01 Mar 2024

While numerous fluid markers flag brain Aβ pathology in Alzheimer’s disease, markers of neurofibrillary tangles are few and far between. Now, scientists led by Oskar Hansson at Lund University in Sweden and Juan Lantero-Rodriguez of the University of Gothenburg in Sweden describe a new marker for tangles: N-terminal tau fragments, dubbed NTA-tau. In the February 17 Molecular Neurodegeneration, they report that people with plaques and tangles had twice as much plasma NTA-tau as did those with neither. It was the tangles that almost exclusively drove the plasma tau signal, the authors found, and only in AD. People with other tauopathies had normal plasma NTA-tau. Furthermore, high baseline levels of this marker predicted worse tangle accumulation, cortical atrophy, and cognitive decline over six years.

“This work once again underscores the complexity of soluble tau forms in disease,” wrote Jeff Dage, Indiana University, Indianapolis (comment below). “Moreover, it adds evidence that exploring post-translational modifications, such as differential proteolytic cleavage, offers additional opportunities for novel biomarker discovery for Alzheimer’s disease and dementias.”

AD pathology is defined by fluid or imaging markers under the amyloid-tau-neurodegeneration (ATN) framework, whereby cerebrospinal fluid phosphotau-181 or tau PET reflect tau proteinopathy. PET scans are more onerous and expensive than plasma analysis, while p-tau181 tracks amyloid pathology as well, if not better, than tangles (Apr 2020 conference news; Sep 2022 conference news; Dec 2022 conference news).

In search of a good tangle marker, co-first authors Lantero-Rodriguez and Gemma Salvadó at Lund and colleagues developed two single-molecular array (Simoa) assays, A and B. They use two antibodies: one against amino acids 159 to 163 to capture tau, the other to N-terminal residues 6 to 18 for detection. The assays capture any tau containing residues 6 to 163, including full-length protein and N-terminal fragments. Lantero-Rodriguez told Alzforum that assay B worked poorly in blood. The A assay picked up N-terminal fragments in the CSF and plasma that correlated with tau PET in 130 amyloid-positive people across the AD spectrum (Snellman et al., 2022; Lantero-Rodriguez et al., 2023).

To test NTA-tau in a larger population, the scientists analyzed CSF and blood samples, PET and MRI scans, and cognitive test scores from 2,226 older adults in the Swedish BioFINDER-1 and BioFINDER-2 cohorts. Of these, 961 were cognitively normal, 354 were amyloid-positive based on CSF, 303 had mild cognitive impairment, 189 had AD dementia, and 419 had been diagnosed with non-AD MCI or dementia. Participants were around age 70; half were women.

Plasma NTA-tau seems to specifically reflect tangles associated with AD. It only increased in people who tested positive for amyloid and for tangles, but not in people who had only tangles (image below). Plasma NTA-tau more accurately correlated with tau PET than with amyloid PET, with areas under the curve of 0.80 and 0.67, respectively. Statistically, tangles, not amyloid or atrophy, explained most of the NTA-tau signal.

At later stages of AD, plasma NTA-tau had doubled (image below). It strongly associated with tangles, and atrophy, in the temporoparietal lobe, an area that accumulates tau during later stages of AD. People with high plasma NTA-tau did poorly on the modified preclinical Alzheimer’s cognitive composite (mPACC) and the Mini-Mental State Exam (MMSE).

Tagging Tangles. While NTA-tau was found in the plasma of amyloid-negative (A-) and tangle-negative (T-) controls (gray, left), levels were slightly higher in A+T- cases (blue, left), and highest in the A+T+ group (green, left). The A-T+ group (yellow, left) had no more plasma NTA-tau than controls. The same trend was seen across the clinical spectrum (right). From A- cognitively unimpaired controls (CU-) through to AD, NTA-tau rose. A- people diagnosed with non-AD dementia had the lowest NTA-tau, but it was higher in the A+ non-AD group. [Courtesy of Lantero-Rodriguez et al., Molecular Neurodegeneration, 2024.]

NTA-tau predicted faster disease progression. Over six years, people with the most plasma NTA-tau accumulated the most tangles in their temporal lobes, had the most cortical atrophy, and slipped the fastest on the mPACC or MMSE (image below). A faster rise in plasma NTA-tau correlated with worse atrophy and cognitive decline. Lantero-Rodriguez and Salvadó think plasma NTA-tau could serve as a screening tool to flag people likely to progress quickly in clinical trials, or as a secondary outcome measure to see how anti-amyloid immunotherapies affect tangles.

NTA-tau Up, Cognition Down. People with the most baseline plasma NTA-tau (purple) accumulated more tangles (top left), had worse cortical atrophy (top right), and slipped faster on the MMSE (bottom left) or mPACC (bottom right) over four to six years than did people with average (green) or low (yellow) plasma NTA-tau. [Courtesy of Lantero-Rodriguez et al., Molecular Neurodegeneration, 2024.]

“This [NTA-tau] assay appears to perform similarly to other new fluid markers postulated to better represent tau tangles, such as MTBR-tau243,” noted Tharick Pascoal of the University of Pittsburgh. Salvadó and Kanta Horie of Washington University in St. Louis previously reported that this chunk of tau’s microtubule-binding region ticked up in the CSF when tangles formed, and it tracked with waning cognition almost as well as did tau PET (Dec 2022 conference news; Aug 2023 conference news). MTBR-tau243 has not yet been measured in plasma.

In blood, another N-terminal tau fragment called NT-1, which spans residues 6 to 198, also closely correlated with tangle accumulation, neurodegeneration, and cognitive decline in AD (Dec 2020 news). That study's first author, Jasmeer Chhatwal at Massachusetts General Hospital, Boston, was encouraged that Lantero-Rodriguez and Salvadó saw similar correlations with plasma NTA-tau. “It makes me more confident about the underlying biology,” he told Alzforum.

Still, neither Chhatwal nor Horie are convinced that N-terminal tau, whether NTA-tau or NT1, directly measures insoluble tau, because these fragments do not end up in neurofibrillary tangles. “Things that correlate in time are not always driven by the same biological processes,” Chhatwal said. Horie noted that MTBR-tau243 is enriched in tangles, hinting it might be a direct marker (comment below).—Chelsea Weidman Burke

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References

News Citations

1. 217—The Best Phospho-Tau Marker for Alzheimer’s? 10 Apr 2020
2. Head-to-Head Study Confirms Plasma p-Tau231 Rises First in Early AD 2 Sep 2022
3. Plasma P-tau217 Picks Up Plaques, Tangles, Future Decline 27 Dec 2022
4. New Data Bolsters MTBR-Tau243 as Fluid Marker for Tangles 28 Dec 2022
5. CSF MTBR-tau-243 Tracks Tangles, Plummets in Response to Antibody 31 Jul 2023
6. Plasma NT1: This Tau Snippet Predicts Cognitive Decline in Alzheimer’s 4 Dec 2020

Paper Citations

1. Snellman A, Lantero-Rodriguez J, Emeršič A, Vrillon A, Karikari TK, Ashton NJ, Gregorič Kramberger M, Čučnik S, Paquet C, Rot U, Zetterberg H, Blennow K. N-terminal and mid-region tau fragments as fluid biomarkers in neurological diseases. Brain. 2022 Aug 27;145(8):2834-2848. PubMed.
2. Lantero-Rodriguez J, Tissot C, Snellman A, Servaes S, Benedet AL, Rahmouni N, Montoliu-Gaya L, Therriault J, Brum WS, Stevenson J, Lussier FZ, Bezgin G, Macedo AC, Chamoun M, Mathotaarachi SS, Pascoal TA, Ashton NJ, Zetterberg H, Neto PR, Blennow K. Plasma and CSF concentrations of N-terminal tau fragments associate with in vivo neurofibrillary tangle burden. Alzheimers Dement. 2023 May 15; PubMed.

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