What is Alzheimer’s?
Alzheimer’s is a type of neurodegenerative disease that mainly affects people over 65. It’s the most common form of dementia, which is an umbrella term for loss of cognitive functioning to the extent that it interferes with daily activities, comprising numerous types such as Alzheimer’s (most common type) Lewy body, Vascular, Frontotemporal, Mixed dementia along with Alzheimer’s.
Alzheimer's accounts for 60-80%, or 2/3 of dementia cases, and is considered the 7th leading cause of death worldwide in 2019 according to WHO. Considering there are 55 million people with dementia worldwide, Alzheimer’s effect is tremendous. Furthermore, by 2050, the number of people having Alzheimer’s is estimated to reach 12.7 million in the US alone, and 153 million globally, suggesting the growing trend that the disease follows.
While the disease affects lots of people across the world, namely nearly 7 million people just in the US, low and middle-income countries are being severely impacted with the Middle East, Africa, and Latin America taking the lead.
The brain disorder is named after German physician Dr. Alois Alzheimer who realized changes in the brain tissue of a patient with symptoms including memory loss, language issues, and unpredictable behavior who died of a mental illness. When Alzheimer's examined the brain through autopsy, he encountered strange clumps and tangled bundles of fibers, which are regarded as the main causes of the disease.
As Dr. Alzheimer observed, Alzheimer’s is caused by abnormal build-up of beta-amyloid and proteins inside and around the brain cells. When amyloid beta protein deposits come together, they form plaques around the brain cells, whereas excessive tau residues create neurofibrillary tangles within the brain cells. Plaques and tangles block communication between neurons and disrupt transport flow, preventing nutrients from reaching a neuron, and ultimately leading neurons to stop functioning, degenerate, and die. This also led to a decrease in neurotransmitters, and as neurons die, other healthy neurons get affected and damage spreads rapidly. Eventually, the brain shrinks significantly and can no longer perform most of its functions. Initial damage usually occurs in the hippocampus and entorhinal cortex, located in the medial temporal lobe, which forms and controls memories. Therefore, in the early stages, one of the most prominent signs of the disease is forgetting recently learned information which turns into total memory loss in the severe phases.
The protein build-up initiates many years, in some cases a decade, before the first symptoms emerge, making it more challenging to early diagnosis. However, the exact cause of the build-up still remains a mystery.
Alzheimer’s is characterized by memory loss, difficulties in language and communication, personality change, poor decision-making, judgment, and organization, decline in thinking, reasoning, and math skills, and disorientation and confusion about time and place. Despite the very initial symptoms being limited to minor memory problems, in the final phase, the person needs extensive care with all basic everyday activities such as bathing and eating since they experience difficulty swallowing, speech has already become limited to a few words, hindering communication skills, in addition to complete memory loss.
One of the most prominent risk factors is age. While Alzheimer’s is definitely not a normal part of the aging process, the likelihood of developing Alzheimer's disease doubles every 5 years after 65. 1/3 of those over 85 have Alzheimer’s. Although it is not common, people may develop Alzheimer’s before 65, which is called “early-onset”, or “young-onset”.
Sex is also another important risk factor, suggesting women are 2 times more likely to have Alzheimer’s than men after age 65. Other risk factors include Down syndrome, health conditions especially cardiovascular diseases, traumatic brain injury, low education status, and lifestyle factors including smoking, excessive alcohol consumption, unhealthy diet, lack of exercise, and poor sleep cycles.
Alzheimer’s does not have a cure, but medications are available. Cholinesterase inhibitors inhibit the breakdown of acetylcholine, a neurotransmitter involved in memory, language, and judgment so that more chemical messengers become available to healthy nerve cells, increasing cell-to-cell communication and improving symptoms. Donepezil (Aricept, Adlarity), galantamine (Razadyne), and rivastigmine transdermal patch (Exelon) are commonly used and among Cholinesterase inhibitors. Menantine (Nemanda) is another medicine that regulates and limits glutamate-cell interaction, since glutamate, another neurotransmitter that takes part in learning and memory, levels are high in Alzheimer’s leading to irregular activity and damage in nerve cells. Therefore, Memantine protects neurons while slowing down the decline in memory and thinking. Antiamyloid treatment or amyloid targeting approaches aim to slow down the decline in memory, reasoning, and other thinking skills by delaying the buildup of amyloid plaques by targeting beta amyloids. However, this approach is mostly preferred in the early stages. Antiamyloid treatment contains Aducanumab (Aduhelm), Lecanemab (Leqembi), and Donanemab (Kisunla) drugs.
Factors that reduce cardiovascular disease risk are linked to factors lowering Alzheimer’s risk that covers a healthy diet, no smoking, cutting down alcohol consumption, and doing regular physical and brain exercises. In short, the key preventive measure is staying mentally, physically, and socially active to keep neurons fresh and vigorous.
To diagnose Alzheimer’s, doctors first take a medical history, followed by some physical and neurological examination to assess overall health. Mentally ability tests, also known as cognitive, functional, and behavioral tests are usually performed to assess the overall cognitive abilities of the patient. After, doctors usually want blood or urine tests which help them exclude other causes of symptoms such as thyroid problems, or vitamin deficiencies. Furthermore, cerebrospinal fluid tests also referred to as lumbar puncture, can be taken to measure the levels of amyloid and tau proteins, especially when the patient’s symptoms accelerate worsening. However, the main diagnosis strategies are brain scans including MRI, CT, and PET that identify other causes, such as brain tumors, and strokes, distinguish between different types of dementia, and demonstrate the degree of degeneration (loss of brain cells). CT (computerized tomography) scan which utilizes X-rays to obtain cross-sectional images of the brain cannot provide details regarding the structure of the brain, thus it checks for indications of brain tumor, stroke, or head injuries, rather than directly diagnosing dementia or its types. On the other hand, MRI (magnetic resonance imaging) creates a detailed view of the brain through radio waves and magnetic fields. Thus, MRI is able to determine the type of dementia since it reveals the shrinkage of brain regions in detail. PET (positron emission tomography) scan employs a low-level radioactive tracer injected into the blood, showing abnormalities in the blood flow in the brain. The most commonly used type of PET is a fluorodeoxyglucose (FDG) PET scan that identifies the brain regions with decreased glucose metabolism. Hence, uncovering patterns in the areas of low metabolism can distinguish between different types of dementia. Other PET scans including amyloid PET imaging and tau PET imaging are mainly employed in research settings, measuring deposits of amyloid and tau proteins directly.
Still, Alzheimer’s is hard to diagnose, often being misdiagnosed by 20% to 30% since various conditions including vascular dementia, depression, thyroid disease, sleep apnea, and even vitamin B12 deficiency can mimic the symptoms of Alzheimer’s as Dr. Oskar Hansson, a professor and senior consultant of neurology at Lund University states.
However, considering before the 2000s, the only way to diagnose Alzheimer’s was through autopsy, medicine has come a long way since then. The problem is both brain scans and spinal taps are expensive, invasive, and uncomfortable, making them harder to access. So, for now, identifying the signs of the disease requires a painful spinal tap or a costly PET scan.
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The Newly-Developed Blood Test for Diagnosis
Blood tests are crucially important in such a way that they further lower barriers to diagnosis.
A new study published recently in JAMA discovered that a blood test diagnoses Alzheimer’s with 90% accuracy. The study had 1213 participants from Sweden with 74 average age and tested their blood for p-tau217 and beta-amyloid 40/42. The results of the study were presented at the Alzheimer’s Association International Conference in Philadelphia took place between July 28 and August 1, 2024.
The blood test accurately diagnosed Alzheimer’s around 90% of the time, a rate much higher than neurologists and specialists who have 73% accuracy, followed by primary care doctors with only 61% only using cognitive ability tests and CT scans as diagnosis methods.
The test primarily focuses on measuring an abnormal protein, the plasma phosphorylated tau 217, or p-tau217 levels, a blood biomarker that scientists work on for diagnosis of mild cognitive impairment and early-stage Alzheimer’s. This biomarker successfully spots the abnormal version of the tau protein present in neurons affected by Alzheimer’s whose small amounts are able to reach the bloodstream.
According to Dr. Sebastian Palmqvist, an associate professor of neurology at Lund University in Sweden and one of the cowriters of the study, “the test measures tau protein 217, which is an excellent indicator of amyloid pathology.” He adds that “increases in p tau-217 concentrations in the blood are quite profound in Alzheimer’s disease. At the dementia stage of the disease, levels are more than 8 times higher compared with elderly without Alzheimer’s”.
Hence, levels of p-tau217 hint at the accumulation of amyloid plaques, and act as a predictor of Alzheimer’s.
In the study, the p-tau217 test was merged with the amyloid 42/40 ratio, another blood biomarker for Alzheimer’s, which measures two types of amyloid proteins. This combination of the amyloid and tau tests called the amyloid probability score was the most indicative of Alzheimer’s. Neurologist Dr. Richard Isaacson, director of research at the Institute for Neurodegenerative Diseases in Florida agrees that using a combination of the 40 to 42 ratio and p-tau217 increases the diagnostic accuracy.
Dr. Maria Carrillo, chief science officer of the Alzheimer’s Association, states they would love to have a blood test for Alzheimer’s just like a cholesterol test that can easily be used by a physician. She further remarks “The p-tau217 blood test is turning out to be the most specific for Alzheimer’s and the one with the most validity. It seems to be the front-runner”, highlighting the p-tau217 test’s promising results. Notably, scientists are continuously discovering new biomarkers for Alzheimer’s, which might output more accurate results than p-tau217 in the near future.
The p-tau217 can be detected only when there is a buildup of amyloids, called amyloid plaques in the brain. Therefore, the test measuring p-tau217 indeed measures the neuronal damage from tau very early on in Alzheimer’s, as Carillo notes. The test does not particularly measure amyloid plaques but rather indicates that they are present, which can be proved by PET scans. Carillo explains the mechanism of the blood test as simple “It’s a beautiful marker for Alzheimer’s: If you don’t have amyloid present, you don’t have Alzheimer’s. If you have elevated tau in your brain, however, then we know that’s a sign of another type of dementia.”
Since accumulation deposits of amyloid begin years before symptoms become visible, early diagnosis through a blood test that checks for plaques can be life-changing and may improve the effectiveness of the treatment methods or preventive measures significantly.
At the end of the study, the 90% accuracy of the blood test was verified through a spinal fluid tap along with an amyloid PET scan.
As the director of the division of neuroscience at the National Institute on Aging, a part of the National Institutes of Health, Dr. Eliezer Masliah emphasizes “All this really points to this idea that we are going to use a blood test to diagnose Alzheimer’s and I think we are very close to that”, adding that “The trend now is to go toward a biological diagnosis of Alzheimer’s disease, a diagnosis based on biomarkers rather than just on clinical symptoms.” which can be found in current methods such as PET scans or cerebrospinal fluid and the blood tests.
It seems like the highly accurate blood tests have the power to transform and revolutionize Alzheimer’s treatment and diagnosis processes, becoming a breakthrough once examined and approved for use by the FDA. However, as Dr. Masliah highlights there are no guidelines for the use of these blood tests, yet. Plus, there are still unknowns about how the test works in diverse populations and there is a need for standardization and guidelines in addition to FDA approval. Therefore, there is still time to know whether you have Alzheimer’s or not through a blood test, nevertheless, these new blood tests and biomarkers being developed as alternative diagnosis methods have already unlocked a new era in the treatment and diagnostics of Alzheimer’s and other neurological diseases.
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