Suspected Non-Alzheimer's Disease Pathophysiology (SNAP) and Its Pathological Backgrounds in the Diagnosis of Preclinical and Clinical Alzheimer's Disease

Abstract

Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker-based condition that is found in individuals with normal levels of amyloid-β protein (Aβ) markers (A-) and abnormal levels of markers of neurodegeneration or neuronal injury (N+). SNAP is found in 20-26% of cognitively normal (CN) individuals aged 65 years or older and 17-35% of individuals with mild cognitive impairment (MCI). Similarly, 7-39% of patients with clinically probable Alzheimer's disease (AD) dementia are negative for Aβ. The ε4 allele of the apolipoprotein E gene is underrepresented in individuals with SNAP compared with amyloid-positive (A+) groups. The progression of the cognitive impairments of individuals with SNAP was slower than that of A+N+ subjects who had a high likelihood of AD pathophysiology and faster than that of A-N- subjects. The pathological backgrounds of the individuals with SNAP were heterogeneous and included cerebrovascular disorders, mixed pathologies, and non-AD neurodegeneration, such as primary age-related tauopathy [PART, also known as senile dementia of the neurofibrillary tangle type (SD-NFT) (tangle-only dementia) at the dementia stage] and argyrophilic grain disease. Further clarification of SNAP is needed to better define the mechanisms underlying the progression of AD pathologies in older individuals.