{"doi":"10.1002/alz.70184","title":"2024 Alzheimer's Association criteria for Alzheimer's disease diagnosis are usually anchored to both plaques and tangles, not Aβ alone","abstract":"We respond to a recent letter by Moscoso and Villain1 titled “2024 AA criteria for Alzheimer's disease diagnosis: Mainly anchored at Aβ not tau.” They assert,1 “… the Revised Criteria implicitly establish the theoretical threshold between normality and AD based exclusively on the presence of Aβ aggregates, regardless of neurofibrillary tangles (NFT).” This is a mischaracterization of the revised criteria,2 which define Alzheimer's disease (AD) as a biological construct first detectable in living persons through early changing “Core 1” biomarkers, which are anchored on abnormal amyloid positron emission tomography (PET) by visual read. This in turn corresponds to moderate/frequent Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuritic plaques,3, 4 a neuropathologic measure of amyloid beta (Aβ) plaques containing tau-positive dystrophic neurites as opposed to Thal amyloid phase 1, which exclusively assesses cortical Aβ deposition. While Thal phase 1 without NFTs may represent early AD neuropathology, the limited sensitivity of in vivo biomarkers for this degree of neuropathologic change places it outside of the “Core 1” positivity threshold used in the revised AD criteria.2 This point was made very clearly in the criteria.2 PET autopsy correlation data show that reliable detection of a positive amyloid PET scan begins at Thal phase 2, not Thal phase 1.5, 6 Furthermore, amyloid PET Centiloid values ≥ 25 (where the 24–30 Centiloid range corresponds to the threshold for a visually positive study), are highly predictive of intermediate/high AD neuropathologic change (ADNC)5, 7, 8-that is moderate/frequent CERAD plaques plus Braak NFT ≥ III. Therefore, the imaging-to-autopsy correlation data support the revised AD criteria2 position that abnormal amyloid PET (and by extension other Core 1 biomarkers) usually conforms to classical neuropathologic intermediate/high ADNC, which was a point of contention.1 The main controversy, however, does not lie with impaired individuals with moderate/frequent CERAD plaques, ≈ 95% of whom also have Braak NFT ≥ III and thus meet criteria for intermediate/high ADNC,2 but rather with cognitively unimpaired (CU) individuals. Therefore, in the second part of their letter, Moscoso and Villain1 examined the National Alzheimer's Coordinating Center (NACC) neuropathology database and found that in CU individuals with moderate/severe CERAD plaques (n = 154), the proportion with Braak NFT scores < III increased significantly with younger age. They then multiplied the NACC-derived age-specific frequencies of moderate/severe CERAD plaques with Braak NFT < III by age-specific estimates of the population frequency of positive amyloid PET scans from a separate source.9 From this they estimated that 64% of all CU individuals with positive amyloid PET scans worldwide would have Braak NFT stage < III. Hence the title of their letter. To assess the validity of these claims,1 we examined the Mayo Clinic Study of Aging (MCSA) autopsy database and found 218 MCSA participants with a last clinical diagnosis of CU and death within 3 years of the last clinical visit. We found that the frequency of the combination of moderate/frequent CERAD plaques and Braak 0 to II remained constant across ages at ≈ 8% (Figure 1). Of the 88 CU cases with moderate/frequent CERAD plaques, 5 (6%) had Braak NFT 0 to I, 16 (18%) had Braak II, while the remaining 67 (76%) had Braak ≥ III and therefore met the criteria for intermediate/high ADNC. Overall, (94%) show tau spreading outside of the entorhinal cortex. Thus, our data suggest that 76% of CU individuals with positive amyloid PET would qualify for intermediate/high ADNC and nearly all (94%) show tau spreading. This is much different from claims by Moscoso and Villain,1 and the question is why? First, their1 conclusions completely depend on an age effect; however, because of very wide confidence intervals, a reliable estimate of the frequency of Braak < III in younger indi","journal":"Alzheimer s & Dementia","year":2025,"id":539324,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9601,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":49955,"name":"David S. Knopman","orcid":"0000-0002-6544-066X","position":1,"is_corresponding":false},{"id":272791,"name":"Heather J. Wiste","orcid":null,"position":2,"is_corresponding":false},{"id":55000,"name":"Reisa A. Sperling","orcid":"0000-0003-1535-6133","position":3,"is_corresponding":false},{"id":51717,"name":"William J. Jagust","orcid":"0000-0002-4458-113X","position":4,"is_corresponding":false},{"id":91825,"name":"Melissa E. Murray","orcid":"0000-0001-7379-2545","position":5,"is_corresponding":false},{"id":282541,"name":"Baayla D.C. Boon","orcid":"0000-0002-4922-3286","position":6,"is_corresponding":false},{"id":259159,"name":"Val J. Lowe","orcid":"0000-0002-5612-1667","position":7,"is_corresponding":false},{"id":263714,"name":"Derek R. Johnson","orcid":"0000-0002-4217-5517","position":8,"is_corresponding":false},{"id":388369,"name":"Brian J. Burkett","orcid":"0000-0002-0457-5712","position":9,"is_corresponding":false},{"id":270813,"name":"Petrice M. Cogswell","orcid":"0000-0002-8128-4476","position":10,"is_corresponding":false},{"id":894741,"name":"Jon Graff‐Radford","orcid":null,"position":11,"is_corresponding":false},{"id":226058,"name":"Prashanthi Vemuri","orcid":"0000-0003-4286-0589","position":12,"is_corresponding":false},{"id":54269,"name":"Ronald Petersen","orcid":"0009-0006-8296-6416","position":13,"is_corresponding":false},{"id":49956,"name":"Clifford R. Jack","orcid":"0000-0001-7916-622X","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-19T02:52:30.048313Z","pmid":"40276985","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":[]}