{"doi":"10.1002/dad2.12348","title":"Uncertainties in the PET defined A‐/T<sub>Neocortical</sub>+ subtype","abstract":"In the 15+ years following the advent of the first promising PET ligand to robustly measure amyloid plaques in vivo,1 the Alzheimer's disease (AD) research field has amassed large cohorts of research participants thoroughly characterized with biomarkers of key AD hallmarks (such as AIBL, ADNI, etc.). These transformative studies address the timely need to evaluate the utility of quantitative biomarkers of amyloid and tau throughout the long disease continuum of AD. An important opportunity that has emerged from these large cohorts of deeply phenotyped research participants is the ability to detect “outliers,” individuals that do not match an expected typical pattern of disease progression. You need hundreds if not thousands of datapoints to find outliers and probe into their meaning. The detection of an outlier oftentimes depends on joint status across modalities, as seen in Krishnadas et al.2 These outlier exceptions give researchers the opportunity to challenge dominant hypotheses, discover additional mechanisms, and assess limitations and nuance in our measurement tools. The work presented by Krishnadas et al.2 leverages the team's extensive dataset of over 450 individuals characterized with both amyloid and tau PET to identify a small set of outliers defined across two key PET modalities. Specifically, the manuscript discusses individuals that are amyloid PET-negative (via 18F-NAV4694) but have clear tau PET signal elevations with 18F-MK6240 throughout neocortex. Of the 452 research participants that contributed to this effort, 276 were Aβ- using a centiloid (CL) threshold of 25. Of the 276 Amyloid- participants, 12 were flagged using quantitative tau PET values in neocortex. Upon a second step that involved a qualitative read by a blinded expert, four of the 12 were confirmed to have unequivocal neocortical tau PET elevations. These four A-/T+ outliers, which reflect 1.4% of the Amyloid- group, form the basis of the manuscript. The possibility of A-/T+ individuals is included in the framework that describes a biological research definition of AD.3 The anticipated likelihood of this combination depends on how T-positivity is defined. It is well established that tau deposition occurs in the brainstem and entorhinal cortex before amyloid-abnormalities,4, 5 and there are also cases described in the postmortem literature that have tangles in hippocampus (Braak III/IV) without evidence of amyloid (a combination that has been labeled “Primary Age-Related Tauopathy,” PART).6 It is generally appreciated that involvement of neocortex (Braak stages V-VI) occurs exclusively in the presence of abnormal amyloid, which is not the case for the four research participants described by Krishnadas. Whereas PART could be more accurately labeled as A-/TMTL+, Krishnadas's four cases could be labeled A-/TNeocortical+. For any approach that involves dichotomization of continuous values, there is always the possibility that the resulting A- classification is merely an artifact of arbitrary threshold selections and measurement error. To this end, we have seen that amyloid PET CL values of 12 align with cerebrospinal fluid (CSF) derived measures of amyloid,7 and CL values of 5–10 predict future longitudinal amyloid accumulation.8 Although, it remains unclear how these CL thresholds vary by amyloid ligand and other methodological details that may influence the precision of these values especially in the low CL range, the overall pattern from the literature highlights that CL values lower than 25 can be an indicator of abnormal amyloid processes and be associated with downstream effects. With that being said, three of the four cases from Krishnadas et al. had CL values strongly indicating Amyloid PET-negativity (CL values between -3 and 2). Participant 4 is an exception with a CL value of 18, so one might wonder if measurement error in that case's PET scan caused it to dip below the positive threshold and should in fact be A+/T+. Further, some studies","journal":"Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring","year":2022,"id":295708,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.946,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":230945,"name":"Philip S. Insel","orcid":"0000-0002-6270-5490","position":1,"is_corresponding":false},{"id":29931,"name":"Elizabeth C. Mormino","orcid":"0000-0002-4542-6537","position":0,"is_corresponding":true}],"reference_count":19,"raw_metadata":null,"created_at":"2026-07-19T00:31:08.861377Z","pmid":"36051175","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}