INTRODUCTION

Dementia isn’t exactly a type of disease but more of a way of describing a set of symptoms
such as poor memory and difficulty learning new information. It’s usually caused by some
sort of damage to the cells in the brain which can cause a variety of diseases. Alzheimer’s
disease is the most common cause of dementia, affecting over 40 million people worldwide.
It is considered a neurodegenerative disease meaning it causes degeneration or loss of
neurons in the brain particularly in the cortex. In 1901, a biopsy was done on a patient and
revealed visible differences in the brain tissue in the form of misfolded proteins called
plaques, and neurofibrillary tangles. Although Alzheimer’s disease isn’t completely
understood, it’s clear these two proteins play a major role in the development of it.

FORMATION
In the cell membrane of a neuron of the brain, there is a molecule called amyloid precursor
protein (APP) which helps the neuron grow and repair itself. Like other proteins, APP gets
used and over time recycled and normally it gets sliced by the enzymes alpha-secretase and
gamma-secretase. The product of this is soluble and can be transported away with no
problems. However, when the enzyme beta secretase is used along with gamma secretase,
the monomer amyloid beta (AB) is formed and this isn’t soluble. AB plaques are chemically
sticky and bond together just outside the neurons and form beta amyloid plaques. The
plaques get in the way of neurons and block signalling and therefore communication
between cells. The plaques also trigger an immune response which causes inflammation and
the death of nerve cells. Amyloid plaques can also deposit around blood vessels in the brain
called amyloid angiopathy which weakens the walls of the blood vessels and increases the
risk of haemorrhage or rupture and blood loss. Another big part of Alzheimer’s disease are
tangles which are found inside the cell as opposed to the plaques. Neurons, like other cells,
are held together by their cytoskeleton which is partly made up of microtubules. These
networks of tubules act like a highway for nutrients and molecules to be transported along
the length of the cell. Usually, a special protein known as tau ensures that these tubules are
straight, allowing molecules to pass through freely. Although it’s not completely understood,
it’s thought that the plaque build up outside the neuron initiates pathways inside the neuron
that leads to the activation of the enzyme kinase which transfers phosphate groups to the
tau protein causing a shape change. Tau can no longer support the microtubules and clumps
up with other tau proteins and gets tangled. This forms neurofibrillary tangles and causes the
microtubules can’t signal as well and sometimes undergo apoptosis or programed cell death.

RESULT & SYMPTOMS

The destructive pairing of plaques and tangles begins in a region of the brain called the
hippocampus, which is responsible for forming memories. This is why short-term memory
loss is usually the first symptom of Alzheimer’s. The proteins then progressively invade other
parts of the brain creating unique changes that signal various stages of the disease. At the
front of the brain (frontal lobe), the proteins destroy the ability to process logical thoughts.
Next, they shift to the region that controls emotions (temporal lobe), resulting in erratic
mood changes. At the top of the brain, they cause paranoia and hallucinations, and once they
reach the brain's rear, the plaques and tangles work together to erase the brain’s long term
memory. The whole process results in cerebral atrophy which is the shrinkage of the brain’s
overall size. Eventually the control centers governing heart rate and breathing are
overpowered as well resulting in death.
RISK FACTORS
Alzheimer’s disease can be split into two groups: sporadic and familial. Sporadic, which
accounts for roughly 90-95% of cases, is used to describe the late onset type where the exact
cause isn’t very well defined. This is probably caused by genetic and environmental risk
factors. The risk for sporadic increases significantly with age affecting 1% of people between
ages 60 and 65 and 50% of people over the age of 85. A gene that has been identified as
possibly contributing to an increase risk of Alzheimer’s disease is the e4 allele apoliprotein E
(APOE e4). Researchers have shown that the risk of developing Alzheimer’s disease increases
for patients that inherit one e4 allele and increases even more for patients who inherited two
e4 alleles, one from each parent. APOE helps break down beta amyloid but the e4 alleles
seem to be less effective than the other alleles (e.g. APOE e2 allele) meaning patients are
more likely to develop beta amyloid plaques.

Familial Alzheimer’s disease on the other hand is used to describe cases where some
dominant gene was inherited that speeds up the progression of the disease and is sometimes
referred to as early onset. It accounts for 5-10% of cases and can be caused by several gene
mutations. First mutation in the PSE-1 and PSE-2 gene, on chromosomes 14 and
chromosome 1 respectively, have been linked to early onset Alzheimer’s. These genes both
encode for presenilin 1 and 2 which are both protein subunits of gamma secretase.
Mutations in these genes can change the location where gamma secretase cuts APP,
producing a different length beta amyloid molecule which seemed to be better at clumping
up and forming plaques. Another known genetic cause is Down syndrome which involves
having an extra copy of chromosome 21. The gene responsible for producing APP is located
on chromosome 21 which means that people with Down syndrome have an extra APP gene
and presumably increase expression of APP. This potentially increases the amount of plaque
build up.

TREATMENT
Diagnosis of Alzheimer’s disease is really tough because the only way to definitively show
that a person had Alzheimer’s is by preforming a brain biopsy after autopsy. Researchers
have looked for a cure but unsuccessful. For this reason, they are more focused on slowing
the disease’s progression. One temporary treatment helps reduce the break down of
acetylcholine, an important chemical messenger in the brain which is decreased in
Alzheimer’s patients due to the death of the nerve cells that make it. Another possible
solution is a vaccine that trains the body’s immune system to attack beta amyloid plaques
before they can form clumps.
Huntington’s disease

Huntington's disease (HD), is an inherited disorder that results in death of brain cells, causing
uncontrolled movements, emotional complications and cognitive dysfunction. Symptoms
usually begin between 30 and 50 years of age but can start at any age. The disease may
develop earlier in life in each successive generation. About 8% of cases start before the age
of 21 years and typically present with symptoms more similar to Parkinson's disease, this
type of Huntington’s disease is known as Juvenile Huntington’s disease.
HD is an autosomal dominant genetic disorder, meaning that one affected copy of the gene
causes the disease and there is a 50% chance of passing the gene onto offspring., although
up to 10% of cases are due to a new mutation. A study by the journal of neurology,
neurosurgery and psychiatry in 2013 suggests that the prevalence of adult HD rose from 5.4%
in 1990, to 12.3% of the population in 2010.

Formation
HD is a neurodegenerative disease that involves a repeated sequence of DNA that leads to
the production of abnormal and toxic mutant huntingtin (mHTT) protein. to form. The
affected gene is the Huntingtin gene on chromosome 4, which contains a triplet repeat of the
trinucleotide CAG. CAG, which codes for the amino acid glutamine, is repeated 10-35 times in
a normal person. However, in a patient suffering from Huntington’s disease, glutamine is
repeated over 36-40 times, therefore Huntington’s diseases can also be referred to as a
polyglutamine disease. The mutated protein aggregates in the neuronal cells of the caudate
and putamen of the basal ganglia causing neuronal cell death, which leads to excitotoxicity;
an excessive signalling of these neurons leading to high intracellular Ca2+. Excessive CAG
affects DNA replication; the DNA polymerase loses track of which CAG within the repeats it is
replicating and therefore adds more CAG to the new DNA. The more repeats that are added
to the DNA, the more unstable the DNA becomes. This also means when a child inherits the
huntingtin gene, they are more likely to have more repeats as repeat expansion, the process
of adding more repeats, which occurs during zygote formation. The more repeats found in
the DNA, the earlier the onset of HD. Anticipation is the earlier onset occurring with each
generation of Huntington’s inherited. Repeat expansion is greater in spermiogenesis than
oogenesis, and as a result anticipation and new disease alleles happen more when the
affected parent is the father.
Huntington’s is a 100% penetrance disease, meaning the presence of more than 36
trinucleotide repeats in DNA results in disease. Tests used to diagnose a patient involve the
counting of repeats in a DNA sample and this determines whether the disease will develop in
an at-risk individual.

Results & Symptoms

The average age of onset is 40 years; however, this can be much earlier in Juvenile
Huntington disease, which has an onset of below 21 years of age.
Symptoms of HD involve progressive central nervous system disturbances, including
movement, cognitive and mood symptoms. Death of neurones in caudate and putamen,
which together form the dorsal striatum in the brain, leads to loss of tissue and therefore an
expansion of the lateral ventricle. These areas of the brain play an important role in inhibiting
movement, so death of neurones in the basal ganglia leads to complications in movement,
leading to two major symptoms: chorea; purposeless dance-like jerking movements, and
athetosis; slow, snake-like movements. These movements can’t be supressed, and only stop
with sleep. Other movements problems include abnormal eye-movements, rigidity and
muscle contracture, known as dystonia, and poor coordination.
Loss of tissue also leads to psychological complications, such as dementia, personality
changes and depression.
Patients with juvenile HD often have a rapid decline in school performance as their ability to
think and reason is weakened, and experience behavioural changes.
Diagnosis & Treatment
HD is typically diagnosed based on clinical findings in the setting of a family history and may
be confirmed with genetic testing. Predictive genetic testing is available for at-risk individuals
and consists of a blood test which counts the numbers of CAG repeats in each of
the HTT alleles.
Regions of the brain affected by HD have: decreased levels of gamma-Aminobutyric acid, or
GABA, an inhibitory neurotransmitter, decreased levels of Acetylcholine, a neurotransmitter
that transmits signals between motor nerves and skeletal muscles and activates muscles,
and increased dopamine levels. Dopamine is a neurotransmitter that affects parts of the
brain, such as emotions and movement. In patients with severe chorea, neuroleptics, which
are dopamine-receptor antagonists, and tetrabenazine, which depletes dopamine, are
administered to treat the symptoms.
Unfortunately there aren’t any pharmaceutical treatments that affects the overall survival
ftomm HD, and death usually happens within 10-20 years from diagnosis, often by aspiration
pneumonia on account of discoordinated swallowing, or suicide due to severe depression.

Clinical trials are currently being carried out in search of treatments in lowering the
formation of the abnormal huntingtin protein. According to the findings of an ongoing Phase
1/2 clinical trial led by UCL scientists, the investigative therapy IONIS-HTTRx effectively
reduced levels of the protein responsible for Huntington’s disease in early-stage patients.
IONIS-HTTRx is a disease-modifying treatment called antisense oligonucleotide (ASO) that
was designed to target and destroy all forms of the huntingtin protein, including the mutated
one. This strategy raises the possibility of treating all Huntington’s patients, regardless of
their individual HTT mutation.
Results from preclinical studies have shown that the investigative drug could suppress
huntingtin protein production in mouse models of the disease. Also, it could effectively delay
disease progression and even reverse disease symptoms.