Alzheimer’s disease – questions without answers?
Dr. Giedrė Krištopaitytė, Republican Panevėžys Hospital
Introduction
Alzheimer's Disease (AD) has been known to the medical community for almost 100 years, yet the disease's pathogenesis is not fully understood, various criteria and questionnaires are used for its diagnosis, and most importantly - an effective treatment has not been discovered. Researchers are aware of about 400 active substances, but the results are discouraging. Such a wide spectrum of clinical research demonstrates the relevance of this disease, as AD is the main cause of dementia syndrome and its prevalence is increasing as the population ages.
This article discusses the etiology and pathogenesis of AD, clinical aspects are briefly reviewed, and diagnostic and treatment possibilities are outlined.
AD - the most common cause of dementia
Researchers estimate that about 35.6 million people worldwide suffer from Alzheimer's Disease (AD), with around 6 million in the European Union (1). Aging significantly impacts its prevalence. The incidence among those aged 65 to 85 increases from 1% to 7% annually, and the prevalence grows from 3% to 50% (2). Both men and women are equally affected by AD. The disease usually begins after age 65. Those who develop it earlier have early-onset AD.
In the pathogenesis of AD, the abnormal β-amyloid protein plays a key role. The body cannot break down and remove this protein from brain tissue, leading to its accumulation. These accumulations form senile plaques and act as neurotoxins, causing neuronal death. Specific gene mutations are found in early cases of AD. These mutations produce abnormal β-amyloid protein or deficiencies in its breakdown. Senile plaques and neurofibrillary tangles, composed of pathologically phosphorylated tau protein, are the main histopathological findings in AD.
Non-genetic risk factors for AD include poor social and economic conditions, low education, female gender, head trauma, and a family history of Down syndrome. Previously, researchers believed smokers were less likely to develop this dementia type. Recent research has either not confirmed this hypothesis (3) or shown that smoking increases the risk (4).
Key Figures and Pathogenesis of Alzheimer's Disease
Researchers estimate that approximately 35.6 million people worldwide suffer from Alzheimer's Disease (AD), and about 6 million in the European Union (1). Aging profoundly impacts the prevalence of AD. For instance, the incidence of new cases among individuals aged 65 to 85 years old increases from 1% to 7% per year, and prevalence rises from 3% to 50% (2). Both men and women are equally susceptible to AD, and the disease usually manifests after age 65. People who develop AD earlier are considered to have early-onset AD.
Role of Genetics and Non-genetic Risk Factors in AD
The abnormal β-amyloid protein plays a central role in the pathogenesis of AD. This protein accumulates in the brain because it cannot be broken down or removed. These accumulations form senile plaques and act as neurotoxins, causing neuronal death. Researchers have identified specific gene mutations in early AD cases. These mutations cause the production of abnormal β-amyloid protein or deficiencies in its breakdown. Senile plaques and neurofibrillary tangles, composed of pathologically phosphorylated tau protein, are the primary histopathological features of AD.
Non-genetic risk factors for AD include poor social and economic conditions, low education, female gender, head trauma, and a family history of Down syndrome. Previously, researchers suggested that smokers might have a lower risk of developing AD. However, recent studies have not confirmed this hypothesis (3) and some have even shown that smoking increases the risk (4).
Table 1. Diagnostic criteria for AD dementia according to the guidelines of the National Institute on Aging and the Alzheimer's Association (2011)
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Face of AD
Most commonly, AD starts with mild, hardly noticeable, but gradually progressing memory impairment. Paradoxically, the patients themselves do not complain of forgetfulness, and often it is family members or friends who first notice it. Gradually, other symptoms are added to the worsening memory - behavioral disorders, delusions, and hallucinations, affective disorders, less frequently - extrapyramidal pathology, seizures, and myoclonus. Nevertheless, the most important place in the clinical picture is occupied by memory problems. The ability to perceive new information is impaired first (short-term memory and learning are affected). Previously acquired information is easier to remember. Along with the deterioration of short-term memory, disorientation in time and space develops. In later stages of the disease, the recall of previously acquired information is also impaired, meaning that the patient forgets the names of relatives, no longer recognizes them, and in the final stages forgets basic life skills and does not recognize themselves in the mirror (2).
Currently, it is believed that there are 3 main stages of AD, defined according to the criteria of the National Institute of Aging of the United States, which were revised in 2011, updating the 1984 AD diagnostic criteria (5). These are the preclinical stage, mild cognitive impairment due to AD, and dementia due to AD.
The preclinical stage refers to changes in the brain that are consistent with an AD diagnosis, meaning that in such individuals undergoing positron emission tomography (PET) scans or cerebrospinal fluid analysis for biomarkers (β-amyloid, tau protein), changes are found that may lead to the development of AD. These individuals do not have clinical A symptoms, and this categorical definition is only applied in biomedical research.
Diagnosing mild cognitive impairment due to AD, certain memory problems are already observed - patients or their relatives report increased forgetfulness, speech disturbances, but these complaints do not yet disrupt daily functioning. The symptoms of this stage can be initial clinical signs of any dementia, so comprehensive cognitive function testing, neurovisual, and laboratory tests are often performed to specify the pathology causing dementia.
As the disease progresses - in the stage of dementia due to AD - there is already a marked cognitive impairment, disrupted daily activities, and emerging changes in character. Additional tests in this stage are useful to determine the severity of dementia and to differentiate between AL and other causes of dementia.
Diagnostic Methodology for Alzheimer's Disease
In clinical practice, patients frequently complain of memory deficits in the latter stages of Alzheimer's disease (AD). Consequently, I will present the diagnostic methodology for these two stages.
Biomarker testing remains primarily accessible to the scientific community, and its reliability is still under investigation. Therefore, clinicians diagnose Alzheimer's disease based on clinical evaluations. A detailed medical history from both the patient and cohabiting relatives is crucial. Clinicians should inquire about memory problems, daily activities, changes in character, interests and initiative, and the emotional sphere. They should exclude somatic, endocrine, and psychiatric pathology that might influence dementia syndrome development. Recommended tests include general blood tests with erythrocyte sedimentation rate, kidney and liver function indicators, thyroid-stimulating hormone and free thyroxine (FT4) tests, brain imaging (computerized or magnetic resonance imaging), and assessments by a neurologist and psychiatrist (9).
Assessing Dementia Depth
Traditionally, clinicians assess dementia depth using the Mini Mental State Examination (MMSE). This test is convenient as a screening tool for family doctors when patients complain of memory problems. For quicker assessment, clinicians can use the Clock Drawing Test where the patient is asked to draw a clock, mark the hours, and set the hands to a specific time (e.g., 10:15). The maximum score is 3: 1 for the clock face, 2 for correctly indicated hours, and 3 for the correctly marked time. More complex scales, such as the Alzheimer's Disease Assessment Scale (ADAS) and the Addenbrooke's Cognitive Examination, allow for a detailed assessment of cognitive impairments such as language, attention, and short-term memory. However, due to their extensive and time-consuming nature, these scales are less commonly used in daily practice. When communicating with relatives, clinicians should complete the Blessed Dementia Scale questionnaire, which assesses the patient's daily functioning. All mentioned scales are validated in Lithuania and available online (6, 7).
Formulating the Diagnosis
Typically, the diagnosis is formulated by identifying the degree of cognitive impairment in Alzheimer's disease: mild (MMSE score 20-24 points), moderate (MMSE score 11-19 points), or severe (MMSE score 0-10 points). These categories partly correspond to the criteria of the National Institute on Aging of the United States. Mild cognitive impairment corresponds to the first group, while the dementia category includes moderate and severe cognitive impairment groups. According to these criteria, the AD-related dementia group is further divided into possible, probable, and definite AD-related dementia groups. This approach aligns with the diagnostic and treatment methodology for AD valid in Lithuania (8, 9) (Table 1).
AL Treatment Options
Medications for AD treatment have been used for just over a decade, but research on neurotransmitter perception and interactions in the brain in AD patients started much earlier. Experts currently believe that acetylcholine deficiency plays a key role in the disease's pathogenesis. Therefore, cholinergic transmission activators, specifically cholinesterase inhibitors (donepezil, rivastigmine, and galantamine), are the most widely used drugs. These drugs compensate for the acetylcholine deficit by inhibiting its breakdown by cholinesterases, but they do not halt the degeneration of cholinergic neurons. These drugs treat mild to moderate dementia in AD patients.
Researchers recently discovered that these drugs are effective in treating severe-stage AD dementia, leading to the development of a new donepezil dose of 23 mg. Typically, doctors start with a donepezil hydrochloride dose of 5 mg once a day in the evening and increase it to 10 mg after a month. Studies show that donepezil improves cognitive functions in cases of AD, vascular dementia, and dementia associated with Parkinson's disease. Donepezil does not require titration in patients with impaired kidney or liver function. Studies confirmed that donepezil treatment improves ADAS and MMSE scores and caregiver assessments, but it does not delay admission to care facilities or improve patients' subjective quality of life. Common side effects include nausea, vomiting, dizziness, and diarrhea, with rare occurrences of bradycardia and syncope. Administer the drug cautiously to patients with sinus node weakness and other supraventricular conduction disorders.
Cholinesterase Inhibitors and Their Impact
The other two cholinesterase inhibitors, not registered in Lithuania, have effectiveness and adverse effect profiles similar to donepezil. Rivastigmine offers a greater variety of therapeutic forms, including a patch form that slowly releases the active substance.
NMDA Receptor-Targeting Drugs in AD Treatment
Another group of drugs for AD treatment targets glutamatergic NMDA receptors. Memantine is the primary drug in this category. It impacts memory formation mechanisms by acting on glutamatergic and nicotinic receptors in the cortex and hippocampus. Researchers believe it has a neuroprotective effect. Studies indicate that memantine effectively treats moderate to severe dementia in AD patients. The initial dose is 5 mg, increased by 5 mg per day every week until reaching 10 mg twice a day. This drug causes fewer adverse effects than anticholinergic drugs, with dizziness, confusion, and hallucinations being the most common. Unlike donepezil, assess kidney and liver function when prescribing memantine (2).
Alternative Treatments and Emerging Therapeutic Methods
Public and healthcare professionals often question the appropriateness of using neuroprotective and nootropic drugs for treating dementia. In Europe, ginkgo (Ginkgo biloba) extract is prescribed for dementia treatment, with clinical trials showing its symptomatic effectiveness in improving daily functioning in AD patients (10). The therapeutic dose is 40-80 mg three times a day or 120 mg twice a day, much higher than most widely available supplements. Vitamin E, selegiline, nonsteroidal anti-inflammatory drugs, and estrogens also have neuroprotective effects, although achieving a positive effect requires relatively high doses, leading to common adverse effects.
New research data on the pathogenesis of AD has spurred efforts to find new treatment methods, including immunotherapy aimed at reducing β-amyloid accumulation in the brain. Methods include direct immunization with synthetic β-amyloid, β-amyloid fragments conjugated with a carrier protein, or monoclonal antibodies. While initially promising, these methods face an unresolved problem: reducing β-amyloid in the brain does not significantly improve cognitive functions (11).
Managing Neuropsychiatric Complications in Dementia
When dementia syndrome accompanies neuropsychiatric complications—such as psychosis, delusions, hallucinations, depression, anxiety, or psychomotor agitation—doctors use psychotropic drugs to treat these symptoms. New-generation antipsychotics like risperidone, olanzapine, and quetiapine effectively treat psychosis. Traditional older neuroleptics may induce parkinsonism. Doctors may prescribe tiapride for increased psychomotor activity, while they should use benzodiazepines cautiously due to the risk of confusion, impaired consciousness, and delirium. For treating depression, doctors choose selective serotonin reuptake inhibitors (sertraline, citalopram, escitalopram, paroxetine) as the first choice while avoiding tricyclic antidepressants due to their anticholinergic side effects (2).
Summary
Alzheimer's Disease (AD) is the main cause of dementia syndrome. Healthcare professionals and the general public must prioritize recognizing, diagnosing, treating, and supporting patients, and caring for their family members. In 2011, AD diagnostic criteria were updated to include AD biomarkers. However, the disease's clinical expression continues to play an essential role.
Alzheimer's disease treatment includes cholinesterase inhibitors, NMDA receptor-targeting drugs, and certain nootropics. These treatments aim to prolong the patient's independence, improve their and their caregivers' quality of life. Despite these treatments, the lack of etiopathogenic options for AD continues to push researchers to explore new treatment possibilities for the disease.
Internist No.10
