Objective: Differentially worse performance on category versus letter fluency suggests greater semantic versus retrieval difficulties. This discrepancy, combined with reduced episodic memory, has widespread clinical utility in diagnosing Alzheimer’s disease (AD). Our objective was to investigate whether changes in semantic processing, as measured by the discrepancy between category and letter fluency, was detectable in preclinical AD: in clinically normal older adults with abnormal ß-amyloid (Aß) deposition on positron emission tomography (PET) neuroimaging. Method: Clinically normal older adults (mean Mini Mental State Exam (MMSE) score = 29) were classified as Aß+ (n = 70) or Aß- (n = 205) using Pittsburgh Compound B–(PET) imaging. Participants completed letter fluency (FAS; word generation to letters F-A-S) and category fluency (CAT; word generation to animals, vegetables, fruits) annually (mean follow-up = 2.42 years). The effect of Aß status on fluency over time was examined using linear mixed models controlling for age, sex, and education. To dissociate effects related to semantic (CAT) versus retrieval processes (CAT and FAS), we repeated models predicting CAT over time, controlling for FAS and likewise for CAT controlling for FAS. Results: At baseline, the Aß+ group performed better on FAS compared with the Aß- group but comparably on CAT. Longitudinally, the Aß+ group demonstrated greater decline on CAT compared with the Aß- group (p = .0011). This finding remained significant even when covarying for FAS (p = .0107). Aß+ participants similarly declined compared with Aß- participants on FAS (p = .0112), but this effect became insignificant when covarying for CAT (p = .1607). Conclusion: These findings provide biomarker validation for the greater specificity of declines in category versus letter fluency to underlying AD pathology. Our results also suggest that changes in semantic processing occur earlier in the AD trajectory than previously hypothesized.
