Background:Alzheimer’s disease (AD) affects an increasing number of individuals in our societies. It is characterized by accumulation of fibrillary amyloid plaques in the brain. Recently, several studies have emphasized the role of positron emission tomography (PET) using amyloid biomarkers which allow in vivo visualization of plaques to distinguish AD pathology from other forms of protein accumulations leading to dementia. However, very few studies have investigated the role of amyloid imaging in the differential diagnosis of atypical/unclear cases, that is complex dementia syndromes where even a comprehensive investigation yields no clear diagnosis. Moreover, no studies have investigated the impact of a correct diagnosis on caregivers and their perception of the process. Methods:Using a novel amyloid tracer (NAV4694), we scanned 20 patients with an atypical/unclear dementia syndrome as determined by an experienced behavioral neurologist from a tertiary care center. All patients had a full work-up (i.e., clinical, blood tests, neuropsychological evaluation, structural and functional imaging) yet no certain diagnosis. Amyloid-PETs were either positive or negative based on qualitative and quantitative reads by two independent readers. A questionnaire was given to the treating neurologist to determine whether amyloid imaging allowed a more accurate diagnosis and changed treatment plans. Caregivers were met one month after the revelation of the diagnosis and completed a questionnaire followed by a standardized interview designed to assess its impact. Results: A statistically significant increase in confidence levels amongst physicians who ordered amyloid imaging in such cases was found. Revelation of diagnosis to caregivers was associated with better acceptance of the disease as well as a clearer view of future challenges. Conclusions: This study suggests that amyloid imaging is useful in the differential diagnosis of atypical/unclear dementias, and has a positive impact on caregivers. AmyloidPET is indicated in the investigation of complex, atypical/unclear dementing disorders.