Atrophy , hypometabolism and clinical trajectories in amyloid negative probable AD patients

About 15% of patients clinically diagnosed with Alzheimer’s disease do not show high tracer retention on amyloid PET. The present study investigates the clinical and demographic features, patterns of brain atrophy and hypometabolism and longitudinal clinical trajectories of these patients, with a particular emphasis on the AD-mimic typical amnestic subgroup. 38 amyloid PET-negative patients carrying a pre-PET diagnosis of AD (Aβneg-AD) from 4 centers (Amsterdam, Melbourne, San Francisco and Caen) were included in this study (11/27 females/males; mean age=67±9). Detailed clinical histories, including the clinical diagnoses before and after the PET scan and at follow-up (>2 years), were collected. Patients were classified according to their pre-PET clinical phenotype as amnestic (memory predominant), non-amnestic (predominant language, visuospatial or frontal symptoms), or non-specific (diffuse cognitive deficits). Demographic, clinical, neuropsychological, MRI and FDG-PET data obtained at the time of the amyloid-PET scan were compared between Aβneg-AD subgroups, 27 Aβ-positive AD cases with a typical amnestic clinical presentation (Aβpos-AD; 14/13 females/males; mean age=71±10) and 29 Aβ-negative cognitively healthy controls (Aβneg-HC; 15/14 females/males; mean age=69±12) matched for age, gender and education. There were 19 amnestic, 13 non-amnestic, and 7 non-specific Aβneg cases. Aβneg-AD subgroups did not differ in age, gender, education or APOE4 proportion. After the PET scan, clinicians altered the diagnosis in 68% of Aβneg-AD cases including 44% of amnestic versus 94% of non-amnestic and non-specific cases. Amnestic Aβneg-AD were most often reclassified as frontotemporal dementia, non-amnestic as frontotemporal dementia or corticobasal degeneration, and non-specific as dementia with Lewy bodies. The longer-term clinical followup was consistent with the post-PET diagnosis in most cases (89%), including in amnestic Aβneg-AD whose post-PET diagnosis remained AD. While the non-amnestic and non-specific Aβneg-AD usually showed patterns of atrophy and hypometabolism suggestive of another degenerative disorder, the amnestic Aβneg-AD had subtle atrophy and hypometabolism, restricted to the retrosplenium – posterior cingulate – posterior hippocampus junction. AβnegAD patients have heterogeneous clinical presentations and likely represent a mixed population of initially misdiagnosed, mostly neurodegenerative, conditions. The clinical, cognitive, MRI and FDG profiles aided to find an alternative post-PET diagnosis in most non-amnestic cases. In the largest and most intriguing subgroup of amnestic Aβneg-AD however, the patients mimic typical AD in their clinical presentation and follow-up, so that an alternative diagnosis was not made in more than half of the cases – highlighting the need for a clinical framework and terminology to define these patients, who may have underlying limbic-predominant, non-Aβdriven pathologies.