Word Generation from Letter and Semantic Categories Across the Alzheimer’s Disease Spectrum

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AbstractBackgroundIndividuals with mild dementia or mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) often have verbal fluency deficits with greater impairment in generating exemplars from a semantic category (e.g., “animals”) than words that begin with a particular letter (e.g., ‘F’). This may reflect early development of pathology in cortical regions mediating semantic knowledge/organization required to efficiently generate words from a conceptually‐related set of exemplars. We sought to determine if this word generation deficit and discrepancy between category and letter fluency emerges in the preclinical stage of AD.Participants and MethodsSemantic and letter fluency tasks were completed by 394 participants. Correct words generated in one minute from each category was summed across animals, fruits, and vegetables (AFV), and across letters ‘F’, ‘A’, and ‘S’ (FAS). CSF was obtained within one year of the fluency tasks and levels of Aβ40, Aβ42, phosphorylated tau (p‐tau), and total tau were measured. Participants were classified as cognitively normal (CN) with negative AD biomarker (CN‐Neg; n = 179), CN with positive AD biomarker (tau/Aβ42 ratio>.609) (CN‐Pos; n = 59), MCI (all biomarker positive; n = 46), and AD dementia (all biomarker positive; n = 110).ResultsA Group X Task repeated measures ANOVA (adjusting for age and education) showed participants generated more correct words for AFV than FAS (F(1,380) = 20.44; p.001), there was a general stepwise decline in words generated across the AD spectrum (AD<MCI<CN‐Pos = CN‐Neg) (F(3,380) = 144.13; p.001), and this decline was greater on AFV than FAS (interaction F(3,380) = 18.59; p.001). CN‐Pos and CN‐Neg did not differ in correct words generated on either task, but AFV (r = ‐.304; p = .018) and FAS (r = ‐.290; p = .025) scores were negatively correlated with levels of p‐tau in amyloid positive (Aβ42/40 ratio<.056), but not amyloid negative, CN individuals.ConclusionsAlthough word generation was not impaired in the CN‐Pos group, a negative relationship with CSF p‐tau in the context of amyloid positivity suggests that changes in verbal fluency may be emerging in preclinical AD. A similar relationship with p‐tau for letter and semantic fluency implies that mechanisms common to both tasks (e.g., initiation of effortful retrieval) are affected earlier than mechanisms with greater specificity to the semantic fluency task (e.g., semantic knowledge/organization).