Blood test for Alzheimer’s may help in making hATTR-PN diagnosis
Study finds 2 blood biomarkers ID'd in test are higher in both diseases
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A blood test commonly used to help diagnose Alzheimer’s disease may also identify people with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN), characterized by damage to the peripheral nerves found outside the brain and spinal cord, according to a new study.
Like in people with Alzheimer’s, a neurodegenerative disease, researchers found significantly higher levels of the biomarkers p-tau181 and p-tau217 in the blood of those with hATTR-PN that could accurately distinguish them from healthy individuals.
The scientists noted that elevated p-tau181 was specific to hATTR-PN and not observed in other forms of transthyretin amyloidosis (ATTR) without nerve damage, or neuropathy, or in neuropathy caused by other conditions.
p-tau181 was also detected in some individuals carrying hATTR-causing mutations but not yet showing symptoms, with higher levels associated with a faster time to eventual symptom onset, the researchers noted.
“These findings suggest that elevated [blood] p-tau levels are not specific to Alzheimer’s disease and may also serve as a diagnostic tool for [ATTR],” the researchers wrote.
The study, “Blood phosphorylated tau elevation as a biomarker in immunoglobulin light chain and transthyretin amyloidosis,” was published in the journal Nature Medicine.
Amyloidosis refers to a group of diseases characterized by misfolded proteins that form clumps called amyloid deposits, which accumulate in organs and tissues, causing damage.
ATTR is a group of amyloidoses caused by amyloid deposits derived from the transthyretin protein, arising from inherited mutations in the TTR gene — when it’s known as hereditary ATTR — or from aging, called wild-type ATTR.
When the toxic clumps, or aggregates, mainly accumulate in the peripheral nerves outside the central nervous system, comprising the brain and spinal cord, the condition is classified as ATTR-PN. When amyloid deposits mainly damage the heart, it is known as transthyretin amyloid cardiomyopathy, or ATTR-CM.
Alzheimer’s is a type of amyloidosis
In AL amyloidosis, the most common form of amyloidosis, abnormal immune cells produce misfolded proteins that form amyloid deposits in multiple organs and tissues. Alzheimer’s is also a type of amyloidosis, in which amyloid deposits made of the beta-amyloid protein in the brain cause nerve damage, cognitive decline, and dementia.
Deposits of beta-amyloid in people with Alzheimer’s has been linked to modified forms of the tau protein, called phosphorylated tau or p-tau. Two forms in particular — p-tau181 and p-tau217 — act as early biomarkers for the disease because their levels rise in the blood and the fluid surrounding the brain and spinal cord for as long as two decades before symptoms appear.
Given this knowledge, a team of scientists from Europe and the U.S. — led by two researchers from the University of Tübingen in Germany and one from Harvard Medical School in the U.S. — sought to learn more. Specifically, the team explored whether changes in p-tau reflected a more universal response to amyloid deposits and could serve as blood biomarkers for bodywide types of amyloidosis, including ATTR amyloidosis.
The scientists collected blood samples from 52 adults with hereditary ATTR, 20 with wild-type ATTR, 97 with AL amyloidosis, and 30 with neuropathy not caused by amyloidosis. Blood samples were also collected from 71 healthy individuals, who served as controls. The samples came from individuals at four centers in Europe: two in Germany and one each in Italy and the Netherlands.
While the wild-type ATTR patients were older on average than those with hereditary ATTR, and had more severe heart involvement, they did not show signs of neuropathy. Most of those with hereditary ATTR had neuropathy.
Using blood test as diagnostic tool had accuracy over 80%
Blood tests showed that people with ATTR had significantly higher p-tau181 levels than the healthy controls. Similar increases were seen in AL patients. These differences remained significant even after adjusting for age, sex, and kidney function, the data showed. In contrast, those with other types of neuropathy did not show higher p-tau181 levels, per the researchers.
Further analysis suggested that in ATTR, higher p-tau181 levels were observed only in hereditary ATTR patients with neuropathy. In contrast, p-tau181 was elevated in AL amyloidosis, whether or not neuropathy was present.
“This suggests that the cause of elevated p-tau levels in people with ATTR and AL was the amyloid, and that people with ATTR and AL with [neuropathy] are likely to be at a more advanced stage of the disease,” the scientists wrote.
The researchers then evaluated how well the blood test could distinguish people with amyloidosis from healthy individuals. Measuring p-tau181 identified ATTR amyloidosis with 83% accuracy, and it performed similarly in AL amyloidosis , with 85% accuracy.
To explore whether the marker could detect disease even earlier, the scientists studied 10 people who carried TTR gene mutations but had not yet developed ATTR symptoms. These individuals’ p-tau181 levels were already elevated, with the highest levels correlating with the shortest time to symptom onset, the scientists found.
The team also compared these findings with Alzheimer’s by measuring p-tau181 in nine people with Alzheimer’s and 16 healthy controls. The Alzheimer’s group had about two times higher levels of the marker in their blood. Interestingly, the magnitude of this increase was similar to that seen in people with ATTR and AL amyloidosis, the researchers noted.
P-tau levels in blood show promise as ‘diagnostic tool’
Finally, the researchers measured p-tau217 in blood samples from one of the study groups. Although its absolute levels were lower than those of p-tau181, the increase was similar, and the two markers were strongly correlated. The p-tau217 test also distinguished ATTR patients from healthy individuals with 79% accuracy, per the data.
“The ability of p-tau181 and p-tau217 to distinguish patients with ATTR and those with AL from controls … supports their potential as biomarkers reflecting [body-wide] amyloid [disease],” the team wrote. The scientists added that, overall, p-tau in the blood may serve “as a diagnostic tool for ATTR and AL amyloidosis.”
