Biomarker validation of a decline in semantic processing in preclinical Alzheimer’s disease.

Objective Differentially worse performance on category vs. letter fluency suggests greater semantic vs. 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 β-amyloid (Aβ) deposition on neuroimaging. Methods Clinically normal older adults (mean MMSE=29) were classified as Aβ+ (n=70) or Aβ− (n=205) using PiB-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 Aβ status on fluency over time was examined using linear mixed models controlling for age, sex, and education. To dissociate effects related to semantic (CAT) vs. retrieval processes (CAT and FAS), models predicting CAT over time were repeated controlling for FAS and likewise for CAT controlling for FAS. Results At baseline, Aβ+'s performed better on FAS compared with Aβ−'s but comparably on CAT. Longitudinally, Aβ+'s demonstrated greater decline on CAT compared with Aβ−'s (p=0.0011). This finding remained significant even when covarying for FAS (p=0.0107). Aβ+'s similarly declined compared with Aβ−'s on FAS (p=0.0112) but this effect became insignificant when covarying for CAT (p=0.1607). Conclusions These findings provide biomarker validation for the greater specificity of declines in category vs. letter fluency to underlying AD pathology. Our results also suggest that changes in semantic processing occur earlier in the AD trajectory than previously hypothesized.