O4‐01‐03: AMYLOID‐B AND HYPERPHOSPHORYLATED TAU SYNERGY DRIVES CLINICAL PROGRESSION TO ALZHEIMER’S DISEASE

Conceptual framework suggests that the synergism between amyloid-β (Aβ) and phosphorylated tau (p-tau) aggregates determines structural and functional abnormalities in cognitively normal individuals. Our study was designed to test the hypothesis that clinical progression to Alzheimer’s disease dementia (AD) in patients with mild cognitive impairment (MCI) is dependent on the synergism between Aβ and p-tau rather than merely additive effects of overlapping brain pathologies. We categorized 310 ADNI participants with amnestic MCI in four biomarker groups based on elevated or non-elevated Aβ positron emission tomography (PET) using [F]Florbetapir ligand and cerebrospinal fluid p-tau biomarkers (Table 1). Clinical and neuropsychological evaluations were performed at baseline and at 2 years including memory, executive function, psychomotor speed processing, and language. Regression interaction models evaluated changes in cognition and clinical status as a function of baseline imaging and fluid biomarkers. Using Voxel-Stats, we built a voxel-based logistic regression model in order to test the association between Aβ PET at every voxel and p-tau status as determinant of progression to dementia, assuming the probability of progression as p’: Log p’ / 1-p’ = β0 + β1(florbetapir SUVR) + β2(CSF p-tau status) + β3(florbetapir SUVR*p-tau status) + covariates + error. All models were adjusted for age, gender, education, APOE ε4 status and corrected for multiple comparison testing using Bonferroni at P < 0.05. We found that Aβ+/p-tau+ individuals had the highest rate of clinical and neuropsychological decline in all cognitive domains as compared to Aβ+/p-tau−, Aβ−/p-tau+ and Aβ−/p-tau−, which did not differ from one another. Notably, regression interaction models confirmed that the synergistic effect between Aβ and p-tau abnormalities best-predicted cognitive decline and clinical progression to dementia, as compared to the sum of their independent effects. Finally, voxel-based logistic regression analysis revealed that the lateral and basal temporal and inferior parietal cortices were the brain regions where the synergistic effect between Aβ and p-tau status determined an increased likelihood of progression to dementia (Figure 1). Together, the present results suggest that clinical progression to AD is driven by a synergistic rather than a merely additive effect between Aβ aggregation and tau hyperphosphorylation.

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