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Is tau in the absence of amyloid on the Alzheimer’s continuum?: A study of discordant PET positivity
Is tau in the absence of amyloid on the Alzheimer’s continuum?: A study of discordant PET positivity
Introduction:
Introduction:
The amyloid cascade model of Alzheimer’s disease (AD) posits the primacy of amyloid beta deposition preceding tau-mediated neurofibrillary tangle formation. The amyloid-tau-neurodegeneration (A/T/N) biomarker-only diagnostic framework similarly requires the presence of amyloid beta for a diagnosis on the Alzheimer’s continuum. However, medial temporal lobe tau pathology in the absence of amyloid beta is often observed at autopsy in cognitively normal individuals, a phenomenon that may reflect a consequence of aging and has been labelled ‘primary age-related tauopathy’ or PART. Alternatively, others argue that this tauopathy reflects an early stage of the developmental continuum leading to AD. We used positron emission tomography (PET) imaging to investigate amyloid beta and tau positivity and associations with cognition to better inform the conceptualization of biomarker changes in Alzheimer’s pathogenesis.
Methods:
Methods:
This study included 523 older adults from the Alzheimer’s Disease Neuroimaging Initiative who had undergone tau PET (flortaucipir) imaging with PET positivity thresholds derived using conditional inference decision tree regression. A subsample of 301 individuals without dementia (i.e. cognitively unimpaired or with mild cognitive impairment) had also undergone amyloid PET (florbetapir) imaging within 12 months and were categorized into one of four groups based on neocortical amyloid and Braak stage I/II tau positivity: A−/T−, A+/T−, A−/T+, or A+/T+. Groups were then compared on clinical and cognitive characteristics.
Results:
Results:
Tau positivity in the absence of amyloid beta positivity (A−/T+) comprised the largest group, representing 45% of the sample. In contrast, only 6% of the sample was identified as A+/T−, with the remainder of the sample falling into A−/T− (22%) or A+/T+ (27%) categories. A−/T− and A+/T− groups had the best cognitive performances across memory, language and executive function; the A−/T+ group showed small-to-moderate relative decreases in cognition across domains; and the A+/T+ group generally had the worst cognitive performances. Furthermore, there were negative associations between Braak stage I/II tau severity and all cognitive domains only in the A−/T+ and A+/T+ groups, with strongest associations for the A+/T+ group.
Conclusions:
Conclusions:
1) Among our sample of older adults across the Alzheimer’s pathological spectrum, far fewer individuals have PET evidence of amyloid beta pathology in the absence of tau pathology than the converse, potentially challenging prevailing models of amyloid beta’s primacy in Alzheimer’s pathogenesis.
2) Given that cognitive performance in the A−/T+ group was poorer than for individuals without either pathology, medial temporal lobe tau without significant neocortical amyloid beta may reflect an early stage on the Alzheimer’s pathological continuum with risk for future progression, although longitudinal studies will be important.
3) Replication of these findings in a more demographically representative sample will better inform the diversity of and interaction between biologic and cognitive changes in AD.
Citation: Weigand, A.J., Bangen, K.J., Thomas, K.R., Salmon, D.P., Galasko, D.R., & Bondi, M.W. (2020). Is Tau in the Absence of Amyloid on the Alzheimer’s Continuum?: A Study of Discordant PET Positivity. Brain Communications, 2(1), fcz046.
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