Amyloid independent pathways have an impact on longitudinal tau deposition. (20th December 2022)

• Record Type: Journal Article
• Authors: Vemuri, Prashanthi; Lesnick, Timothy G.; Przybelski, Scott A.; Graff‐Radford, Jonathan; Ramanan, Vijay K; Lowe, Val J.; Machulda, Mary M.; Mielke, Michelle M.; Petersen, Ronald C.; Knopman, David S.; Jack, Clifford R.
• Is Part Of: Alzheimer's & dementia. Volume 18(2022)Supplement 6
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-20
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.067607
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Amyloidosis‐driven tau deposition has been a significant focus of imaging research in Alzheimer's disease (AD). However, the 3R/4R tau seen in AD can be observed in the transentorhinal/entorhinal regions (Braak I/II) in the absence of amyloidosis. The underlying drivers of this phenomenon are not well understood. Our goal was to examine amyloid‐independent pathways of longitudinal Tau‐PET SUVR progression in the entorhinal cortex (ERC) using a broad range of risk and protective factors. Method: We identified 449 participants from the population‐based sample of Mayo Clinic Study of Aging >50 years old with baseline amyloid PET and at least two serial tau PET scans (mean number of scans=2.3; mean follow‐up time=3.2 years). Using an amyloid SUVR cut‐point of 1.48, we categorized participants into A+ (n=167; mean age=77.5 years; 56% male; baseline ERC tau=1.20; 83% cognitively unimpaired) and A‐ (n=282; mean age=67.5; 56% male; baseline ERC tau=1.07; 92% cognitively unimpaired). We used an ERC tau SUVR cut‐point of 1.21 to determine T+. We fit mixed effects and growth curve models with age, sex, baseline amyloid, risk factors (midlife activities, sleep, stress, education/occupation, cardiovascular metabolic conditions) as predictors and longitudinal ERC tau as the outcome. We fit separate models in A‐, A+, and all participants. Results: For models of all participants and A+ participants, the only predictors of higher rates of ERC tau deposition were increasing age and amyloid SUVR (p<0.05). In the A‐ models (figure below), amyloid SUVR and age were predictors of baseline, but not longitudinal ERC tau. However, a greater number of cardiovascular metabolic conditions predicted a higher rate of ERC tau accumulation (0.007 (0.002), p<0.05). Only 13% of the 23 A‐T+ participants were APOE4 carriers (compared to 31% in the overall sample), suggesting the role of non‐ APOE4 pathways to tau deposition. Conclusion: Our results support previous evidence that significant amyloidosis is causal to higher rates of tau deposition. However, in those without significant amyloidosis, cardiovascular metabolic conditions predicted higher rates of ERC tau accumulation. Further work is warranted to investigate the mechanisms through which genetics, comorbidities, and lifestyle may play a role in early tau deposition.