Attention Measures of Accuracy, Variability, and Fatigue Detect Early Response to Donepezil in Alzheimer's Disease: A Randomized, Double-blind, Placebo-Controlled Pilot Trial

Abstract

Objective: Donepezil is widely used to treat Alzheimer's disease (AD), but detecting early response remains challenging for clinicians. Acetylcholine is known to directly modulate attention, particularly under high cognitive conditions, but no studies to date test whether measures of attention under high load can detect early effects of donepezil. We hypothesized that load-dependent attention tasks are sensitive to short-term treatment effects of donepezil, while global and other domain-specific cognitive measures are not.

Method: This longitudinal, randomized, double-blind, placebo-controlled pilot trial (ClinicalTrials.gov Identifier: NCT03073876) evaluated 23 participants newly diagnosed with AD initiating de novo donepezil treatment (5 mg). After baseline assessment, participants were randomized into Drug (n = 12) or Placebo (n = 11) groups, and retested after approximately 6 weeks. Cognitive assessment included: (a) attention tasks (Foreperiod Effect, Attentional Blink, and Covert Orienting tasks) measuring processing speed, top-down accuracy, orienting, intra-individual variability, and fatigue; (b) global measures (Alzheimer's Disease Assessment Scale-Cognitive Subscale, Mini-Mental Status Examination, Dementia Rating Scale); and (c) domain-specific measures (memory, language, visuospatial, and executive function).

Results: The Drug but not the Placebo group showed benefits of treatment at high-load measures by preserving top-down accuracy, improving intra-individual variability, and averting fatigue. In contrast, other global or cognitive domain-specific measures could not detect treatment effects over the same treatment interval.

Conclusions: The pilot-study suggests that attention measures targeting accuracy, variability, and fatigue under high-load conditions could be sensitive to short-term cholinergic treatment. Given the central role of acetylcholine in attentional function, load-dependent attentional measures may be valuable cognitive markers of early treatment response.

Keywords: Alzheimer dementia; Attention; Cholinesterase inhibitors; Donepezil; Treatment outcome.

Fig. 1.

Participant flow diagram following CONSORT 2010 guidelines.

Fig. 2.

Treatment effects on top-down accuracy comparing accuracy percentage at T1 to T2. Error bars denote adjusted standard error to reflect within-group error variance (Field, 2009). SOA = Stimulus Onset Asynchrony; ms = milliseconds; T1 = baseline; T2 = after ≈6 weeks of treatment with donepezil. *indicates p < .05.

Fig. 3.

Treatment effects on variability comparing RT standard deviation from T1 to T2. Error bars denote adjusted standard error to reflect within-group error variance (Field, 2009). RT = Response Time; SOA = Stimulus Onset Asynchrony; ms = milliseconds; T1 = baseline; T2 = after ≈6 weeks of treatment with donepezil. * indicates p < .05.

Fig. 4.

Treatment effects of fatigue at T2 comparing Drug versus Placebo group RT mean across blocks in the Covert Orienting and Foreperiod Effect task. Error bars denote adjusted standard error to reflect within-group error variance (Field, 2009). RT = Response Time; SOA = Stimulus Onset Asynchrony; ms = milliseconds; T1 = baseline; T2 = after ≈6 weeks of treatment with donepezil. * indicates p < .05.