See O'Sullivan and Vann (doi:10.1093/aww166) for a scientific commentary on this article.About 15% of patients clinically diagnosed with
Alzheimer's disease do not show high tracer retention on
amyloid positon emission tomography imaging. The present study investigates clinical and demographic features, patterns of brain
atrophy and hypometabolism and longitudinal clinical trajectories of these patients. Forty
amyloid-negative patients carrying a pre-scan diagnosis of
Alzheimer's disease dementia from four centres were included (11/29 females/males; mean age = 67 ± 9). Detailed clinical histories, including the clinical diagnoses before and after the
amyloid scan and at follow-up, were collected. Patients were classified according to their pre-scan clinical phenotype as amnestic (memory predominant), non-amnestic (predominant language, visuospatial or frontal symptoms), or non-specific (diffuse cognitive deficits). Demographic, clinical, neuropsychological, magnetic resonance imaging and (18)F-fluorodeoxyglucose positon emission tomography data were compared to 27
amyloid-positive typical
Alzheimer's disease cases (14/13 females/males; mean age = 71 ± 10) and 29
amyloid-negative controls (15/14 females/males; mean age = 69 ± 12) matched for age, gender and education. There were 21 amnestic, 12 non-amnestic, and seven non-specific
amyloid-negative
Alzheimer's disease cases.
Amyloid-negative subgroups did not differ in age, gender or education. After the
amyloid scan, clinicians altered the diagnosis in 68% of
amyloid-negative patients including 48% of amnestic versus 94% of non-amnestic and non-specific cases. Amnestic
amyloid-negative cases were most often reclassified as
frontotemporal dementia, non-amnestic as
frontotemporal dementia or
corticobasal degeneration, and non-specific as
dementia with Lewy bodies or unknown diagnosis. The longer-term clinical follow-up was consistent with the post-scan diagnosis in most cases (90%), including in amnestic
amyloid-negative cases whose post-positon emission tomography diagnosis remained
Alzheimer's disease. While the non-amnestic and non-specific
amyloid-negative cases usually showed patterns of
atrophy and hypometabolism suggestive of another degenerative disorder, the amnestic
amyloid-negative cases had subtle
atrophy and hypometabolism, restricted to the retrosplenial/posterior cingulate cortex. Patients with a negative
amyloid positon emission tomography scan following an initial clinical diagnosis of
Alzheimer's disease have heterogeneous clinical presentations and neuroimaging profiles; a majority showed a
clinical progression that was consistent with a neurodegenerative condition. In contrast, in the subgroup of amnestic
amyloid-negative cases, the clinical presentation and follow-up usually remained consistent with
Alzheimer's disease. An alternative diagnosis was not made in about half of the amnestic
amyloid-negative cases, highlighting the need for a clinical framework and terminology to define these patients, who may have underlying limbic-predominant, non-
amyloid-related pathologies.