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An investigational PET imaging agent detected tau pathology related to Alzheimer’s disease (AD) earlier than the tracer currently used in PET scans, which could speed AD diagnosis, a new study showed.

The new agent, MK-6240, also identified tau in more patients, detecting medial temporal lobe (MTL) tau pathology in 15% of cognitively unimpaired amyloid-positive individuals compared with just 6% with flortaucipir, the tracer currently used in PET scans.

MK-6240 also detected greater tau involvement in cognitively impaired participants and showed higher accuracy in distinguishing cognitive impairment related to AD vs impairment caused by other conditions.

“Tau PET positivity is crucial for determining whether individuals with amyloid pathology are truly on the AD pathway, since amyloid alone does not equate to clinical AD,” senior investigator Tharick A. Pascoal, MD, PhD, associate professor of psychiatry and neurology at the University of Pittsburgh in Pittsburgh, told Medscape Medical News.

“A more sensitive tracer can identify patients at the earliest stages of tau accumulation — precisely the population most likely to benefit from anti-amyloid therapies,” he said.

The study was published online on May 28 in The Lancet.

Head-to-Head Design

Tau pathology is more closely linked than amyloid to AD severity, progression, and cognitive decline. Although flortaucipir is the only FDA-approved tau PET tracer for clinical use in the US, its sensitivity for detecting early medial temporal tau pathology is limited.

MK-6240 was designed to improve tau detection through a higher signal-to-noise ratio, potentially allowing for earlier identification.

To compare tracer efficacy, investigators conducted the prospective, cross-sectional HEAD study, including 775 participants across eight sites in the US and Canada. A total of 682 individuals (55% women; 93% White individuals) completed all study components between March 2022 and August 2025 and were included in the final analysis.

The analysis included 38 young healthy control individuals aged 19-27 years and 644 older adults aged 50-89 years. Among the older participants, 362 were cognitively unimpaired, 183 had mild cognitive impairment (MCI), and 99 had dementia.

All participants underwent amyloid PET imaging, detailed cognitive testing, MRI, and paired tau PET scans using both flortaucipir and MK-6240 within a 45-day window.

The coprimary outcomes were diagnostic accuracy for AD-related cognitive impairment and the detection of tau pathology in medial temporal and neocortical regions, which represent earlier and later stages of disease involvement, respectively.

Earlier Detection With MK-6240

Compared with flortaucipir, MK-6240 demonstrated a significantly greater diagnostic accuracy for distinguishing AD dementia from non-AD cognitive impairment.

For AD dementia, the area under the curve was 0.93 with MK-6240 vs 0.86 with flortaucipir (P < .0001).

The largest differences were seen in the detection of early tau pathology. MTL tau positivity was detected in 15% of cognitively unimpaired participants with the new agent vs 6% with flortaucipir. Among cognitively unimpaired amyloid-positive participants, tau positivity rates were 39% with MK-6240 vs 16% with flortaucipir (prevalence ratio, 2.43; P = .0003).

MK-6240 also identified more tau-positive cases, accurately identifying tau in 23 more patients per 100 amyloid-positive cognitively unimpaired individuals scanned.

Discordant cases largely favored MK-6240. Of the 84 participants with differing results between tracers, 89% were positive only on MK-6240. Compared with participants negative on both scans, these individuals had significantly greater amyloid burden (64% vs 17%), higher APOE epsilon 4 carrier frequency (55% vs 28%), and worse memory performance (-0.63 vs -0.24).

MK-6240 also became positive at lower levels of amyloid burden. The estimated threshold for a 50% probability of MTL tau positivity was 53 Centiloids for MK-6240 vs 81 Centiloids for flortaucipir.

Other Key Differences

Differences between the tracers were also found beyond early disease detection.

Among cognitively impaired amyloid-positive participants, neocortical tau positivity was detected in 28% with MK-6240 vs 16% with flortaucipir (prevalence ratio, 1.74; P < .0001).

The newer agent identified approximately 15 additional MCI cases and 21 dementia cases per 100 participants scanned.

The tracer also assigned patients to more advanced Braak stages of tau pathology. Although overall concordance between tracers was moderate, 95% of discordant staging cases were classified at a higher stage by MK-6240.

Key limitations of the study include the lack of postmortem pathological validation, and most participants were White individuals, which may limit generalizability and the ability to fully confirm tracer-specific differences in early tau detection.

What Drives MK-6240 Performance?

The performance of MK-6240 appears to be driven largely by differences in biologic binding characteristics, said Pascoal, who is also a behavioral neurologist at the University of Pittsburgh School of Medicine.

“The main driver is biological affinity: MK-6240 binds tau tangles with roughly sixfold higher affinity than flortaucipir, as demonstrated in post-mortem tissue,” he explained. “This translates into a stronger signal-to-noise ratio in vivo, allowing detection of the sparse, early tangle deposits in medial temporal regions that flortaucipir tends to miss.”

However, access to this newer tau PET tracer remains limited, he acknowledged.

“Availability remains a real barrier,” Pascoal said. “MK-6240 is currently produced at a limited number of academic and trial-affiliated PET centers and is not yet approved as a routine clinical test.”

The new agent received FDA Fast Track designation in 2025. The agency is expected to issue a decision on the manufacturer Lantheus’ new drug application expected in August, the company reported in a statement.

The study provides evidence supporting sensitive approaches to tau detection, said Stephen Salloway, MD, director of Neurology and the Memory and Aging Program at Butler Hospital in Providence, Rhode Island, who was not part of the research.

“Early detection of AD pathology will be critical for testing new interventions to slow or prevent cognitive decline in individuals at risk for AD,” and MK-6240 is better at detecting early stages of tau pathology than the currently available tracer, Salloway told Medscape Medical News.

However, he cautioned that broader clinical implementation will require additional work to standardize interpretation and staging.

“Better molecular staging of AD is needed to improve diagnostic accuracy and to identify individuals most likely to benefit from treatment,” he said. “Nuclear medicine specialists, radiologists, and dementia experts need experience and training to interpret tau PET scans.”

The study was funded by the National Institute on Aging. Disclosure information for study authors is available in the original study publication. Salloway reported having no relevant financial disclosures.