This article will discuss the pathophysiology of Alzheimer’s and the mechanisms of actions of medications to treat dementia and Alzheimer’s.
Introduction of Alzheimer’s Disease
There are three stages of Alzheimer’s disease:
- Stage I: Cognition is intact, but the amyloid level is elevated
- Stage II: Mild cognitive impairment characterized by episodic memory deficits and elevated tau protein
- Stage III: Severe cognitive deficits. There is where treatment typically starts.
Genetic Predisposition
Apolipoprotein E (APOE) is a protein that helps carry cholesterol in the bloodstream. It has been demonstrated that having a certain variation of the APOE gene on chromosome 19 can increase the risk of Alzheimer’s.
There are many different forms of the APOE gene, and each individual has two APOE genes, one from each parent.
The APOE E3 is the most common allele and is considered to be a neutral allele where it neither increases nor decreases the risk of Alzheimer’s.
The APOE E2 is rare and may provide protection against Alzheimer’s. Patients with this gene tend to develop Alzheimer’s much later in life.
The APOE E4 has been shown to increase the risk of Alzheimer’s as demonstrated by patients having earlier onsets of the disease. About 25% of the population carry one copy of the APOE E4, and about 2-3% carry two copies.
Aside from the APOE E4 gene, there are three other single-gene mutations associated with early-onset of Alzheimer’s:
- Amyloid precursor protein (APP) on chromosome 21 – this is why individuals with Down’s Syndrome tend to have Alzheimer’s later in life as well.
- Presenilin 1 (PSEN1) on chromosome 14
- PSEN 2 on chromosome 1.
Early-onset Alzheimer’s accounts for less than 10% of individuals with Alzheimer’s. The onset is usually between 30-60 years of age.
Alzhimer’s Disease Pathology
There are two primary abnormalities commonly observed in Alzheimer’s.
- Tau protein tangles
- Beta-amyloid plaques
These changes are the results of neuronal dysfunction involving abnormal processing of APP.
Amyloid angiopathy describes the phenomenon where beta-amyloid accumulates on the inside of the blood vessels. This is also referred to as cerebrovascular plaques.
Beta Amyloid Proteins
Normally, APP is cleaved by alpha and gamma secretases to form non-harmful soluble proteins. When APP is cleaved by beta and gamma secretases instead, beta-amyloid protein is formed instead. Over time, this causes a pathological accumulation of beta-amyloid proteins, leading to the formation of beta-amyloid protein plaques and tangles seen in Alzheimer’s.
The composition of the gamma-secretase is crucial in the management of beta-amyloid proteins. Gamma-secretase is comprised of four proteins: PS1, nicastrin, APH-1, and PEN-2. PS1 is the control point and cleaves C terminal fragment to release beta-amyloid. The phosphorylation of PS1 at Ser367 promotes autophagic, which reduces beta-amyloid protein levels. Ser367 acts as a switch to convert PS1 between the beta-amyloid protein-producing state and the degrading state. If there is no phosphorylation, there will be an accumulation of beta-amyloid proteins.
Over time, the accumulation of beta-amyloid proteins clumps together to form oligomers and then into amyloid plaques. These begin to interfere with synaptic function and activate inflammatory responses from microglia and astrocytes through proinflammatory cytokine and oxygen-free radicals.
Furthermore, the plaques can activate kinases, leading to the phosphorylation of tau proteins and causing a tangle of microtubules.
The combination of amyloid plaques and tau protein tangle ultimately leads to neuron apoptosis and neuronal network destruction.
PET imaging was performed to visualize the amount of beta-amyloid proteins using a dye that binds to a beta-amyloid protein called compound B. In patients with cognitive impairment, there is an increase in beta-amyloid proteins. In patients with Alzheimer’s disease, there is a marked increase in beta-amyloid proteins compared to cognitive impairment. The beta-amyloid protein accumulation seems to be concentrated in the parietal, occipital, temporal, and striatum.
Alternative Hypothesis: APOE
This hypothesis revolves around the APOE proteins. Good APOE binds to beta-amyloid proteins and removes them to prevent Alzheimer’s. Bad APOE cannot bind or clear beta-amyloid proteins, leading to amyloid plaque.
The APOEs are associated with different risks for Alzheimer’s disease.
APOE E4 is the most concerning APOE risk factor for Alzheimer’s.
Tau Proteins
The normal function of Tau Proteins is to act as microtubules regulator (MAP) by binding and stabilizing microtubules. They work with tubulin to promote and facilitate this process.
In Alzhimer’s, there is a reduction in Tau proteins’ ability to bind to microtubules and promote microtubule assembly. This is due to the tau protein being hyper-phosphorylated by beta-amyloid proteins. This causes tau proteins to detach from microtubules and stick together with other tau proteins instead, creating a tangle.
The tangle causes a destabilization of the microtubule network and interferes with axonal transport, leading to neuronal death.
Tau aggregate/tangle can be passed across synaptic, which is the underlying mechanism of how tau proteins are able to spread. It is unknown how this mechanism came to be.
Hypometabolism
A PET imaging of FDG (a type of glucose) demonstrated that an individual with mild cognitive impairment has lower glucose metabolism than a normal individual. An individual with Alzheimer’s has an even lower glucose metabolism when compared to a mild cognitive impairment individual.
Acetylcholine
Acetylcholine (ACh) is reduced in Alzheimer’s as well as ChAT, which synthesizes ACh. Interestingly, there is an increased level of AChE (an enzyme that breaks down ACh) around amyloid plaques and tau tangles. AChEs form a stable complex with the plaques, leading to further neuro-toxicity.
There is also an alteration in the cholinergic reactions in Alzheimer’s patients. A post-mortem brain study demonstrated a reduction in the a4B2 subtype of the nicotinic receptor. There is also a decrease in alpha-7 nicotinic acetylcholine receptors in the cortex and hippocampus, which is correlated with an earlier onset of Alzheimer’s. This may be due to beta-amyloid proteins binding to the alpha-7 subunit with high affinity, leading to the accumulation of beta-amyloid proteins.
Butyrylcholinesterase is an enzyme that also breaks down ACh. It plays a significant role in pathology as well. This enzyme is found mostly in the liver, but also a little in the lower levels of the brain. In patients with Alzheimer’s, there is an increased level of this enzyme in a certain cortical region as well as nearby the plaque and beta-amyloid protein deposit. There are many variances of this enzyme. The K variant is thought to be associated with Alzheimer’s, but it is currently unknown whether this variant promotes or prevents Alzheimer’s.
Treatment of Alzheimer’s Disease
The mainstay of Alzheimer’s treatment is acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine). The treatment can then be supplemented with an NMDA receptor antagonist (memantine) or adjunct therapies, such as antidepressants and antipsychotics.
Acetylcholinesterase Inhibitors
Rivastigmine (Exelon) is a pseudo-irreversible inhibitor, meaning that it reverses itself over hours. It is intermediate-acting and is selective for AChE in the cortex and hippocampus. It also works on the BuCHe in glial cells. Ultimately, rivastigmine enhances ACh levels within the CNS. This becomes important due to the development of gliosis.
Donepezil (Aricept) is a reversible, long-acting, selective inhibitor. There is no action on BuCHe. It is selective in both pre-and post-synaptic.
Galantamine has a unique, dual mechanism where it also matches AChE with positive allosteric modulation (PAM) of nicotinic cholinergic receptors. This leads to an increase in acetylcholine-induced current.
NMDA Receptor Antagonist
Memantine (Namenda) is currently the only medication in this class. It is a non-competitive low affinity NMDA receptor antagonist that binds through the magnesium site. Memantine only binds when the channel is in the open configuration. This is why memantine is also known as the “open-channel antagonist.” Memantine has a low affinity, which allows a phasic burst to bump memantine off and allow normal neurotransmission. When bound, memantine blocks glutamate by binding to the NMDA ion channel, leading to an improvement in memory and prevention of neurodegeneration.
Another benefit of memantine is also due to its low affinity because long-term blocking can interfere with memory formation and neuroplasticity.
Recent Treatment of Alzheimer’s
Lecanemab (Leqembi) is a relatively new medication that went through accelerated approval from the FDA. It showed to slow cognitive decline by 27%. It is a monoclonal antibody that targets beta-amyloid.
Three study participants died during the clinical trial due to brain swelling and bleeding.
Another potential therapeutic target is to inhibit beta-secretase and gamma-secretase, but there is currently no approved agent under this mechanism.
Traumatic Brain Injury (TBI)
Traumatic brain injury can produce cognitive impairment. There are two types of TBIs: coup and contrecoup. This depends on the site of impact. Coup TBI is where the damage is at the site of impact. Contrecoup is where the damage is on the opposite side of the impact.
A repeated concussion can result in persistent and profound cognitive impairment, dementia, Parkinsonian symptoms, and nerve damage. A repeated concussion is also known as chronic traumatic encephalopathy (CTE). The only way to know if it is a CTE for sure is with a brain autopsy, but a diagnosis is made based on symptoms, such as memory loss, confusion, personality change, and erratic behavior.
CTE is characterized by tau tangles, but unlike Alzheimer’s, the tangle appears around small blood vessels and beta-amyloid proteins are not always present. The accumulation of tau tangle is greater in CTE than in Alzheimer’s, especially in the amygdala and midbrain. An important note is that the midbrain is where serotonin neurons are, and dysfunction here can lead to mood destabilization.
A human post-mortem on a TBI subject was performed to measure the neuron density in the dorsal raphe. The study shows that there is a loss of serotonin and NE neurons, although the loss is not statistically significant.
There is no treatment or cure for CTE. The treatment course is to treat symptoms.
- Mood change: Typical antidepressants and anxiolytics
- Memory problems: Dementia-related medication
- Behavioral therapy: Memory training exercises