The implications of different approaches to define AT(N) in Alzheimer's disease

Objective: To compare different amyloid-β (A),
tau (T) and neurodegeneration (N) [AT(N)] variants within the
Swedish BioFINDER studies. Methods: A total of490 participants
were classified into AT(N) groups. These include  53
cognitively unimpaired (CU) and 48 cognitively impaired (CI)
participants (14 mild cognitive impairment [MCI] and 34 AD
dementia) from BioFINDER-1 and 389 participants from BioFINDER-2 (245 CU
and 144 CI subjects [138 MCI and six AD
dementia]).Biomarkers for “A” were CSF Aβ42 and Amyloid-PET
([18F]flutemetamol); for “T” CSF P-tau and Tau-PET ([18F]flortaucipir);
and for “(N)” hippocampal volume, temporal cortical thickness and CSF
neurofilament light (NfL). Binarization of biomarkers was
achieved using cut-offs defined in other cohorts. The relationship between
different AT(N) combinations and cognitive trajectories (longitudinal Mini
Mental State Examination (MMSE) scores) was examined using linear mixed
modelling and coefficient of variation. Results: Among CU
subjects, A-T-(N)- or A+T-(N)- variants were most common. However, more T+
cases were seen using P-tau than Tau-PET. Among CI subjects,A+T+(N)+ was
more common; however, more (N)+ cases were seen for MRI-measures relative
to CSF NfL. Tau-PET best predicted longitudinal cognitive decline in CI
and P-tau in CU
subjects. Among CI subjects, continuous T (especially Tau-PET) and (N) measures improved the prediction of cognitive decline compared to binary measures.   Conclusions: Our findings show that different AT(N) variants are not interchangeable, and that optimal variants differ by clinical stage. In some cases, dichotomizing biomarkers may result in loss of important prognostic information.