Behavioral correlates of anxiety and depression in a <i>Drosophila melanogaster</i> model of Alzheimer’s disease

The relationship between anxiety, depression, and cognitive decline in Alzheimer’s disease (AD) remains incompletely understood, despite their frequent co-occurrence. This study quantitatively examined how anxiety- and depression-like phenotypes influence cognitive behavior using Drosophila melanogaster as a model organism expressing human amyloid-β (Aβ). A total of 104 flies (52 AD model; 52 wild-type controls) were tested in the Open-field test (OFT), forced swim test (FST), and Y-maze test (YMT). In the OFT, AD flies displayed significantly lower exploratory activity (mean inner-zone entries = 2.3 ± 0.8) compared to wild-type flies (4.2 ± 1.1; t(102)=8.14, p&lt;0.001, d=1.60, 95% CI [1.19, 2.02]). In the FST, AD high-anxiety flies exhibited shorter struggle durations (38.2 ± 10.7 s) than wild-type low-anxiety flies (76.1 ± 9.8 s; t(50)=11.4, p&lt;0.001, d=2.52). Decision latency in the YMT was highest (lowest success rate) in AD flies with high-anxiety and high-depression profiles (success rate 10.8%, 95% CI [8.1%, 13.5%]) compared to wild-type low-anxiety/low-depression flies (success rate 88.2%, 95% CI [84.5%, 91.9%]). The interactions between anxiety, depression and genotype suggested that Decision Latency or Stress Altered Reward Valuation (DL/SARV) – but not exploration or persistence – was affected to a disproportionate extent in AD flies when compared to wild-type flies. These findings suggest that comorbid anxiety and depression exacerbated the DL/SARV related AD-associated behavioral and cognitive deficits in Drosophila. The results highlight a potential link between affective dysregulation and some aspects of cognitive inflexibility, offering a behavioral basis for investigating the interplay between neurodegeneration and psychiatric symptoms.