Amyloid‐dependent and amyloid‐independent effects of Tau in individuals without dementia

Abstract

Objective To investigate the relationship between the topography of amyloid‐β plaques, tau neurofibrillary tangles, and the overlap between the two, with cognitive dysfunction in individuals without dementia. Methods We evaluated 154 individuals who were assessed with amyloid‐β PET with [18F]AZD4694, tau‐PET with [18F]MK6240, structural MRI, and neuropsychological testing. We also evaluated an independent cohort of 240 individuals who were assessed with amyloid‐β PET with [18F]Florbetapir, tau‐PET with [18F]Flortaucipir, structural MRI, and neuropsychological testing. Using the VoxelStats toolbox, we conducted voxel‐wise linear regressions between amyloid‐PET, tau‐PET, and their interaction with cognitive function, correcting for age, sex, and years of education. Results In both cohorts, we observed that tau‐PET standardized uptake value ratio in medial temporal lobes was associated with clinical dementia rating Sum of Boxes (CDR‐SoB) scores independently of local amyloid‐PET uptake (FWE corrected at p < 0.001). We also observed in both cohorts that in regions of the neocortex, associations between neocortical tau‐PET and clinical function were dependent on local amyloid‐PET (FWE corrected at p < 0.001). Interpretation In medial temporal brain regions, characterized by the accumulation of tau pathology in the absence of amyloid‐β, tau had direct associations with cognitive dysfunction. In brain regions characterized by the accumulation of both amyloid‐β and tau pathologies such as the posterior cingulate and medial frontal cortices, tau’s relationship with cognitive dysfunction was dependent on local amyloid‐β concentrations. Our results provide evidence that amyloid‐β in Alzheimer’s disease influences cognition by potentiating the deleterious effects of tau pathology.

Regional Tau Deposition Reflects Different Pathways of Subsequent Neurodegeneration and Memory Decline in Cognitively Normal Older Adults

“…Taken together, our findings suggest that the successive involvement of tau, which begins in and remains confined to the MTL in normal aging, 8 is initially independent of Aβ 14,51 and associated with subsequent hippocampal atrophy, likely leads to memory deficits in normal older people. With Aβ pathology, MTL tau may be initiated to spread to the neocortex, and tau in multiple regions across the brain exhibits a relatively widespread cortical influence beyond MTL that is related to memory decline in early AD.…”

Do microbes play a role in Alzheimer's disease?

“…The amyloid cascade hypothesis posits that AD pathogenesis is caused by the accumulation of Aβ in the brain, triggering a cascade of inflammation, tau accumulation and the generation of neurofibrillary tangles, synaptic dysfunction, and subsequent neuronal death (Hardy & Allsop, 1991 ; Mattsson‐Carlgren et al., 2021 ; Therriault et al., 2021 ). However, after over 400 clinical trials targeting brain‐derived Aβ, such a strategy has not proven to be very effective (Banik et al., 2015 ; Cummings et al., 2014 ; Geldenhuys & Darvesh, 2015 ; Knopman, Jones, & Greicius, 2021 ).…”

Therapeutic Targets for Alzheimer’s Disease: Amyloid Vs. Non-Amyloid. Where Does Consensus Lie Today? An CTAD Task Force Report

“…e are in a stage of paradigm shift in the therapeutic field of Alzheimer`s disease (AD) from an era of symptomatic therapies to disease modification, now that a first monoclonal antibody against beta-amyloid has received Food and Drug Administration approval. There are major advances in our understanding of the interaction between amyloid and tau pathologies thanks to in vivo brain imaging using Positron Emission Tomography (PET) (1), as well as the interaction between tau pathology and microglial activation (2). On the other hand, there is awareness that while progressive beta-42 amyloid deposition and spreading of hyperphosphorylated tau fibrils are required findings in the current biological definition of AD (3), they may not sufficient for dementia to be manifest clinically, particularly in older persons, where other pathologies, such as vascular lesions, neocortical Lewy bodies and TDP-43/hippocampal sclerosis may interact with the primary AD pathologies (4).…”