Clinical Manifestations.

Background: Practice effects are a well-known cognitive phenomenon that is reduced in patients with Alzheimer's disease (AD). We aimed to investigate whether cognitively unimpaired (CU) individuals within the Alzheimer's continuum (i.e., positive amyloid-β biomarker) display decreased practice effects on serial neuropsychological testing.

Methods: We included 310 CU from four Spanish research centers, classified into controls (n = 250) or Aβ+ (n = 60). In the main cohort (Cohort A; n = 209), participants underwent neuropsychological assessment at baseline and annually during a 2-year follow-up (FU and FU). A "long-term cohort" (Cohort B; n = 101) was employed to assess practice effects over longer time periods (i.e., two follow-up sessions at years 3 and 6 from baseline). Practice effects were defined as simple discrepancy scores (SDS) by subtracting Z-scores at FU from Z-scores at baseline for each neuropsychological variable, and linear mixed effects models (LME) were run to assess the temporal evolution of practice effects according to the two groups.

Results: There were no cross-sectional differences between the control and Aβ+ groups in none of the neuropsychological scores at baseline (Fig. 1). The Aβ+ group displayed lower practice effects than the controls in terms of SDS in several neuropsychological outcomes (Fig. 2). In Cohort A, LME showed negative slopes by the Aβ+ group in verbal memory measures such as the free learning score (β = -0.37, SD = 0.12, p = 0.0034), delayed free recall (β = -0.43, SD = 0.15, p = 0.0047) and delayed total recall (β = -0.46, SD = 0.17, p = 0.0069) from the Free and Cued Selective Reminding Test; as well as in language tasks (Boston Naming Test; β = -0.26, SD = 0.087, p = 0.0025) and executive function measures (Trail Making Test; β = -0.33, SD = 0.12, p = 0.0094) (Fig. 3A). In Cohort B, similar findings were observed in visual memory measures, such as the Rey-Osterrieth Complex Figure immediate (β = -0.80, SD = 0.35, p = 0.024) and delayed (β = -1.25, SD = 0.34, p = 0.00038) recall (Fig. 3B).

Conclusions: Individuals with normal cognition who are in the Alzheimer's continuum show decreased practice effects over serial neuropsychological testing. Our findings suggest the reduction of practice effects, particularly in memory measures, as an indicator of subtle cognitive decline in the earliest phase of the Alzheimer's continuum and could be particularly relevant for the design and interpretation of primary prevention trials on disease-modifying therapies.