Domain 1 ‐ Patient selection
Description	Describe methods of participant selection and characteristics of the included population
Type of bias assessed	Selection bias, spectrum bias
Review question	People with MCI (symptoms, clinical and neurological examinations, neuropsychological tests) tested by brain structural MRI for early diagnosis of AD
Information collected	Study objectives, study population, selection (inclusion/exclusion criteria), study design, clinical presentation, age, gender, number of enrolled and number available for analysis, setting, place and period of the study
Signalling question	Was a consecutive or random sample of participants enrolled?
Yes	If a consecutive sample or a random sample of eligible participants was included in the study
No	If a non‐consecutive sample or a non‐random sample of eligible participants was included in the study
Unclear	All studies that did not specify enrolment as a consecutive or random sample of patients were classified as 'no'; therefore none of the included studies were classified as 'unclear'
Signalling question	Did the study avoid inappropriate exclusions?
Yes	If all MCI participants with suspected AD were included, with an exception for those not able to undergo MRI (e.g. participants with metallic implants or claustrophobia) or for those with alternative diagnosis, e.g. a history of major stroke, a history of neurological or major psychiatric disease, in whom AD would not be suspected in clinical practice
No	If the study excluded participants with co‐morbidities, e.g. with depression, diabetes, cardiovascular disease, or excluded participants on the basis of MRI findings, e.g. presence of ischaemic lesions, lacune
Unclear	If the study did not provide clear definition of inclusion/exclusion criteria and 'no' judgement was not applicable
Signalling question	Was a case‐control design avoided?
Yes	If no selective recruitment of participants with a diagnosis of dementia of any type or MCI and a control group of healthy patients was done, or a nested case‐control design systematically and randomly selected from a defined population cohort was used
No	If retrospective selection of participants with a diagnosis of dementia or MCI and a control group of healthy patients was reported. These studies were excluded; therefore none of the included studies were classified as 'no'
Unclear	All studies that did not provide clear definition of the study design were excluded; therefore none of the included studies were classified as 'unclear'
Risk of bias	Could the selection of participants have introduced bias?
High	If 'no' classification for any of the above 2 questions: 'Was a consecutive or random sample of participants enrolled?' and 'Did the study avoid inappropriate exclusions?'
Low	If 'yes' classification for above 3 questions
Unclear	If 'unclear' classification for the above question' Did the study avoid inappropriate exclusion' and 'high risk' judgement was not applicable
Concerns about applicability	Are there concerns that included participants do not match the review question?
High	If the study population differed from the population defined in the review question in terms of clinical features and co‐morbidity, e.g. studies with multiple sets of inclusion criteria with respect to clinical presentation, including participants who would not have undergone MRI in real practice
Low	If the study included a clinically relevant population who would have undergone MRI in real practice
Unclear	If this information was unclear
Domain 2 ‐ Index test
Description	Describe the index test, how it was conducted and interpreted
Type of bias assessed	Test review bias, clinical review bias, interobserver variation bias
Review question	Volumetric imaging of the whole brain or ROI (hippocampus, ventriculi, entorhinal cortex, amygdale, medial temporal lobe, temporal lobe, cingulate gyrus) by either qualitative visual assessment or by quantitative volumetric measurements, including manually outlining the structure and semi‐automated or automated computer‐based methods
Informaton collected	Index test name, sequences, ROI, measurement techniques, magnetic field, description of positive case definition by index test as reported, examiners (numbers, level of expertise, blinding), interobserver variability
Signalling question	Were the index test results interpreted without knowledge of results of the reference standard?
Yes	If the volumetric imaging was conducted and interpreted before the clinical diagnosis of AD. If imaging results were interpreted at later date through the follow‐up and the study reported a description of whether the interpretation of imaging was performed blind to the clinical diagnosis of AD.
No	If the volumetric imaging was interpreted retrospectively after clinical diagnosis of AD had been done and blinding was not reported
Unclear	If this information was unclear
Signalling question	Did the study provide a clear prespecified definition of what was considered to be a 'positive' result of the index test?
Yes	If study provided clear definition of positive MRI findings, and this was defined before execution/interpretation of MRI
No	If definition of positive MRI result was not provided, or if study described findings derived from MRI and not defined before its execution/interpretation
Unclear	If it was unclear whether the criteria were prespecified
Signalling question	Was the index test performed by a single operator or interpreted by consensus in a joint session?
Yes	If MRI was performed/interpreted by single operator or was interpreted after collegial discussion of the case
No	If MRI was performed/interpreted by various operators for different participants
Unclear	If this information was unclear
Risk of bias	Could the conduct or interpretation of the index test have introduced bias?
High	If 'no' classification for any of the above 3 questions
Low	If 'yes' classification for all the above 3 questions, or if 'unclear' classification for question 'Was the index test performed by a single operator or interpreted by consensus in a joint session?' and ”yes' classification for the remaining 2 questions
Unclear	If 'unclear' classification at least for the question 'Did the study provide a clear pre‐specified definition of what was considered to be a 'positive' result of MRI?' and 'high risk' judgement was not applicable
Concerns about applicability	Are there concerns that the index test, its conduct or its interpretation differs from the review question?
High	We did not consider studies in which MRI looked at other target conditions not specified in the review (e.g. studies aimed at classifying brain atrophy in people with dementia); therefore, none of the included studies was classified as 'high concern'
Low	We considered all types of volumetric MRI modalities, i.e. by manual delineation of regional structures or by semi‐automated or automated techniques, as eligible; therefore, all included studies were classified as 'low concern'
Unclear	Only studies with sufficient information on the volumetric MRI were included; therefore, none of the included studies was classified as 'unclear concern'
Domain 3 ‐ Reference standard
Description	Describe the reference standard, how it was conducted and interpreted
Type of bias assessed	Verification bias, bias in estimation of diagnostic accuracy due to inadequate reference standard
Review question	Target condition ‐ AD; reference standard ‐ clinical follow‐up diagnosis of AD according to the criteria of the NINCDS‐ADRA; McKhann 1984). Clinical follow‐up of ≥ 1 year
Informaton collected	Target condition, prevalence of target condition in the sample, reference standard, description of positive case definition by reference test as reported, examiners (numbers, level of expertise, blinding)
Signalling question	Is the reference standard likely to correctly classify the target condition?
Yes	If the study reported diagnosis of AD according to the NINCDS‐ADRA criteria with a mean clinical follow‐up ≥ 1 year
No	If the study reported criteria for the diagnosis of AD not included in the review protocol, such as use of MRI or beta amyloid or combination of biomarkers. These studies were excluded; therefore none of the included studies were classified as 'no'
Unclear	If diagnostic criteria probably were consistent with our methods description, but not fully reported
Signalling question	Were reference standard results interpreted without knowledge of results of the index tests?
Yes	If clinicians diagnosing AD were unaware of the results of the MRI
No	If clinicians diagnosing AD were aware of the results of the MRI
Unclear	If this information was unclear
Risk of bias	Could the reference standard, its conduct or its interpretation have introduced bias?
High	If 'no' classification for the above question 'Were reference standard results interpreted without knowledge of results of the index tests?'
Low	If 'yes' classification for both of the above 2 questions
Unclear	If 'unclear' classification for either of the above 2 questions and 'high risk' judgement was not applicable
Concerns about applicability	Are there concerns that the target condition as defined by the reference standard does not match the question?
High	We excluded studies in which participants did not undergo at least 1 year's follow‐up for clinical diagnosis of AD according to the NINCDS‐ADRA criteria; therefore, none of the included studies were classified as 'high concern'
Low	In the light of inclusion criteria, all studies were classified as 'low concern'
Unclear	In the light of inclusion criteria, no included studies were classified as 'unclear concern'
Domain 4 ‐ Flow and timing
Description	Describe any participants who did not receive MRI or the reference standard, or who were excluded from the 2 x 2 table; describe the interval and any interventions between MRI and the reference standard
Type of bias assessed	Bias of diagnostic performance due to different reference standard, missing data
Review question	We had chosen an arbitrary minimum follow‐up period of 12 months after MRI to assess whether AD is present. Studies indicate that annual rates of progression from MCI to clinical AD are approximately 10% to 15%
Informaton collected	Time interval between MRI and clinical diagnosis of AD, withdrawals and losses to follow‐up (overall number reported and whether they were explained)
Signalling question	Was there an appropriate interval between index test and reference standard?
Yes	If follow‐up period was reported and was at least 12 months
No	We excluded all studies for which the follow‐up period was < 12 months; therefore, no included studies were classified as 'no' for this item
Unclear	If the time interval was not stated clearly but the study authors' description allowed one to assume that the interval was reasonably long
Signalling question	Did all participants receive the same reference standard?
Yes	If all MCI patients, or a random sample of them, who received MRI were followed up to receive verification of AD diagnosis according to the NINCDS‐ADRA criteria
No	If some of the MCI participants who received MRI were diagnosed throughout the follow‐up using different diagnostic criteria, e.g. some received diagnosis of AD according to the NINCDS‐ADRA criteria and some according to the composite Dubois's criteria where MRI forms part of the Alzheimer diagnosis (incorporation bias)
Unclear	If this information was unclear
Signalling question	Were all participants included in the analysis?
Yes	If all participants were included in the analysis, or if participants were excluded because they did not meet inclusion criteria or if participants withdrew from the study or were lost to follow‐up did not differ systematically from those who remained
No	If any participants were excluded from the analysis because of uninterpretable results, because of non random selection of participants who were followed, e.g. selection was associated with the results of MRI, or reasons for withdrawals were not explained
Unclear	No studies were classified as 'unclear' for this item
Risk of bias	Could the participant flow have introduced bias?
High	If 'no' classification for any of the above 3 questions
Low	If 'yes' classification for all of the above 3 questions
Unclear	If 'unclear' classification for any of the above 3 questions and 'high risk' judgement was not applicable
AD: Alzheimer's disease; MCI: mild cognitive impairment; MRI: magnetic resonance imaging; NINCDS‐ADRA: National Institute of Neurological and Communication Disorders and Stroke‐Alzheimer's Disease and Related Disorders Association; ROI: region of interest