In 2011, NIA-AA (National Institute on Aging/Alzheimer’s Association) workgroups published multiple recommendations for AD diagnostics and evaluation in different progression stages of the disease (preclinical, mild cognitive impairment, and dementia) ^[1-3]. With new advances in AD research, these guidelines were updated in 2018 and were called a ‘research framework’ ^[4], as it was meant for research purposes rather than clinical care. These guidelines used an AT(N) classification system, which relied heavily on the presence of AD biomarkers (amyloid and tau) detected in cerebrospinal fluid and in amyloid PET imaging, but also characteristics of neurodegeneration in individuals.

In light of recent advances in AD research, in late 2023, the Alzheimer’s Association Workgroup (AAW) drafted and presented a new proposal at meetings and for comment. This proposal, which was finalized in June 2024 and published in Alzheimers & Dementia, redefines the established classification system, prioritizing “AT” biomarkers over neurodegeneration and cognitive decline in AD diagnosis ^[5].

These propositions caused a backlash from the scientific community highlighting the potential of future overdiagnosis of asymptomatic individuals and severe conflicts of interest among the original authors. Already in 2023 and early 2024, several researchers in the field published their criticism, openly addressing these issues (see below). In a commentary subsequent to their manuscript, the AAW addressed parts of the criticism ^[6]. Here we present some of the critically discussed viewpoints.

Is AD diagnosis without symptoms accurate?

One major criticism argued that excluding characteristics of neurodegeneration (the N in AT[N]) from AD diagnosis is insufficient for proper disease classification. The American Geriatrics Society (AGS) described the proposed approach as inconsistent and commented that diagnosing asymptomatic patients with positive testing for biomarkers exhibits potential harm (financial, psychological, or social) and lacks any benefit. Rather, they advocated labeling asymptomatic biomarker-positive individuals with “at elevated risk” instead of assigning them a clinical AD diagnosis ^[6].

The authors of the revised criteria proposal answered those concerns from a different viewpoint. The AAW committee countered that diagnosing Alzheimer’s disease in asymptomatic individuals is valid and aligns with practices in other medical fields, where early diagnosis leads to more effective treatment. They also clarified that biomarker testing should not be performed outside research contexts, aiming to avoid harm without benefit. They noted, however, that this might change in the future, depending on the results of ongoing trials ^[7].

How reliable are biomarkers?

Further criticism focused on the validity of the so-called core 1 biomarkers which are proposed for diagnostic purpose. In a commentary published in the Journal of the AGS, Eric Widera from the University of California, San Francisco, argued that there is no significant evidence that “the presence of amyloid in a cognitively normal individual should lead to the initiation of any clinical intervention, let alone that removing amyloid helps these individuals” ^[8]. He adressed that current research proposes more factors that contribute to AD progression beyond just amyloid. The AGS also proposed that there needs to be more data on “the clinical significance of biomarkers across all population groups” in order to prevent confusion and potential harm in the future ^[6].

In a late 2023 View Point article in Aging Research Reviews, Høilund-Carlsen and and colleagues referred to a lack of correlation between the biomarkers and cognitive decline, as well as to an unproven causal link between Aβ and AD. Regarding the proposition that AD diagnosis should be based solely on the presence of cerebral Aβ and tau (“A” and “T” from AT[N]), disregarding neurodegeneration (“N”), they strongly stated that they “believe this is an artificial and misleading suggestion. It is artificial because it relies on biomarkers whose significance remains obscure and where the detection of ‘A’ is based on a never-validated PET method using a tracer that marks much more than amyloid-beta” ^[9].

The AAW committee reacted to these statements by acknowledging the current developmental state of plasma biomarkers but also pinpointed the strict criteria a biomarker must fulfill to be considered ready for diagnosis ^[7].

Are these new guidelines still considered a “research framework”?

In one of the earlier drafts of the new guidelines, the authors described an advance from research-only towards the clinical context. The AGS highly opposed this advancement in its first response letter from August 2023 ^[10]. After revision by the committee, the AGS reiterated its position as the wording still implies an expansion into the clinical environment ^[6]. Høilund-Carlsen and colleagues also warned about potential harm that comes from an early shift into the clinical practice. They further hypothesized that future clinical trials might consider drugs that inhibit neuronal degeneration as failures if amyloid and tau levels remain unaffected⁸.

The AAW committee reacted by including a text passage in the guidelines, stating that “[t]his is a forward-looking document based on current scientific evidence that provides a common framework for AD diagnostic and staging criteria to inform both research and clinical care.” They further asserted that they “do not provide detailed guidance on clinical workflow or treatment protocols; formal clinical practice guidelines will appear in a subsequent document” and that they “therefore view these criteria as a bridge between research and clinical care” ^[7].

Who should decide about the redefinition of disease diagnosis? 

The most raised concern—supported by the AGS, Høilund-Carlsen and colleagues, and Eric Widera—was featured in Forbes Magazine and concerns potential conflicts of interest among the authors of the proposal. Widera established that around two-thirds of the 22 members are either employed in industrial positions or have other significant conflicts of interest. The Forbes article by Gleckman wrote that “[o]f the 22 members, 16 either work for or have received consulting fees or research grants from drugmakers or the Alzheimer’s Association, which itself is heavily funded by the drug industry. Only two independent researchers participated, and no representatives of people living with Alzheimer’s, their families, or consumer groups” ^[11].

The AGS further emphasized the need for transparency in the process of development, review, and approval of those criteria, especially concerning the involvement of the National Institute of Aging (NIA). They recommended that the document include workgroup members’ disclosures, and a description of how conflicts of interest related to industry were resolved ^[6].

Widera proposed to follow an 8-item checklist, for the future, developed by a Guidelines International Network (G-I-N) workgroup and reminded “that the majority of clinical guideline panels be comprised of members who are free of conflicts and that there be a process for identifying and resolving any potential conflicts”, which was recommended by the Institute of Medicine of the National Academies of Science and the Council of Medical Specialty Societies (CMSS) ^[10].

As a result of these voiced concerns, the NIA removed its name from the criteria list.

Reactions from the scientific community are still incoming. For further reading, please also confer, e.g., Zhou et al. 2024 ^[12].

References:

[1] Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:280–292. DOI: 10.1016/j.jalz.2011.03.003

[2] Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:270–279. DOI: 10.1016/j.jalz.2011.03.008

[3] McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:263–269. DOI: 10.1016/j.jalz.2011.03.005

[4] Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, Liu E, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC, Scheltens P, Siemers E, Snyder HM, Sperling R (2018) NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement 14:535–562. DOI: 10.1016/j.jalz.2018.02.018

[5] Jack CR, Andrews JS, Beach TG, Buracchio T, Dunn B, Graf A, Hansson O, Ho C, Jagust W, McDade E, Molinuevo JL, Okonkwo OC, Pani L, Rafii MS, Scheltens P, Siemers E, Snyder HM, Sperling R, Teunissen CE, Carrillo MC (2024) Revised criteria for diagnosis and staging of Alzheimer’s disease: Alzheimer’s Association Workgroup. Alzheimers Dement 20:5143–5169. DOI: 10.1002/alz.13859

[6] American Geriatrics Society. (2023, November 26). American Geriatrics Society Response – Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease: Alzheimer’s Association Workgroup. Retrieved July 20, 2024.

[7] Jack CR, Andrews SJ, Beach TG, Buracchio T, Dunn B, Graf A, Hansson O, Ho C, Jagust W, McDade E, Molinuevo JL, Okonkwo OC, Pani L, Rafii MS, Scheltens P, Siemers E, Snyder HM, Sperling R, Teunissen CE, Carrillo MC (2024) Revised criteria for the diagnosis and staging of Alzheimer’s disease. Nat Med 30:2121–2124. DOI: 10.1038/s41591-024-02988-7

[8] Widera E (2024) Who gets to decide on what it means to have Alzheimer’s disease? J Am Geriatr Soc 72:1939–1941. DOI: 10.1111/jgs.18793

[9] Høilund-Carlsen PF, Alavi A, Barrio JR, Castellani RJ, Costa T, Herrup K, Kepp KP, Neve RL, Perry G, Revheim M-E, Robakis NK, Sensi SL, Vissel B (2024) Revision of Alzheimer’s diagnostic criteria or relocation of the Potemkin village. Ageing Res Rev 93:102173. DOI: 10.1016/j.arr.2023.102173

[10] American Geriatrics Society. (2023, August 16). American Geriatrics Society Response – Draft NIA-AA Revised Clinical Criteria for Alzheimer’s Disease. Retrieved July 20, 2024.

[11] Gleckman, H. (2023, October 31). NIH Steps Back From Development Of New Alzheimer’s Diagnostic Standards. Forbes. Retrieved July 20, 2024

[12] Zhou RZ, Wimo A, Winblad B (2024) Editorial: on the 2024 Alzheimer’s Association criteria: still not ready for clinical use. J Prev Alzheimers Dis 11:895–896. DOI: 10.14283/jpad.2024.141