Exploring discordant low amyloid beta and high neocortical tau positron emission tomography cases

Abstract

Introduction Neocortical 3R4R (3‐repeat/4‐repeat) tau aggregates are rarely observed in the absence of amyloid beta (Aβ). 18 F‐MK6240 binds specifically to the 3R4R form of tau that is characteristic of Alzheimer's disease (AD). We report four cases with negative Aβ, but positive tau positron emission tomography (PET) findings. Methods All Australian Imaging, Biomarkers and Lifestyle study of aging (AIBL) study participants with Aβ ( 18 F‐NAV4694) and tau ( 18 F‐MK6240) PET scans were included. Centiloid <25 defined negative Aβ PET (Aβ–). The presence of neocortical tau was defined quantitatively and visually. Results Aβ– PET was observed in 276 participants. Four of these participants (one cognitively unimpaired [CU], two mild cognitive impairment [MCI], one AD) had tau tracer retention in a pattern consistent with Braak tau stages V to VI. Fluid biomarkers supported a diagnosis of AD. In silico analysis of APP, PSEN1, PSEN2 , and MAPT genes did not identify relevant functional mutations. Discussion Discordant cases were infrequent (1.4% of all Aβ– participants). In these cases, the Aβ PET ligand may not be detecting the Aβ that is present.

Amyloid and tau‐PET in early‐onset AD: Baseline data from the Longitudinal Early‐onset Alzheimer's Disease Study (LEADS)

“…Additional genetic and biofluid analyses, and ultimately autopsy data, will be helpful to better interpret these PET results and clarify the underlying cause of cognitive impairment in these patients. A likely hypothesis, supported by Krishnadas et al., 47 is that these patients could have underlying AD with a false negative amyloid‐PET due to a relative low burden of neuritic plaques 39 or rare Aβ conformation that are not detected by the radiotracer 48–51 . Alternatively, PET results could reflect a false positive tau‐PET or a true tau tangle‐only disease, such as primary age‐related tauopathy 52 or MAPT variants associated with tau‐PET‐positive Frontotemporal lobar degeneration (FTLD)‐tauopathy 53 …”

“…See Table S4 and Figure S3 for statistical comparisons. EOAD, early-onset Alzheimer's disease; EOnonAD, early-onset non-Alzheimer's disease; PCA, posterior cortical atrophy; PET, positron emission tomography; PPA, primary progressive aphasia; SUVR, standardized uptake value ratio et al, 47 is that these patients could have underlying AD with a false negative amyloid-PET due to a relative low burden of neuritic plaques 39 or rare Aβ conformation that are not detected by the radiotracer. [48][49][50][51] Alternatively, PET results could reflect a false positive tau-PET or a true tau tangle-only disease, such as primary age-related tauopathy 52 or MAPT variants associated with tau-PET-positive Frontotemporal lobar degeneration (FTLD)-tauopathy.…”

Tau Pathology Without Aβ—A Limited PART of Clinical Progression

“…Studies have generally agreed with these findings and concluded that PART has some features in common with, but is distinct from, AD . However, there are critical methodologic differences in how PART is defined in neuropathologic and biomarker studies that complicate comparisons.…”

“…Studies have generally agreed with these findings and concluded that PART has some features in common with, but is distinct from, AD. [11][12][13][14][15] However, there are critical methodologic differences in how PART is defined in neuropathologic and biomarker studies that complicate comparisons. Participants in observational studies are younger than individuals in neuropathologic cohorts, limiting direct comparison of this agerelated pathologic condition.…”

Neuroimaging in Dementia

“…Amyloid-positive patients with MCI show greater tau deposition than amyloid-negative patients with MCI, with very few individuals showing high tau deposition in the absence of amyloid deposition 33 . In fact, amyloid-negative patients with tau positivity in the cortex have recently been postulated to be false-negative amyloid PET cases 34 . Longitudinal studies have suggested that patients with MCI show a more pronounced rate of accumulation of tau relative to cognitively normal people.…”