Dementia and Alzheimers

What is Dementia?

The term used to describe when a person experiences a gradual loss of brain function due to physical changes in the structure of their brain

What is Alzheimer’s?

The most common form of dementia as well as the most comon cause of dementia, with symptoms such as loss of memory, impaired reasoning, reduced language skills, and loss of daily living skills

Mild symptoms of Alzheimer’s include…?

Confusion, memory loss, disorientation of familiar and unfamiliar surroundings, problems with routine tasks, changes in personality and judgement

Moderate symptoms of Alzheimer’s include…?

Difficulty with activities of daily living such as feeding and bathing, anxiety, suspiciousness, agitation, sleep disturbances, wandering/pacing, difficulty recognising familiar faces such as family and friends

Severe Symptoms of Alzheimer’s include…?

Loss of speech, loss of appetite; weight loss,; loss of bladder and bowel control

How are Phonemic and Semantic Verbal Fluency (SVF) measures used regarding dementia/Alzheimer’s?

Tests of phonemic and semantic verbal fluency are widely used in the assessment of individuals with memory complaints and in the clinical diagnosis of Alzheimer’s disease. In these measures, patients are asked to generate as many words as they can either starting with a certain letter of the alphabet (phonemic fluency) or belonging to a certain semantic category eg. animals (semantic fluency). People with dementia exhibit a steeper and more significant cognitive decline over a 15 month period

What is the primary risk factor for Alzheimer’s?

Age (65 years +)

The likelihood of developing the condition increases by how much after you reach what age?

Likelihood doubles every five years after you reach 65

How does the aging population impact Alzheimer rates?

30% of the world’s population over 65 has Alzheimer’s (50 million cases worldwide), but by 2050, it will rise to approximately 100 million cases worldwide. This has a huge personal and economic burden, on course to take on the combined economic burden of both heart attack and stroke.

What are the other risk factors for Alzheimer’s, particularly early onset?

Family history and genetic disposition (especially when linked to PSEN1, PSEN2, APP gene mutations). If one of your parents has early onset AD, there is a 50% you will develop it.

What are modifiable riske factors for dementia?

Poor education, hearing loss, higher LDL cholesterol, obesity, TBI/concussion, hypertension, alcoholism, mid-later life depression, smoking, physical inactivity, diabetes, social isolation, air pollution, late-life vision loss

How many cases of dementia, worldwide, are considered ‘potentially modifiable’?

40-45%

Summarise the ‘Minnesota Nun Study’ (Iacona et al 2009)?

Notre Dame nuns age 75-102 had started early life autobiographies aged 12 (average) → higher idea density scores in early life are associated with intact cognition in late life, even if AD lesions were present

What causes Alzheimer’s (what are the pathological hallmarks)?

‘Plaques’, ‘Tangles’ and cholinergic projection neurons loss- Plaques are clumps of beta-amalyde that clump together outside the effects and impair synaptic function, ‘tangles’ and neurofibrillary tangles are clumps of protein inside the cell and impair intracellular functions, eventually killing the neurons. The loss of cholinergic projection neurons of the basal forebrain causes reductions in critical neurotransmitters for memory function including acetylcholine. These neurons are lost early into the onset of AD.

How is acetylcholine loss treated in AD patients?

Acetylcholine normally gets broken down rapidly after cholinesterase after carrying a message across the synapse. Mild to moderate AD can be treated by cholinesterase inhibitors (AChE-Is) which gives the acetylcholine a greater amount of time to transmit signals. However, these drugs only work if there is still a sufficient amount of acetylcholine (you can’t amplify a signal that doesn’t exist)

What are Amyloid Precusor Proteins are Beta Amyloid Segments, and why are they significant in AD patients?

APP is a protein that plays a role in synaptic plasticity, and beta amyloid is produced when APP is cleaved into segments by secretases. Beta Amyloid is overproduced in AD patients, and forms ‘toxic’ fibrillar plaques on the outside surface of the cells, distributed through the cortex (the ‘Plaque’ hallmark). We don’t have a solid understanding of why this happens.

What are the current issues with the APP hypothesis?

It maps poorly onto symptoms, and when you target BA in treatments symptoms do not tend to improve. One exception to this is Donanemab (2023 developed drug), which shows some promise slowing cognitive decline by around 35% of 18 months. Additionally, several papers associated with oligomer treatments for BA have been noted for ‘data irregularity’ and have been retracted since 2006 on accusations of fraudulent data.

What are ‘tau proteins’?

The ‘tangle’ - tau protein molecules usually sit on the outside of the neuronal microtubals. However, these tau proteins may become hyperphosphorelated and ‘let go’ of the microtubalar structure, causing it to disintegrate which compromises the structure and health of the neuron. Additionally, these freefloating tau proteins are ‘sticky’ and form aggregate tangles inside the cells, which causes significant intracellular impairment. This hypothesis, comparatively, maps much better onto symptoms and progression maps of AD.

What gene is associated with sporadic (late onset) AD?

APOE gene on chromosome 19. The three major variations aka alleles are APOE2, APOE3, APOE4. These variations produce slightly different forms of the Apolipoprotein E ApoE protein, produced mainly by astrocytes, and transports cholesterol to neurons. E4 confers to a higher riske of Alzheimer’s - having 2 copies of E4 carries a 5-8 times higher risk of AD, and having 1 copy of E4 has a 2-3 times higher risk of AD.

What is the blood-brain barrier?

The semipermeable membrane between the blood and the brain that regulates the movement of molecules and ions between the two.

The BBB has ‘tight junctions’ formed by pericyctes. Why?

To restrict blood-borne substances from entering the brain

How does the allele APOE4 confer to increased risk of AD, specifically, what is it’s relationship to the blood-brain barrier?

APOE4 is associated with the disruption of TJs, opening the BBB → harmful substances can enter the brain → accelerates the development of Alzheimers