Diagnosis for Alzheimer’s Diseases (AD)
In earlier read, we discuss about the Alzheimer’s disease symptoms. Now there is detail explanation of diagnosis methods of Alzheimer’s disease.
Alzheimer’s Disease Symptoms: Early Warning Signs and Disease Progression
Risk Factors of Alzheimer’s Disease: Lifestyle, Genetic, and Medical Causes
BLOOD TESTS
Amyloid beta and tau protein levels
Recent studies show that the ratio of Aβ42 to Aβ40 proteins in blood plasma can help distinguish people without AD and people with AD. These proteins are forms of beta‑amyloid, which accumulate in the brain of AD patients.
But this technology is not available in most healthcare facilities.
Researchers also observed that change in Aβ42 levels in blood plasma are similar to those seen in cerebrospinal fluid (CSF). This suggests that beta-amyloid may move between the brain and blood through the blood–brain barrier.
Plasma Aβ42 levels are stable and sensitive, this test may help detect amyloid accumulation in the cerebrospinal fluid (CSF).
What is Aβ42/40 ratio in blood plasma?
The Aβ42/40 ratio compares the amount of beta-amyloid Aβ42 to Aβ40 in blood plasma or cerebrospinal fluid.
In healthy individuals – Aβ42/40 ratio is higher or normal
In Alzheimer’s disease – Aβ42/40 ratio decreases
Plasma P-tau181
Researchers found that plasma P-tau181 levels increase in early Alzheimer’s disease, It’s levels increase further during mild cognitive impairment (MCI) and they increase even more in dementia stages.
Plasma P-tau 181 is another marker that is used to detect AD from other neurodegenerative diseases.
Inflammatory markers
Inflammation-related biomarkers are used to detect or monitor Alzheimer’s disease. In AD, changes inside brain cells (intracellular alterations) occur early. These changes can sometimes be detected through inflammatory markers in the blood.
Studies have shown that certain inflammatory cytokines are found at higher levels in AD patients, such as interleukin‑6, 12, 18, tumor necrosis factor (TNF) and transforming growth factor (TGF). In AD patients, these markers are significantly high which indicate inflammation in the brain of AD patients.
These biomarkers are used to detect Alzheimer’s disease.
Glial cells in inflammation– The brain contains support cells called glial cells, mainly microglia and astrocytes. When these cells are activated for a long time in Alzheimer’s disease, they can become pro-inflammatory and cause neuroinflammation.
Both microglia and astrocytes produce an inflammatory marker called Chitinase‑3‑like protein 1 also known as YKL-40. In AD, astrocytes located near beta‑amyloid plaques produce YKL-40.
In AD, the level of YKL-40 increases with tau protein and YKL-40 is used as detection method for AD.
GFAP biomarker- Glial Fibrillary Acidic Protein (GFAP) is mainly produced by astrocytes. Study found that individuals with preclinical Alzheimer’s disease had higher plasma GFAP levels than healthy individuals.
This suggests that GFAP may help detect Alzheimer’s disease even before symptoms appear.
CEREBROSPINAL FLUID (CSF) ANALYSIS
Aβ and tau protein levels in CSF
Amyloid beta (Aβ) detection in CSF
Amyloid beta (Aβ) is released into the Cerebrospinal fluid (CSF). In AD patients, the level of Amyloid beta 42 (Aβ42) in CSF is significantly reduced. It became approximately half of the normal level.
CSF Aβ42 levels reduced because it aggregates and forms amyloid plaques in the brain. Because much of Aβ42 becomes trapped in plaques, less of it remains free to enter the CSF. Therefore, CSF Aβ42 levels decrease in Alzheimer’s disease.
Aβ42/Aβ40 ratio as a diagnostic marker in CSF
Different forms of amyloid beta exist in CSF and Amyloid beta 40 (Aβ40) is most common one, Aβ40 is about 10 times more abundant than Aβ42 in CSF.
In Alzheimer’s disease, CSF Aβ42 decreases and CSF Aβ40 remains relatively unchanged. Because of this, researchers use the Aβ42/Aβ40 ratio, which is more accurate for detecting Alzheimer’s disease than Aβ42 alone. This ratio is therefore clinically useful for diagnosing AD.
Tau protein in CSF
Another important biomarker for AD is tau protein. In AD, tau becomes hyperphosphorylated, it moves from the axon to the somatodendritic region, misfolds and forms aggregates (neurofibrillary tangles).
When neurons are damaged or die, tau protein is released into the CSF. Therefore, in Alzheimer’s disease, CSF tau levels increase.
However, tau levels can also increase in other conditions. For example, Traumatic brain injury causes CSF tau levels to rise within days after the injury and remain high for weeks.
Interestingly, in some pure tau-related diseases, CSF tau levels may not increase even though severe tau pathology exists.
Phosphorylated tau levels
Phosphorylated tau (p-tau) isoforms
Scientists use antibodies that detect specific phosphorylation sites on the Tau protein. These phosphorylated forms are called p-tau. Certain p-tau isoforms are strongly associated with Alzheimer’s disease, such as p‑tau18, p‑tau199, and p‑tau23.
These biomarkers can help distinguish Alzheimer’s disease from other neurological disorders, such as frontotemporal dementia, dementia with Lewy bodies, vascular dementia, and major depressive disorder.
Importance of p-tau217
p-tau217 levels increase significantly about 21 years before Alzheimer’s symptoms appear. The increase closely correlates with accumulation of Amyloid beta in the brain.
As the disease progresses, levels of p-tau217 and p-tau181 decline near symptom onset. Meanwhile, total tau and non-phosphorylated tau forms (Tau217 and Tau181) continue to increase.
This pattern suggests that changes in tau phosphorylation are complex and reflect the progression of AD symptoms, rather than simply changes in total tau protein levels.
Note: Because of its strong early signal, p-tau217 is considered a promising biomarker for early detection and disease monitoring, although more studies are needed to standardize testing and obtain regulatory approval.
p-tau231 cause change in brain structure
p-tau231 levels decrease as AD progresses from mild to moderate stages. Baseline p-tau231 levels correlate with Hippocampus shrinkage (hippocampal atrophy).
Neurofilament light chain levels
Neurofilaments (Nf-L) are intermediate filament proteins present in neurons. Abnormalities in Neurofilament cause neurological diseases including AD.
In AD, neurofilaments may aggregate abnormally and leads to neuronal axons structural change. These changes indicate damage or degeneration of neurons.
Studies show that patients with AD have higher CSF Neurofilaments levels compared with healthy individuals.
Limitation of Nf-L as a biomarker- Although Nf-L levels increase in Alzheimer’s disease, they are also elevated in many other neurodegenerative conditions. Therefore, Nf-L is not specific to Alzheimer’s disease.
However, CSF Nf-L levels are strongly associated with brain atrophy, indicating general neuronal or axonal damage.
NOVEL DIAGNOSTIC BIOMARKERS
MicroRNAs
MicroRNAs as emerging biomarkers- Scientists are also studying MicroRNA (miRNA) as potential biomarkers.
Some miRNAs found at higher levels in AD patients such as miRNA-9, miRNA-125b, miRNA-146a, miRNA-155. These miRNAs are associated with inflammatory processes in AD and are found in extracellular fluid and CSF.
Imaging tests for diagnosis of Alzheimer’s disease
Magnetic resonance imaging
MRI is a non-invasive brain imaging technique that uses strong magnetic fields and radio waves to produce detailed images of brain structures.
In Alzheimer’s diagnosis, MRI is mainly used to:
- Examine brain structure
- Detect brain atrophy (shrinkage)
Rule out other causes of cognitive problems, such as brain tumor and vascular dementia or other vascular abnormalities
In AD, MRI scans often show brain atrophy in memory-related regions, especially the hippocampus.
Since the hippocampus plays a key role in memory formation, its shrinkage is a common feature of Alzheimer’s disease.
Advanced MRI methods can also measure brain volume loss, detect microstructural brain changes and help monitor disease progression.
Limitation of MRI
Although MRI is useful, it cannot diagnose Alzheimer’s disease by itself because its diagnostic accuracy is limited. For patients with Mild Cognitive Impairment (MCI):
- Sensitivity: 73% (ability to correctly identify AD cases)
- Specificity: 71% (ability to correctly identify non-AD cases)
Therefore, MRI is usually combined with other diagnostic tools such as biomarker analysis (Aβ and tau), PET imaging and clinical cognitive tests
Computed tomography (CT)
CT is brain imaging technique used in the evaluation of Alzheimer’s disease, although it is used less frequently than MRI. A CT scan produces detailed cross-sectional images of the brain, which helps doctors to rule out other conditions that may cause symptoms similar to AD and detect structural brain abnormalities.
CT scans may show changes such as ventricular enlargement (expansion of brain ventricles) and cortical atrophy (shrinkage of the cerebral cortex). These structural changes are often associated with Alzheimer’s disease.
Advantages of CT
Compared with MRI, CT scans are more widely available and faster to perform. Because of this, CT is often used in clinical situations where MRI cannot be performed, such as when a patient has certain implanted medical devices or cannot tolerate MRI.
However, MRI is generally preferred because it provides more accurate evaluation of hippocampal atrophy in the medial temporal lobe which is main features of AD.
Positron emission tomography (PET)
PET is a functional brain imaging technique that shows how the brain is working, not just its structure. It measures brain metabolism, molecular changes and disease-related protein accumulation.
PET can detect key features of Alzheimer’s disease, including amyloid beta plaques, tau protein neurofibrillary tangles (NFTs) inside neurons and changes in brain glucose metabolism
Amyloid PET scans identify the accumulation of amyloid plaques in the brain.
Three amyloid radiotracers approved by the U.S. Food and Drug Administration (FDA) are 18F‑florbetaben, 18F‑florbetapir, and 18F‑flutemetamol. These tracers bind to amyloid-β deposits, allowing doctors to visualize plaque accumulation in the brain.
Amyloid PET is also used to select patients for clinical trials and monitor the effects of amyloid-targeting therapies.
PET tracers
Scientists have also developed PET tracers that detect tau pathology, which is strongly linked to disease progression. Examples of second-generation tau tracers include 18F‑MK6240, 18F‑PM‑PBB3, 18F‑RO948,18F‑PI‑2620, 18F‑JNJ311 and Genentech Tau Probe 1. Another FDA-approved tracer is 18F‑flortaucipir
This tracer helps visualize the distribution and density of neurofibrillary tangles in patients with cognitive impairment. Because tau accumulation closely correlates with cognitive decline, tau PET is valuable for diagnosis and tracking disease progression over time.
FDG-PET and brain metabolism
PET can also measure glucose metabolism in the brain using the tracer 18F‑fluorodeoxyglucose (FDG). FDG-PET shows areas of reduced neuronal activity, indicating brain dysfunction.
In Alzheimer’s disease, reduced glucose metabolism (hypometabolism) commonly occurs in temporal lobe, parietal lobe and posterior cingulate cortex. These metabolic patterns help distinguish AD patients from healthy individuals.
Research shows Amyloid PET is highly sensitive and specific for confirmed AD and FDG-PET is highly sensitive but moderately specific.
