The latest diagnostic work-up for Alzheimer’s disease.
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
