10.3 Introduction to Alzheimer’s Disease

Pathophysiology

To fully understand how a drug alters symptoms, it is important to understand the pathophysiology of the disease being treated at the biochemical level. In most central nervous system disorders, the existing knowledge is limited. The brain is a complex structure, and the overall neuronal degeneration and cerebral atrophy recognized in AD has been theorized to result from a variety of changes. Researchers are still trying to unravel the underlying pathophysiology of AD. The following is a list of alterations that have been identified as origins for the cognitive decline seen with this disease (Huang, 2023):

• Degeneration of neurons: This destruction of neurons first occurs in the hippocampus, the area of the brain that plays an essential role in memory. The degeneration of these neurons will cause short-term memory loss. When neurons of the cerebral cortex begin to degenerate, speech, reasoning, and other higher cognitive functions become impaired.
• Beta-amyloid plaques: These plaques form outside neurons. Their central core is composed of beta-amyloid, a protein fragment of amyloid precursor protein (APP). Accumulation of beta-amyloid begins very early in the disease before any appearance of clinical manifestations. It is believed this protein plays a central role in AD.
• Neurofibrillary tangles and abnormal tau protein: These tangles form inside neurons. They result when the orderly arrangement of microtubules becomes disrupted. Microtubules are responsible for bringing nutrients to the axons and back. Normally, tau protein binds to these microtubules and provides stability. In AD, tau protein becomes “sticky” and tangles together with other tau threads. The microtubule is unable to transport nutrients, so the neuron can no longer function and eventually dies. As more and more neurons die, the brain atrophies.
• Oxidative stress: Oxidative stress produces reactive oxygen species (ROS), such as free radicals. These cause brain cell damage and cellular apoptosis. Oxidative stress is the term used to describe damage to cellular components caused by ROS. Due to their characteristic unpaired electrons, ROS can set off chain reactions where they remove electrons from other molecules, which then become oxidized and reactive and do the same to other molecules, causing a chain reaction. ROS can cause permanent damage to cellular lipids, proteins, carbohydrates, and nucleic acids. Damaged DNA can lead to genetic mutations and even cancer.
• Deficiency of ACh: The loss of ACh is crucial for two reasons: (1) it is an important transmitter in the hippocampus and cerebral cortex, where the degeneration is occurring; and (2) this transmitter is critical in forming memories.
• Genetics: Apolipoprotein E is known for its role in transporting cholesterol. One form of apolipoprotein E is associated with AD. Genetic research has shown that those with one or two copies of the gene that codes for apolipoprotein E4 (APOE-e4) are at a higher risk for developing AD. Additional genes have been identified as being definitively associated with AD. These include amyloid precursor protein (APP) gene, presenilin-1 (PS1) gene, and presenilin-2 (PS2) gene. A person who has any mutation to these genes will produce proteins that have neurotoxic properties, which will promote neuronal death. Additionally, these mutations can lead to the formation of neurofibrillary tangles and plaques.

Etiology

An underlying single cause for AD has yet to be discovered. There have been important theories and findings, but it is not known how these pieces fit together. Interestingly, the major pathologic findings begin to develop a decade or more before clinical manifestations are even observed. At this point, the etiology is considered multifactorial. Current potential causes of AD include:

• Degeneration of neurons in the hippocampus and cerebral cortex that subsequently cause cerebral atrophy
• Formation of beta-amyloid plaques
• Accumulation of neurofibrillary tangles and chemically altered tau protein
• Oxidative stress forming free radicals that damage cellular components caused by ROS (This is discussed more in the following section.)
• Deficiency of acetylcholine
• Genetics

Figure 10.3 compares a cross-section of a normal brain with one from a client with Alzheimer’s disease.

Figure 10.3 Compared with a normal brain (left), the brain from a client with Alzheimer’s disease (right) shows a dramatic neurodegeneration, particularly within the ventricles and hippocampus. (credit: modification of work from Biology 2e. attribution: Copyright Rice University, OpenStax, under CC BY 4.0 license)

Diagnostics

Although it is impossible to definitively diagnose AD without a postmortem autopsy, the diagnosis is made based on symptoms and exclusion of alternative pathology. During the autopsy, the typical characteristics of senile plaques and neurofibrillary tangles can be visualized.

Clinical Manifestations

As the disease progresses, the clinical manifestations worsen to the point where the client is unable to independently perform their activities of daily living (ADL). They become reliant on others for assistance. Early in the disease, the following mild manifestations may be witnessed: confusion, memory loss, disorientation, getting lost in familiar surroundings, problems with routine tasks, and changes in personality and judgment. Moderate manifestations include difficulty with ADLs (feeding and bathing), impaired organization and planning, impaired mathematical ability, anxiety/agitation, sleep disturbances, wandering, and difficulty in recognizing family and friends. Late manifestations include loss of speech, anorexia, impaired swallowing, weight loss, difficulty with movement, loss of ability to appropriately respond to the environment, sense of paranoia, delusions, hallucinations, and inability to control bladder and bowel function. At this point, the client is completely dependent on caregivers. AD will eventually destroy enough brain function to cause death.

Pharmacological Management

Currently, there is no known cure for AD. Drugs given for AD may at best slow the loss of memory and cognition in hopes of affording the person extra time to be able to continue functioning independently. Unfortunately, often the person observes minimal and short-term clinical efficacy from these medications. The AChE inhibitors (also known as cholinesterase inhibitors) were the first class of drugs approved by the FDA to treat AD. There are currently three drugs within this class. The other drug class, which currently contains one drug, is the N-methyl-D-aspartate (NMDA) receptor antagonist. In 2014, a capsule containing a combination of memantine hydrochloride ER (NMDA receptor antagonist) and donepezil hydrochloride (AChE inhibitor) was approved for the treatment of moderate to severe dementia of the Alzheimer’s type. This drug has the capability of targeting two different sites of action.