.....Here, we review data suggesting that prefibrillar tau oligomers mediate cognitive decline early in the disease. Objective: It was our aim to study the presence of tau-positive pretangle neurons and correlate findings with cognitive test scores. Methods: Pretangle antibodies (TOC1 and pS422) were applied to tissue containing cholinergic basal forebrain neurons from people who died with a premortem clinical diagnosis of no cognitive impairment, mild cognitive impairment and AD. Results: Data lend support to the concept that tau oligomers are the toxic form of tau, that non-fibillar tau relates to cognitive dysfunction and that the earliest pretangle pathology occurs in neuritic processes. Conclusions: Clinicopathological findings highlight the importance of studying tau modifications in neuronal soma and neuritic processes, which may be the earliest pathological lesions that correlate with cognitive status.