2.2. Global Deterioration Scale (GDS)DS classification

The patients' degree of cognitive decline was staged according to the Global Deterioration Scale (GDS). 11 The GDS classifications were made using the following instruments: Variables 13‐20 of the Stepwise Comparative Status Analysis (STEP) 12 (ie, memory disturbance, disorientation, reduced abstract thinking, visuospatial disturbance, poverty of language, sensory aphasia, visual agnosia, and apraxia); IFlex, which is a short form of the Executive Interview (EXIT) 13 (ie, number‐letter task, word fluency, anomalous sentence repetition, interference task, Luria hand sequences, and counting task); Min Mental State Examination (MMSE) 14 ; and Clinical Dementia Rating (CDR). 15 The CDR sum of boxes assessment was based on information from both the patient and an informant. The guidelines for the classification were as follows: For GDS 2 (subjective cognitive impairment [SCI]) participants should have MMSE ≥28, CDR ≤0.5, I‐FLEX <3, and no positive outcomes on variables 13‐20 of STEP; GDS 3 (MCI) corresponds to MMSE ≥26, CDR >0.5, I‐FLEX ≤3, and one or fewer positive outcomes on variables 13‐20 of STEP; and for GDS 4 (mild dementia) participants should have MMSE ≤25, CDR >1.0, STEP >1, and I‐FLEX >3. When the guidelines were not applicable, a consensus decision among the physicians at the clinic was made to determine the appropriate GDS score.

Systematic review: We analyzed articles that have referenced the 2018 NIA‐AA (National Institute on Aging and Alzheimer's Association) research framework, with particular emphasis on studies applying and evaluating the ATN system (amyloid beta [Aβ] aggregation [A], tau aggregation reflecting neurofibrillary tangles [T], and neurodegeneration [N]) on a clinical or general population. We additionally searched PubMed using the term “ATN system” for any articles that we have missed.

Interpretation: Our findings validate the use of the ATN system in a memory clinic sample with different clinical outcomes and different underlying disorders. However, the ATN system does not seem to cluster patients subsequently converting to forms of dementia other than Alzheimer's disease (AD).

Future directions: Although the group fulfilling the criteria for biological AD were highly represented among the patients converting to AD or mixed dementia, 35% did not develop manifest dementia during the course of the study. Longer follow‐up times are needed to ascertain that biological defined AD will also manifest itself clinically.

Participants classified as GDS 4 were further classified according to the following etiological dementia criteria: AD according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS‐ADRDA) criteria 16 and subcortical vascular dementia (SVD) according to the Erkinjuntti criteria, 17 frontotemporal dementia (FTD) according to, 18 and Lewy body dementia (LBD) according to. 19 For mixed dementia, AD criteria had to be fulfilled as well as moderate/severe WMC (Fazekas score ≥2) on MRI or alternatively, mild WMC in combination with a marked frontosubcortical‐dysexecutive syndrome. If no diagnostic criteria could be fulfilled, the patient was classified as unspecified dementia. The clinician who set the dementia diagnoses had access to clinical symptomatology and MRI images but was blinded to volumetric data, neuropsychological test results, and CSF biomarker data. The guidelines and diagnostic procedures have been described in detail previously. 9