Alzheimer's disease (AD) is marked by the spread of misfolded amyloid-β and tau proteins throughout the brain. While it is commonly believed that amyloid-β abnormality drives the cascade of AD pathogenesis, several in vivo and post mortem studies indicate that in some subjects localized tau-based neurofibrillary tangles precede amyloid-β pathology. This suggests that there may be multiple distinct subtypes of protein aggregation pathways within AD, with potentially different demographic, cognitive and comorbidity profiles. We investigated this hypothesis, applying data-driven disease progression subtyping models to post mortem immunohistochemistry and in vivo positron emission tomography (PET) and cerebrospinal fluid (CSF) based measures of protein pathologies in two large observational cohorts. We consistently identified both amyloid-first and tau-first AD subtypes, where tau-first subjects had higher levels of soluble TREM2 compared to amyloid-first subjects. Our work provides insight into AD progression that may be valuable for interventional trials targeting amyloid-β and tau.

Tau-first subtype of Alzheimer's disease consistently identified across in vivo and post mortem studies