Alzheimer’s Disease

Learning Goals

• Grasp the anatomical alterations linked to Alzheimer’s disease.
• Explore the contributing factors associated with Alzheimer’s development.
• Comprehend how Alzheimer’s is diagnosed and assessed.
• Examine established treatment methods and the latest therapeutic drugs.
• Delve into the potential causes behind the progression of the disease.
• Analyze new diagnostic techniques and treatment options that are emerging.
• Recognize important dental care considerations, particularly around informed consent challenges.

Typical Brain Structure and Functionality

The human brain, in its normal state, carries out a vast array of regulatory tasks while managing significant amounts of information. Our capability to communicate effectively, recall memories, execute everyday activities, and exhibit appropriate social behaviors hinges on the proper functioning of countless nerve cells located within the cerebral cortex. What seems routine to us is, in reality, an intricate and highly coordinated series of neurophysiological processes.

Neurons, the cells that form the nerve fibers in the brain, operate in a discontinuous manner. Signals travel between these cells across a gap known as the synapse. In order for nerve impulses to cross this synapse, specific chemicals, called neurotransmitters, must be released by one neuron and detected by another. A key neurotransmitter implicated in Alzheimer’s Disease is acetylcholine. Following signal transmission, it is essential for neurotransmitters to be broken down to avoid prolonged stimulation of the receiving neuron. Enzymes, specifically cholinesterases in the case of acetylcholine, are responsible for breaking down these neurotransmitters. Under normal conditions, acetylcholine is produced in the correct amounts, and cholinesterase enzymes perform their function efficiently within the synapse.

Cognitive processes are also influenced by the brain’s gross and microscopic anatomy. Healthy neural tissues contain intricate networks of dendrites, while the overall brain structure remains intact without signs of atrophy. Moreover, the brain's naturally occurring spaces, called ventricles, maintain their normal size and do not show abnormal enlargement.

Disease Development and Causes

As people age, it’s common for brain functions related to memory and cognition to decline, with many individuals beginning to experience cognitive deficits in their later years, particularly in their seventies. Given the increasing number of elderly individuals, addressing the risk of widespread dementia is becoming crucial. For instance, projections show that in the United States, the elderly population (aged 65 and over) will rise from 1 in 9 in 2023 to 1 in 6 by 2050. This trend is important in the context of Alzheimer’s Disease because the likelihood of developing dementia doubles every five years after the age of 65. Recent data from 2023 suggest that around 6.7 million Americans are currently affected by Alzheimer's, with that number anticipated to increase to 7.7 million by 2030 and reach 14 million by 2050. Approximately 10.7% of Americans aged 65 and older are currently suffering from the disease, making it the most prevalent form of dementia, accounting for 60-80% of dementia cases in the U.S.

Alzheimer’s was first recognized in 1906 by Dr. Alois Alzheimer, a German neurologist who discovered it while examining a patient’s brain under a microscope. The patient had suffered progressive cognitive decline and memory loss in her final years. During his examination, Dr. Alzheimer noticed abnormal structures in her brain, such as twisted and knotted neurons, which he termed neurofibrillary tangles. Additionally, he found accumulations of cellular debris around neurons, which he labeled as senile plaques. These observations led him to theorize that these tangles and plaques were responsible for the patient’s mental decline, and his findings were later confirmed by other physicians, with the disease subsequently named after him.

Current research continues to affirm that these microscopic changes are associated with the development of Alzheimer’s:

• Neurofibrillary Tangles: These contain a mutated form of a protein called tau, along with glycosaminoglycans, which impair the normal function of nutrient tubules in neurons.
• Senile Plaques: Now referred to as neuritic plaques, these consist of a distinct protein known as beta-amyloid.
• Beta-Amyloid Protein: This protein is thought to contribute to Alzheimer’s by:
  • Generating harmful oxygen-free radicals that damage neurons and their membranes.
  • Narrowing blood vessels, depriving brain cells of oxygen.
  • Decreasing acetylcholine levels, which are crucial for nerve signal transmission.

Genetic factors appear to play a critical role in Alzheimer’s disease development. One focus of current research is the gene responsible for coding apolipoprotein ApoE4, a molecule involved in the repair and development of neural tissues. ApoE4 primarily functions by mobilizing cholesterol, aiding in cellular repair and growth, and possibly contributing to the accumulation of beta-amyloid protein. Each individual inherits one ApoE gene from each parent. Two other forms of the gene, ApoE2 and ApoE3, are not considered pathogenic. In fact, ApoE2 may have a protective effect, helping nutrient tubules maintain their integrity, much like how certain cholesterol types are categorized as “good” (HDL) or “bad” (LDL, VLDL).

ApoE4 becomes potentially harmful only when an individual inherits two copies—one from each parent. However, individuals with a single copy (combined with ApoE2 or ApoE3) do not seem to face a higher risk of developing Alzheimer’s. Even those with two ApoE4 copies are not necessarily destined to develop the disease.

Recent findings also suggest that defective mitochondrial genes may play a role in Alzheimer’s. In patients with Alzheimer’s, levels of cytochrome c (associated with the pathological depolarization of mitochondrial walls) have been found to increase by 300% in brain cells. This mitochondrial defect seems to contribute to excessive beta-amyloid plaque buildup, presenting new avenues for potential genetic treatments in the future and offering a diagnostic tool in the near term. Moreover, because this genetic malfunction leads to higher oxidative stress within cells, antioxidant therapies may prove effective against Alzheimer’s.

The research team led by Dr. Joel Rothman at the University of California, Santa Barbara, has made significant progress in understanding the genetic underpinnings of Alzheimer’s. They identified the gene ICD-1 (inhibitor of cell death gene 1), which may be involved in the premature and inappropriate degeneration of brain cells in Alzheimer’s patients. The team’s research, published in the August issue of Nature, has focused on the body’s ability to prevent cancer by triggering the self-destruction of potentially harmful cells. The hypothesis is that the ICD-1 gene malfunctions in Alzheimer’s patients, causing the premature death of healthy brain cells and leading to cognitive decline. With the ability to selectively turn genes on or off, Dr. Rothman’s team is now exploring the potential for genetic treatments targeting degenerative neurological conditions such as Alzheimer’s.

Another intriguing area of research involves the concept of Alzheimer’s as “Type 3 Diabetes,” based on the shared molecular and cellular traits with Type 1 and Type 2 diabetes. Studies have shown that insulin plays a key role in activating glycogen synthase kinase 3B, an enzyme that promotes the phosphorylation of tau protein, contributing to the formation of neurofibrillary tangles. Insulin is also thought to influence the formation of beta-amyloid plaques in the brain. This line of research suggests that diabetes treatments could also be beneficial in treating Alzheimer’s.

Signs, Symptoms, and Diagnosis

Alzheimer’s disease is tentatively diagnosed through clinical assessment based on observed signs and symptoms, utilizing standardized tools like the Mini-Mental and Blessed Neurologic Deficiency Tests. The diagnosis is made by evaluating the severity and progression of symptoms, ensuring no other systemic diseases or pathological conditions are responsible for the mental deficits. Common signs and symptoms include:

• Memory Loss: Patients often experience a loss of recent memories that affects daily living or job performance.
• Difficulty with Familiar Tasks: There is a noticeable decline in performing routine activities, such as tying shoelaces or buttoning clothes.
• No Disturbance of Consciousness: Alzheimer’s symptoms do not involve a loss of consciousness. If consciousness is impaired, a different diagnosis should be considered.
• Onset After Age 65: Although most cases begin after age 65, the onset can occur as early as 40 or as late as 90.
• Confusion with Location: Patients may become lost or disoriented even in familiar places, such as their own neighborhood or backyard.
• Confusion with Time: The inability to recall dates, appointments, or accurate time perception.
• Loss of Social Judgment: A lack of appropriate judgment in social settings, such as dressing inappropriately for the occasion or wearing dirty clothes without awareness.
• Misplacing Objects: Not just ordinary forgetfulness, but placing objects in inappropriate locations, such as a purse being placed in the freezer.
• Mood Swings: Sudden and extreme mood changes, such as switching between rage and calmness quickly and without clear cause. Emotional, verbal, and physical outbursts may occur.
• Loss of Language Skills: Patients may demonstrate inaccurate word use, confused speech, or a decline in overall communication ability.
• Insomnia: Difficulty sleeping, with irregular patterns, often staying awake throughout the night.
• Delusions: An inability to distinguish between reality and fantasy.
• Family History: A familial predisposition to Alzheimer’s can also be a contributing factor.
• Cerebral Atrophy: Ongoing imaging tests, such as CT scans, reveal progressive brain atrophy, including enlargement of the brain's ventricles over time.

As Alzheimer’s disease progresses, patients often experience emotional disorders, such as depression, which require appropriate psychiatric support. The evaluation of symptoms should be accompanied by clinical documentation, using recognized mental acuity tests, and subjective symptoms must be validated through specific neuropsychological assessments.

Life expectancy following diagnosis typically ranges from 5 to 10 years. In later stages, patients may become bedridden and are likely to pass away due to complications such as pneumonia, cardiac disease, or stroke. Historically, a definitive diagnosis could only be made through direct brain biopsy or autopsy. However, advancements in technology are providing potential avenues for earlier and more definitive diagnoses.

One such advancement involves the discovery that elevated levels of myoinositol, a compound found in the brain of Alzheimer’s patients, could serve as an early diagnostic marker. These increased myoinositol levels, detectable via magnetic resonance imaging (MRI), are associated with the inflammatory changes in the brain that accompany Alzheimer’s disease, although there is no evidence that myoinositol directly causes the pathology. Researchers have linked higher levels of myoinositol to an increased rate of brain cell death in Alzheimer’s patients.

Another diagnostic approach under development includes the intravenous injection of radiolabeled amyloid beta-peptide, which can be tracked using photon emission computed tomography (PET) scanning. These molecules bind to any amyloid plaques present in the brain. If successful, this technique would enable earlier diagnosis and monitoring of amyloid plaque accumulation, offering a less invasive alternative to biopsy or autopsy. While currently in the animal testing phase, human trials are planned.

Additional diagnostic methods show promise as well. For instance, P300 Latency testing, an electrophysiological test that measures memory impairment, is gaining recognition for its ability to detect early-stage Alzheimer’s. A study from the University of North Texas revealed that up to 65% of early Alzheimer’s cases could be missed using only standard clinical tests, while P300 Latency testing, which takes about 15 minutes, demonstrated high reliability.

Another breakthrough involves Pittsburgh Compound B (PIB), a chemical capable of crossing the blood-brain barrier and binding directly to amyloid plaques. Researchers at the University of Pittsburgh are preparing to test this method in human patients after successful trials in mice. As published in the Proceedings of the National Academy of Sciences, amyloid plaques start forming about a decade before symptoms appear, and detecting them early could significantly improve treatment outcomes.

Ongoing research has also noted the loss of olfactory sensitivity as a potential early indicator of Alzheimer’s. Over-the-counter home test kits for Alzheimer’s screening are now becoming available, offering the public a convenient way to monitor for early signs of the disease.

Risk Factors

Several potential risk factors have been identified in the onset of Alzheimer’s disease, all of which are the focus of extensive research. These factors, along with various physiological abnormalities, support the hypothesis that Alzheimer’s results from multiple mechanisms and causes. Key risk factors include:

• Age: The risk of developing Alzheimer’s increases with age. Approximately 32% of individuals over the age of 85 exhibit significant symptoms.
• Genetic Factors:
  • ApoE4 Gene: The presence of two copies of the ApoE4 gene is a significant risk factor. By age 85, the risk of developing Alzheimer’s is:
    • 50% to 90% with two copies of ApoE4.
    • 25% to 60% with one copy of ApoE4.
    • 9% to 20% with no copies of ApoE4.
  • Early-Onset Alzheimer’s: An aggressive form of the disease that occurs before age 65 is associated with specific genetic defects.
• Down Syndrome: Nearly all individuals with Down syndrome (Trisomy-21) who live past the age of 40 develop Alzheimer’s symptoms.
• Environmental Factors: Studies show that certain ethnic groups with lower rates of Alzheimer’s in their native countries have higher rates after emigrating to the U.S., indicating that environmental factors may contribute.
• Metal Exposure:
  • Aluminum: Initially suspected as a contributing factor, aluminum exposure has since been ruled out as a cause of Alzheimer’s. However, research suggests that the disease may promote the deposition of aluminum ions in neural cells.
  • Zinc: Elevated zinc levels have been linked to plaque formation in neural tissues, and Alzheimer’s patients often exhibit abnormal zinc metabolism.
• Immune Response: Research is investigating whether an inflammatory response by the body could trigger the disease, similar to autoimmune disorders where the body attacks its own cells.
• Gender: Women, particularly those with the ApoE4 gene and hormonal issues such as estrogen loss, may face a higher risk of developing Alzheimer’s.
• Head Trauma: Although no direct link between head trauma and the onset of Alzheimer’s has been established, studies suggest that multiple head injuries could increase the expression of symptoms in predisposed individuals. It is advisable for at-risk individuals to avoid activities that may lead to concussions.
• Cardiovascular Health: Recent studies suggest that poor cardiovascular health may raise the risk of Alzheimer’s. Proper management of conditions like hypertension, diabetes, and high cholesterol is crucial to maintaining vascular health, which may help reduce the risk.
• Diabetes: Emerging research shows common cellular mechanisms in the progression of both diabetes and Alzheimer’s, indicating that diabetes may be a significant risk factor for Alzheimer’s disease.

Treatment

The Treatment Protocols for Alzheimer's focus primarily on symptom management, as no current treatment can cure or prevent the disease. However, several therapeutic approaches aim to slow the progression and improve quality of life. Here are key treatment categories and their respective methods:

1. Supportive Care

• Many Alzheimer’s patients can be cared for at home with close supervision, but due to the elderly nature of caregivers (often spouses), long-term nursing care may become necessary.
• Caregivers often face challenges when patients exhibit severe mood swings or violent behavior.

2. FDA-Approved Drug Therapies

• As of 2023, six drugs have received FDA approval, with Leqembi (approved January 2023) and donanemab being the latest innovations under accelerated approval programs.
• These treatments only manage symptoms or slow the progression but cannot halt or reverse the disease.

Cholinesterase Inhibitors

• Mechanism: These drugs work by inhibiting the breakdown of acetylcholine, a neurotransmitter, thereby increasing its availability in the brain.
• Common Drugs:
  • Cognex (tacrine): Effective in 30% of patients but has serious side effects like liver damage and requires frequent liver enzyme monitoring.
  • Aricept (donepezil): More brain-specific and has fewer side effects compared to Cognex. It’s taken once daily and doesn’t affect liver function.
  • Exelon (rivastigmine tartrate): Associated with weight loss in some patients due to gastrointestinal side effects like nausea and diarrhea.
  • Reminyl (galantamine HBr): The newest acetylcholinesterase inhibitor approved for treatment.

Namenda (Memantine)

• Approved for late-stage Alzheimer’s, Namenda works by blocking excess glutamate, which can damage neurons.
• Though not a "breakthrough" drug, it shows promise in slowing physical and mental deterioration, especially in combination with Aricept.

Leqembi (lecanemab-irmb)

• A monoclonal antibody that targets beta-amyloid plaques, reducing their presence in the brain.
• Administered intravenously, it is indicated for early-stage Alzheimer’s. Common side effects include headaches, cough, and diarrhea, with the risk of intracerebral hemorrhage in patients on anticoagulants.
• Currently not covered by Medicare pending full FDA approval.

Donanemab

• A drug that reduces beta-amyloid plaque burden and shows promising results in clinical trials, with many patients showing no cognitive decline after one year of treatment. Full FDA approval is expected by mid-2023.

3. Adjunctive Treatments

• Estrogen Therapy: Post-menopausal women on estrogen supplements show a lower incidence of Alzheimer’s, though it increases the risk of breast cancer.
• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Long-term NSAID users for arthritis have lower rates of Alzheimer’s development, though aspirin did not show a significant effect.
• Antioxidants: Nutrients like vitamins A, C, E, and selenium may reduce oxidative stress, with studies linking diets high in antioxidants to reduced Alzheimer’s risk.
• Fish Consumption: Studies suggest omega-3 fatty acids in fish can reduce Alzheimer’s risk by 60%. Research continues on the association between diet and disease prevention.
• Ginko Biloba: Certain extracts, specifically EGb 761, show cognitive improvements in Alzheimer’s patients within 26 weeks of treatment.

4. Experimental Treatments

• Antipsychotic Drugs: Used to manage aggressive behaviors, allowing patients to remain home longer.
• NS-2330: An experimental drug in development, targeting mood swings, anxiety, and apathy by increasing serotonin and norepinephrine levels.
• Alzheimer’s Vaccine: A vaccine in early development stages aims to slow or reverse disease progression by targeting amyloid proteins.

5. Lifestyle and Additional Considerations

• Physical and Mental Activities: Continuing physical and cognitive activities can help maintain patients’ health and quality of life.
• Diabetes Treatment: Since diabetes and Alzheimer's share cellular disease progression pathways, managing diabetes may slow Alzheimer's progression.

Dental Considerations in Alzheimer’s Disease
When treating patients with Alzheimer’s disease, dental professionals encounter a range of challenges related to oral hygiene, pathology, access to care, and informed consent. The key difficulties in maintaining oral health for these patients include:

• Oral Hygiene: A hallmark of Alzheimer’s in dental patients is the rapid decline in oral hygiene. Patients may forget to brush their teeth or become unable to perform these tasks. Caregivers often struggle to provide adequate oral care, especially in institutional settings, where hygiene is frequently neglected. Electric toothbrushes can be a helpful tool in the early stages of Alzheimer’s.
• Patient Communication and Understanding: As Alzheimer’s progresses, clear communication with the patient becomes increasingly difficult. Patients may not fully understand or retain information about their treatment. It is essential to include a responsible family member or caregiver in discussions, frequently consult with them about the patient's status, and document these interactions. Alzheimer’s patients require repeated instructions and should be spoken to slowly, distinctly, and with simple language. Scheduling these patients when the office is less busy and allowing extra time for appointments is recommended.
• Informed Consent: Determining whether an Alzheimer’s patient is competent to understand treatment options and make decisions can be challenging. Caregivers need to have documented legal authority, such as power of attorney, to make decisions on the patient’s behalf. Careful documentation of discussions about treatment options, including potential failure rates due to the patient's condition, is crucial.
• Patient Compliance: Compliance with oral hygiene and care instructions is a significant issue. The patient’s inability to follow through with treatment plans should be considered when planning dental care, as failure rates are typically high in this population.
• Periodontal Deterioration: Periodontal disease is common due to age and poor hygiene, with institutionalized patients at greater risk.
• Root Caries: Cervical root surfaces are particularly vulnerable, often deteriorating rapidly despite restorative efforts. New remineralization technologies may help, but patient compliance remains a challenge.
  • Silver Diamine Fluoride (SDF): SDF can be applied to prevent caries, though informed consent is essential due to its cosmetic side effects (blackened teeth). If the patient is unaware of their appearance or indifferent, caregivers with legal authority may choose this option to avoid more extensive dental work.
• General Restorative Issues: Recurrent caries and periodontal disease often compromise restorative treatments. The prognosis of dental work is typically poor as the disease progresses. In some cases, extraction of unstable teeth may be necessary, but consideration must be given to the patient’s ability to wear removable appliances.
• Access to Care: As mobility declines, it becomes increasingly difficult for patients to visit the dental office. Even though dental treatment becomes more necessary, the patient’s cooperation diminishes, often making sedation necessary. In institutional settings, dental care is rarely provided, leading to rapid oral health deterioration.

Treating Alzheimer’s patients places dental professionals in a challenging position. The definition of “ideal” care evolves as the patient’s ability to tolerate treatments diminishes, often leaving them with compromised oral health and limited treatment options.

Quiz For Alzheimer's Disease