Alzheimer's disease (AD) is a non-reversible brain disorder that develops over a number of years - AQA - A-Level Biology - Question 10 - 2017 - Paper 1

Donepezil improves communication between nerve cells by inhibiting the enzyme acetylcholinesterase, which is responsible for breaking down acetylcholine in the synaptic cleft. By reducing the breakdown of acetylcholine:

1. More acetylcholine remains available for binding to receptors on the postsynaptic neuron, enhancing signal transmission.
2. This increased availability helps to generate a stronger depolarization/action potential in the receiving neurons, thereby improving communication and potentially alleviating some symptoms of AD.

1. Founder Effect: The population of Yaramul is historically isolated, creating a scenario where a small group of individuals carried the E280A mutation. Over generations, this high frequency may persist due to limited genetic diversity and mating within the small population, leading to a higher prevalence of the mutation.

2. Inbreeding: Due to the geographical isolation of Yaramul, there may be a higher occurrence of inbreeding. This enhances the likelihood of homozygosity for the mutation, allowing it to be passed down through successive generations without being diluted by other alleles.

Natural selection has not reduced the frequency of the E280A mutation in Yaramul possibly because individuals with the mutation still survive to reproductive age. Moreover, since the E280A mutation causes early-onset AD at a mean age of 49, individuals may have already reproduced before the onset of symptoms. Therefore, the mutation can be passed on without being selected against, allowing it to persist in the population.

One reason for the variation in the age at which the E280A mutation is expressed to cause AD might be environmental factors. These factors can include variations in diet, lifestyle, or exposure to neuroprotective agents in different individuals, which could influence the onset and progression of the disease. Such genetic-environment interactions can lead to a range of expression of the mutation, modifying the age of onset.

The discrepancy between the number of detected E280A mutations (75) and the observed potential AD cases (74) could arise for several reasons:

1. False Positives: The method used for detecting mutations may have yielded false positives, misclassifying some individuals as having the mutation when they do not.
2. Non-penetrance: Some individuals might carry the E280A mutation without exhibiting clinical symptoms of AD due to various genetic or environmental factors, resulting in fewer diagnosed cases than expected.

A DNA probe for the mutated triplet was not considered suitable because it may bind elsewhere in the genome rather than specifically to the E280A mutation. This can lead to challenges in accurately identifying individuals with the mutation, resulting in unreliable tests, which might not provide conclusive results.