Suspected non-Alzheimer's pathology - Is it non-Alzheimer's or non-amyloid?

Neurodegeneration, the progressive loss of neurons, is a major process involved in dementia and age-related cognitive impairment. It can be detected clinically using currently available biomarker tests. Suspected Non-Alzheimer Pathology (SNAP) is a biomarker-based concept that encompasses a group of individuals with neurodegeneration, but no evidence of amyloid deposition (thereby distinguishing it from Alzheimer's disease (AD)). These individuals may often have a clinical diagnosis of AD, but their clinical features, genetic susceptibility and progression can differ significantly, carrying crucial implications for precise diagnostics, clinical management, and efficacy of clinical drug trials. SNAP has caused wide interest in the dementia research community, because it is still unclear whether it represents distinct pathology separate from AD, or whether in some individuals, it could represent the earliest stage of AD. This debate has raised pertinent questions about the pathways to AD, the need for biomarkers, and the sensitivity of current biomarker tests. In this review, we discuss the biomarker and imaging trials that first recognized SNAP. We describe the pathological correlates of SNAP and comment on the different causes of neurodegeneration. Finally, we discuss the debate around the concept of SNAP, and further unanswered questions that are emerging.