Differential associations between neocortical tau pathology and blood flow with cognitive deficits in early-onset vs late-onset Alzheimer's disease.

Abstract

Early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) differ in neuropathological burden and type of cognitive deficits. Assessing tau pathology and relative cerebral blood flow (rCBF) measured with [¹⁸F]flortaucipir PET in relation to cognition may help explain these differences between EOAD and LOAD. Seventy-nine amyloid-positive individuals with a clinical diagnosis of AD (EOAD: n = 35, age-at-PET = 59 ± 5, MMSE = 23 ± 4; LOAD: n = 44, age-at-PET = 71 ± 5, MMSE = 23 ± 4) underwent a 130-min dynamic [¹⁸F]flortaucipir PET scan and extensive neuropsychological assessment. We extracted binding potentials (BP_ND) and R₁ (proxy of rCBF) from parametric images using receptor parametric mapping, in medial and lateral temporal, parietal, occipital, and frontal regions-of-interest and used nine neuropsychological tests covering memory, attention, language, and executive functioning. We first examined differences between EOAD and LOAD in BP_ND or R₁ using ANOVA (region-of-interest analysis) and voxel-wise contrasts. Next, we performed linear regression models to test for potential interaction effects between age-at-onset and BP_ND/R₁ on cognition. Both region-of-interest and voxel-wise contrasts showed higher [¹⁸F]flortaucipir BP_ND values across all neocortical regions in EOAD. By contrast, LOAD patients had lower R₁ values (indicative of more reduced rCBF) in medial temporal regions. For both tau and flow in lateral temporal, and occipitoparietal regions, associations with cognitive impairment were stronger in EOAD than in LOAD (EOAD BP_ND - 0.76 ≤ stβ ≤  - 0.48 vs LOAD - 0.18 ≤ stβ ≤  - 0.02; EOAD R₁ 0.37 ≤ stβ ≤ 0.84 vs LOAD - 0.25 ≤ stβ ≤ 0.16). Compared to LOAD, the degree of lateral temporal and occipitoparietal tau pathology and relative cerebral blood-flow is more strongly associated with cognition in EOAD.