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Evaluation of the ATN model in a longitudinal memory clinic sample with different underlying disorders

Abstract Introduction To evaluate the usefulness of the 2018 NIA‐AA (National Institute on Aging and Alzheimer's Association) research framework in a longitudinal memory clinic study with different clinical outcomes and underlying disorders. Methods We included 420 patients with mild cognitive impairment or subjective cognitive impairment. During the follow up, 27% of the patients converted to dementia, with the majority converting to Alzheimer's disease (AD) or mixed dementia. Based on the baseline values of the cerebrospinal fluid biomarkers, the patients were classified into one of the eight possible ATN groups (amyloid beta [Aβ] aggregation [A], tau aggregation reflecting neurofibrillary tangles [T], and neurodegeneration [N]). Results The majority of the patients converting to AD and mixed dementia were in ATN groups positive for A (71%). The A+T+N+ group was highly overrepresented among converters to AD and mixed dementia. Patients converting to dementias other than AD or mixed dementia were evenly distributed across the ATN groups Discussion Our findings provide support for the usefulness of the ATN system to detect incipient AD or mixed dementia.

studies have evaluated the ATN system in relation to clinical outcome.
The A+T+N+ group has been linked to clinical or cognitive deterioration in the general population, 4 and studies in memory clinic populations found that the A+T+N+ group was more prevalent when the clinical symptoms were severe or when the risk of future conversion to AD was elevated. [5][6][7] A biological definition of AD using the ATN system could simplify the diagnostic process and result in early identification of individuals with the potential to benefit from disease-modifying therapies. This addresses one commonly stated reason for the so-far negative results from recent AD trials, namely that the therapies were given too late in the disease process. 8 Although promising, the ATN construct needs further validation, preferable in the general population with long-term follow-up or in clinical populations reflecting the inflow of patients with cognitive complaints. The objective of the present study was therefore to apply the ATN system in a naturalistic memory clinic sample with different clinical outcomes and different underlying disorders.

The Gothenburg MCI study
The Gothenburg MCI (mild cognitive impairment) study is a monocenter, clinically based longitudinal study that aims to identify neurodegenerative and vascular disorders prior to the development of dementia. 9 The Gothenburg MCI study was approved by the local ethics committee in Gothenburg (approval number: L091-99, 1999; T479- 11,2011

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

The study population
In the present study, we included all participants in the Gothenburg MCI study that were classified as either SCI or MCI at baseline and had at least one follow-up examination. This resulted in a study popu-  -AMYLOID  , respectively) from Innogenetics, Gent. 20 CSF Ptau levels for 16 study participants were analyzed using the xMAP AlzBio3 kit (Innogenetics, Ghent, Belgium) and were used together with enzyme-linked immunosorbent assay (ELISA) results after applying a correction factor, as described previously. 21 The CSF samples were processed at the Clinical Neurochemical Laboratory at Sahlgrenska University Hospital as part of clinical routine on multiple occasions during the course of the study. Still, the analytical variability was low. 22 Apolipoprotein E (APOE) 4 status was analyzed using solid-phase minisequencing. 9

Neuropsychological assessment
The Gothenburg MCI study includes a comprehensive neuropsychological test battery, which has previously been described in detail. 23 The following tests were included in the present study: Trail

Neuroimaging
Baseline MRI data from a 1.

ATN classification
All patients were classified according to the ATN classification system signifying the presence or absence of amyloid deposition (A), tau aggregation (T), and neurodegeneration (N). 1 We used CSF biomarker data for the classification of ATN groups; as described by, 1 we used A 42 for the classification of A, P-tau for the classification of T, and T-tau for the classification of N. More specifically: for A, CSF A 42 ≤482 ng/L was required for a positive classification; for T, CSF P-tau ≥52 ng/L was classified as T+; and for N, CSF T-tau ≥320 ng/L was classified as N+. Cutoff values were derived from. 24 Based on these criteria, the study participants were then divided into one of the eight possible ATN groups.

Statistical analyses
Demographic differences between the A-T-N-group versus the other ATN groups combined were analyzed using the independent samples t

RESULTS
Demographic data of the ATN groups are presented in Table 1.
Although there were no differences regarding years of education and MMSE score, the A-T-N-group was younger and less likely to carry an APOE 4 allele compared to most of the other groups.  Follow-up time was defined as the time until conversion or to last follow-up and is presented as the mean ± SD. ATN groups were compared to the A-T-Ngroup. Furthermore, in each ATN group, converters were divided in two groups depending on whether the conversion occurred within or after 3 years from baseline. Then, these groups were further divided based on whether the conversion was to AD/mixed dementia or SVD/other dementia. Between-group differences were analyzed using 2  Results from the follow up examinations are presented in Table 3.

A+T+N+ A+T-N-A-T+N+ A-T+N-A-T-N+ A-T-N-
The follow-up status differed between the groups, as <10% of participants in the A-T+N-and A-T-N-group had converted to dementia compared to more than half in the A+T+N+ group. Of note, most converters in groups with N+ tended to convert within 3 years from the baseline examination. Figure 1 displays follow-up status in ATN groups. Figure 2 displays ATN groups in the participants converting to dementia.

DISCUSSION
We applied the ATN system retrospectively to the Gothenburg MCI study and found that 23% of the study population were classified as A+T+N+. However, this group accounted for a majority of the patients subsequently converting to dementia, with 89% of converters converting to either AD or mixed dementia. In contrast, only a few participants in the A-T+N-and A-T-N-groups converted to dementia.
The accumulation of A deposits has been found to start early in adult life. 3 A strict biological definition of AD using the ATN system could therefore enable researchers to undertake intervention studies already in the presymptomatic stages of AD. Nevertheless, it is still unclear whether all patients fulfilling the criteria for biologically defined AD will develop clinically manifest AD and, if so, in which time frame. Previous reports suggest that there is a group of individuals that exhibit all the pathological hallmarks of AD without obvious signs of cognitive deterioration, 25 suggesting that biologically defined AD is more prevalent than the traditional definition. Indeed, the results of a recent population study supported this notion, reporting that biologically defined AD was up to three times more prevalent than clinically defined AD depending on the age group studied. 26 In our study, 35% of the patients in the A+T+N+ group did not convert to dementia during follow-up. This does not necessarily invalidate the ATN concept, but could be secondary to insufficient length of the follow-up time (mean 32 months in the A+T+N+ group). Therefore, although a longer follow-up time would have been preferable, is clear that a proportion of individuals with A+T+N+ will not convert to dementia in a relatively long time. This might in turn provide an opportunity for early identification of individuals with the potential to benefit from disease modifying therapies.
It should be noted that 23% of our patients were classified as A+T+N+, which is higher than that reported in most previous studies. Two population-based studies found prevalence levels between 8% and 10%, 27,28 and two clinically based studies observed a prevalence of A+T+N+ of around 20%. 5,6 The prevalence of A+T+N+ in the clinically based study by Altomare et al. was only marginally lower than that F I G U R E 1 Follow-up status in ATN groups. The top panel displays the number of patients who had recovered, been stable, and converted to dementia in each ATN group. The bottom panel displays the proportion of patients in the ATN groups who had recovered, been stable, or converted to a specific dementia diagnosis found in our study, but their study included relatively young patients and also patients with dementia at baseline, who showed the highest prevalence of A+T+N+ (35%). 5 Although this difference in the composition of study participants highlights the high prevalence of A+T+N+ in the present study, our results concur with the previous findings of increased prevalence of A+T+N+ with increasing age and more severe clinical symptoms. In addition, our findings are in line with a previous study from the Gothenburg MCI study, evaluating the NIA-AA guidelines from 2011 on a smaller data set, finding that patients positive for amyloid and either t-tau or P-tau were most likely to convert to AD. 29 The distribution of SCI patients differed between the groups, with the highest prevalence was seen in the A-T+N-, A-T-N+, and A-T-N-groups.
These groups also had the lowest rate of conversion to dementia, which is consistent with the view that SCI has a lower conversion rate than MCI, 30 and also with studies finding that A 42 is the best individual predictor for clinical progression in SCI. 31 Examination of the baseline neuropsychological test performance showed that the A+T+N+ group clearly stood out compared to the model. The low number of converters to AD in the A-/N-groups is in line with results of a previous study. 35 We found, however, that the A-T+N+ group is not only quite prevalent, but also accounts for a large proportion of patients converting to AD and mixed dementia, second only to the A+T+N+ group. This raises questions regarding this group.
A-with either T+, N+, or both, is commonly classified as Suspected Non-Alzheimer Pathology (SNAP), and although there have been discussions about whether SNAP should be regarded as an early manifestation of AD, 36 the current interpretation of the A-T+ groups is that they do not reflect the AD pathologic change. 1 Instead, it has been suggested that A-T+ may reflect the primary age-related tauopathy (PART). 37 Although this merits further study, the relatively young age of the patients in our A-T+N+ group is not fully consistent with PART, but rather favors the view that tauopathy may have a more prominent role in the pathophysiology of AD. 38 Another interesting aspect of the A-T+N+ group is the high number of patients with one or more APOE 4 alleles. ApoE binds to A and the 4 variant has been linked to A deposition, which is believed to be the reason for the increased risk of AD for APOE 4 patients. 39 However, a recent study supports the idea that that APOE 4 is involved also in tau-mediated neurodegeneration independent of A , 40 which could explain the findings in the A-T+N+ group.

LIMITATIONS
A consequence of evaluating a system with eight study groups is the difficulty of having enough power to analyze all groups, especially with regard to longitudinal outcome. Despite including 420 memory clinic patients at baseline, the low frequencies of some ATN groups precluded meaningful statistical analysis of these groups. Consequently, we believe it could be beneficial to cluster some groups to improve the statistical power, as has previously been suggested. 5 Another drawback is the diagnostic accuracy of dementia. Evaluating a biological definition of AD should ideally be compared with a definite diagnosis obtained through neuropathological examination.
Furthermore, although the diagnostic system in the Gothenburg MCI study is carefully constructed, the possibility cannot be excluded that some of the dementia patients were misclassified. This risk of misclassification is likely greatest in the spectrum of AD and mixed dementia.
Reflecting this, we opted to group AD and mixed dementia together in some analyses.

CONCLUSION
The high frequency of converters to AD and mixed dementia in the

ACKNOWLEDGMENTS
We would like to thank Marie Johansson and Eva Bringman for administrating the study, Erik Olsson and Niklas Klasson for help with the MRI analyses, and the staff at the memory clinic in Mölndal and the staff at the Neurochemical Laboratory for data collection and analyses.

CONFLICTS OF INTEREST
The authors have no competing interests to report.