Over the past three decades, the diagnostic work-up for Alzheimer’s disease has made significant advances discussed in this article.  We have learned about the pathology and the potential causes of the disease. AD is a chronic and progressive brain disease that starts 20 years before the symptoms are present. The initial symptoms include short term cognitive problems such as misplacing personal items, forgetting recent conversations and repeating. In addition, there are language deficiencies such as word-finding difficulty and naming familiar objects. Although these are the initial symptoms, the disease eventually progresses to affect other areas of cognitive domains such as driving, direction, handling finances, making decisions and impaired judgment. Over the past thirty years, we have been working on diagnostic modalities to detect and intervene before the damage is too advanced to be able to appropriately treat the condition.

The initial work-up includes an accurate and detailed history, physical and neurological evaluation. This is followed by cognitive testing, imaging studies and the initial laboratory work-up to rule out the reversible causes of dementia such as vitamin B12, Folic acid, vitamin D deficiency along with thyroid function test and rare infectious etiologies such as tertiary syphilis. The MRI can rule out strokes that can cause vascular dementia. Now we know the pathological changes in the brain such as Amyloid and Tau proteins that have been implicated as the initial insult that starts the cascade of producing Amyloid plaques and neurofibrillary tangles. The hallmark of the disease.  The ways to detect these changes have been through Amyloid PET scans or spinal fluid analysis.

The initial symptomatic drugs such as Donepezil, Rivastigmine, Galantamine and Memantine provide short lived benefit and do not change the course of the disease. Scientists have been working on disease modifying drugs that can slow the progression of the disease. In 2021, FDA gave conditional approval to Aducanumab, the first monoclonal anti-amyloid antibody for the treatment of earliest stages of Alzheimer’s disease, including Mild Cognitive Impairment (MCI) and mild stage Alzheimer’s disease.  In many cases MCI is the Pre-Alzheimer’s stage.  Once diagnosed with MCI, there is a risk of developing AD withing five years.  Lecanemab and Donanemab were approved by FDA in 2023 and 2024 respectively and are now available to patients through certain IV centers throughout the country.

Given the cost and availability of Amyloid PET and the discomfort and the patient fear factor associated with spinal taps, scientists have developed blood-biomarkers to detect these pathological changes years before the symptoms appear. This method is widely available and more practical from the financial aspect. This has been a breakthrough in the diagnostic modality of identifying the at-risk population. These are Amyloid Ratio and Phosphorylated Tau that indirectly measure the amount of these proteins in the brain. Although the exact mode of inheritance for AD is not known, we do know that AD runs in families and now a susceptibility gene APOE4 can be determined by examining the saliva to determine the risk. This is not a marker but simply assessing the risk since APOE either heterozygous 2 E4E4 or homozygous one E4 are associated with higher risk of developing Alzheimer’s disease.

The fact that AD can be diagnosed several years before the symptom presentation, the scientists are looking at prevention trials This will enable us to identify the at-risk populations and start the treatments before the point of no return.  Although the current disease-modifying drugs do not halt or reverse the process, we are now able to intervene and significantly slow the progression of the disease. We encourage early work-up and intervention to provide a better quality of life for patients and help families to manage the disease.

M. Reza Bolouri, MD, Board Certified Neurologist                                                                                                              Alzheimer’s Memory Center

Once the work up is completed and the diagnosis is given, the tough job is not only dealing with the diagnosis, but also handling the day to day challenges they confront from that point forward. It is already hard enough to see your loved one begin to lose the ability to perform their usual activities but also become someone who acts and behaves differently. They may exhibit behaviors that sometimes are uncharacteristic. This can be present in their eating, sleeping and social activities.

Initially, patients with Alzheimer’s disease are able to drive locally, pay some bills and perform their activities such as cooking, cleaning and taking care of their hygiene. They may repeat themselves and have difficulty finding the right words in the conversation, but eventually they will lose the ability to perform some or all of these activities. It is up to the family to recognize this very slow loss of the abilities and intervene when appropriate.

The caregiver’s burden begins when their love one starts getting lost while driving, forgets to pay bills or leaves the stove on after finishing the cooking. This becomes more difficult when the patient is unaware and unwilling to follow instruction and listen to the family’s advice.
When someone in the family suffers from Alzheimer’s disease, the safety and well-being of the patient is extremely important. When the behavioral manifestation of the disease starts to surface as the disease progresses, the caregiver faces new challenges. These can be refusal to eat, restless nocturnal activities such as walking around the house, waking everyone up, getting agitated, aggressive and paranoid behaviors. There might come a time when the patient does not recognize his/her house or even the family members.

In order to better manage this traumatic challenge of a lifetime, it is important to educate the family and support them by empowering them and showing them the best way to deal with the day to day challenges. I recommend family and professional help, support groups and working closely with your healthcare provider for the best results. It is important for the caregiver to be realistic about their abilities and get help when needed. The Alzheimer’s Memory Center has a support group to discuss these challenges and shares experiences to better care for our patients and caregivers. The group is held the third Friday of each month at our facility located at 7809 Sardis Road at 10am.

Professionals who are typically involved in AD care include, but are not limited to: physicians, physician’s assistants, nurse practitioners, social workers, geriatric care managers, and care givers. Given the complexity of the disease, it is crucial for each member of the care team to have a clear understanding of the nature of the disease, progression, fluctuation and overall management.

In the beginning or mild stage of AD, patients are initially not aware of occasional forgetfulness, and this can go unnoticed by patients, family members and even healthcare providers. However, patients with more information on early detection are able to get help when it is most effective. Some patients go through a period of denial and blame their failing memory on aging or stress factors.

More than just the memory is affected in AD; other cognitive functions such as speech, word finding, judgment and problem solving are also affected. Typically, the primary caregiver will begin the search for help when it’s apparent that there is significant cognitive decline.

We live in a culture that views forgetfulness as a normal part of aging. Some physicians might miss the early warning signs. Others may feel that since AD it is an incurable disease, treatment is futile. As physicians, we need to build an alliance with patients and their caregivers in order to address relevant issues. These include medication management as well as addressing behavioral issues such as sleep disturbance, eating difficulties, weight loss, agitation, paranoid delusions, hallucinations and inter-current illnesses (i.e. urinary tract infections and pneumonia).

Although, the medications currently approved for the treatment of AD have only modest effect, research has shown that these drugs do in fact help improve the overall quality of life for patients.

There are demonstrated improvements in behavior, personality and cooperativeness when these medications are initiated. Evidence also proves that the earlier the treatment is initiated, the more robust the benefits.

Primary care physicians and geriatricians see approximately 85% of the patients with AD. Neurologists and psychiatrists see the remaining 15%. As the first line of caregiving defense, primary care physicians and personal caregivers should learn and utilize all available resources and research to help provide a comprehensive care plan that allows for the best quality of life for both the person with AD and their caregiver.

M. Reza Bolouri, MD
Alzheimer’s Memory Center

Since 1994 we have had a total of six medicines that have been approved by the Food and Drug Administration for use in Alzheimer’s disease. These include, Tacrine (Cognex), Donepezil (Aricept), Rivastigmine (Exelon capsule and patch forms), and Galantamine (Razadyne), collectively a class of cholinesterase inhibitors, Memantine (Namenda), an NMDA receptor antagonist and Axona, a medical food.  Unfortunately, these drugs are only beneficial for symptom improvement and do not offer a lasting benefit nor do they modify the course of the disease.  The reason behind developing cholinesterase inhibitors was the discovery of acetylcholine deficiency due to the effect of the disease in cholinergic system. Multiple cholinomimetic drugs were tested but were not successful because acetylcholine-like substances would not survive the stomach acidity, and hence would not get to their destination, the brain.  Further research finally determined that the cholinesterase inhibitor, an indirect way of delivery of these compounds, proved to be the most effective way to enhance cholinergic stimulation.

There have been hundreds of drugs tested since then, including multiple calcium channel blockers, serotonin antagonists and neurotrophic factors, but unfortunately none have been approved for one reason or another such as safety concerns or lack of efficacy.  We are still not certain about the mechanism or mechanisms that lead to the neuronal damage leading to the Alzheimer’s disease development. This is because the pathological findings seen in patients with Alzheimer’s disease brain is also seen in some individuals who do not develop Alzheimer’s disease. Many theories exist such as amyloid hypothesis, inflammation, tau hypothesis and multiple other possible ways the disease is developed.  So far amyloid and tau proteins as possible initiating factors have gained more legitimacy. This combined with the development of APOE genes as well as markers of inflammation and the advancements in brain Amyloid PET imaging, and spinal fluid analysis have improved our ability to identify the susceptible individuals. This will allow us to develop drugs that will target this population so we can develop more effective treatments through controlled clinical trials.  We are searching for disease modifiers, drugs that stop or slow the progression of the disease.

Despite recent disappointments with some anti-amyloid antibodies and multiple beta amyloid secretase (BASE) inhibitors, there are several promising drugs that are currently under investigation as disease modifiers that seem to be safe and well tolerated. Currently, there are several anti-amyloid antibodies, anti-tau antibodies, anti-inflammatory agents, antibiotics, anti-cancer drugs and receptor modulators that are in various stages of development. The effectiveness and safety of these drugs can only be observed through carefully crafted and controlled clinical trials.

In addition to experimental drug trials, our understanding of non-medical approaches has significantly improved. We now know that reducing certain unhealthy diets such as various forms of carbohydrates, alcohol, carbonated beverages, high fat content foods, such as fried meals have significant beneficial effects. Careful monitoring and treatment of heart disease, hypertension, dyslipidemia and diabetes during routine physical check-ups is generally a good practice to prevent potential cardiovascular diseases.  We have also learned about the benefits of mental and physical and mental stimulating activities such as regular physical exercise and mental activities such as cross word puzzles, word search, Sudoku and playing cards.

As our understanding of the cause (s) of Alzheimer’s disease improves, we will be able to discover more markers such as blood tests and other modalities to better understand this disease and subsequently find more effective treatments. I believe that the ideal treatment for Alzheimer’s disease may be a combination or a cocktail of drugs with different mechanisms of action to address the multitude of insults to the brain that lead to the development of the disease. My advice to everyone affected by this disease is to keep an open mind about research and give themselves or their loved ones a chance to explore research options. This will allow the scientific community to develop more effective treatments. The Alzheimer’s Association and Clinicaltrials.gov are excellent sources for information to learn about the research programs and the closest research center near you.

M. Reza Bolouri, MD

Alzheimer’s Memory Center

Charlotte, North Carolina