Alzheimer's Disease (AD)

Question 1

What are the symptoms of AD?

Answer 1

Cognitive impairment, confusion, loss of memory, initial short-term loss of memory that later progresses, lack of understanding of time/place/day. For a diagnosis, the disease must significantly affect everyday life.

Question 2

Name two types of structures in the brain affected in AD.

Answer 2

NFT - neurofibrillary tangles

Plaques - extracellular structures

Question 3

Evidence to show that AD increases with age?

Answer 3

Less than 1% of people have AD over the age of 60; around 10% have it over the age of 65; and ~50% over the age of 85.

Mostly late onset AD (LOAD), but some early-onset.

Question 4

What are two key factors increasing the likelihood of AD?

Answer 4

Age! and having a family history.

10-15% autosomal dominant (but difficult to test because of the disease’s late onset), 90% sporadic.

Question 5

What is generalised cortical atrophy?

Answer 5

Loss of neurones and the connections between them. Brain has generally shrunk in size.

Question 6

What areas of the brain are affected?

Answer 6

Hippocampus, entorhinal cortex, amygdala, cerebral association cortices, selected subcortical nuclei

Question 7

What chromosome is affected in AD?

Answer 7

Chromosome 21 (trisomy 21 - Down’s syndrome - those with Down’s syndrome also get AD around the age of 30, with pathology like that of LOAD)

Question 8

What gene is affected?

Answer 8

APP (apoliprotein). Mutations of this gene and overexpression of it.

When we are young, APP is cleaved by alpha-secretase - forms neurofibrils and plaques. When we are old, beta-secretase cleaves APP, causing formation of pathogenic beta-amyloid precursor proteins. These protiens are broken down by the ubiquitin proteosome proteolytic pathway (UPPP), resulting in neurotoxicity and therefore AD.

Question 9

What other chromosomes are affected?

Answer 9

Presenilin 1 (hChr14) and presenilin 2 (hChr1) - cleavage of the APP gene

Question 10

What are other (more common) mutations?

Answer 10

PSEN1

Question 11

Is there a good correlation between APP and AD?

Answer 11

No, but a better correlation exists between AD and Tau (MAPT).

Question 12

What does MAPT stand for?

Answer 12

microtubule-associated protein tau

Question 13

What causes tau to misform?

Answer 13

amyloid…

Question 14

What are extracellular senile plaques?

Answer 14

Round, spherical, around 20 micrometres. A peripheral rim of abnormal neuronal processes (neurites). Can be diffuse/pre-amyloid, or classic/neuritic plaque.

Question 15

What is neurofibrillary pathology?

Answer 15

Neurofibrillary tangles, neuropil threads, dystrophic neurites of neuritic plaques. An intracellular accummulation of paired helical filaments - basic component = hyperphosphorylated plaques

Question 16

What happened to Henry Modaison?

Answer 16

He fell off his bike at the age of 9 and then experienced epileptic seizures from banging his head. Doctors removed the medial temporal lobe (includes part of the hippocampus) in attempt to stop the seizures, but this made him unable to form memories. This shows that this part of the brain forms memories.

Question 17

Diagnosis of AD?

Answer 17

A scoring system - e.g. standard questions about name, age, family members, occupation, current PM (here, patients often name a previous one). This is follwed by CT scans, fMRI.

More recently, VR used to test spacial awareness and navigation: this is a something that fails in AD and early-onset can be diagnosed by these tests.

Question 18

What cells are involved in spacial navigation in the hippocampus?

Answer 18

Grid cells and place cells

Question 19

What do grid cells do?

Answer 19

They provide a space in time and link any associated memories.

Question 20

What does tau pathology have to do with AD?

Answer 20

Tau pathology initiated in the entorhinal cortex causes deficits in grid cell firing, hence the deterioration of spacial navigation in AD. Linked with hyperphosphorylation of MAPT.