cholinergic targets still present-> late in illness-> degenaration of neurons that have postsynaptic ACh receptors-> drug may lose benefits

Glutamate (currently used)

Glutamate hypothesis of cognitive deficiency in Alzheimer's disease

Hypothesis: glutamate released in excess during AD (perhaps in part triggered by neurotoxic amyloid plaques and neurofibrillary tangles)

In resting state: glutamate is quiet, NMDA receptor is physiologically blocked by magnesium ions

Normal excitatory neurotransmission-> glutamate released

Postsynpatic NMDA receptor allows inflow of ions if

1. neuronal depolarization

2. glutamate occupying its binding site on NMDA receptor

3. cotransmitter glycine occupying its site on NMDA receptor

If plaques and tangles cause steady "leak" of glutamate-> interferes with finetuning of glutamate neurotransmission-> possibly interfere with memory and learning, but not necessarily damaging

Hypothetically: as disease progresses-> glutamate release increased to level that is tonically bombarding postsynaptic receptor-> killing of dendrites-> killing off full neurons due to excitotoxic cell death