Cognition and wellbeing in middle-aged early treated people with phenylketonuria: Preliminary results and methodological lessons.

The first cohort of early-treated adults with phenylketonuria (PKU) is reaching middle-age and moving towards old age. We do not know if and how the effects of an aging brain may interact with the effect of PKU. This study compared wellbeing and cognition in 19 middle-aged adults with PKU (age 40+ mean = 45.8) and in a younger adult PKU group (age 18-36 mean = 26.7). The middle-aged PKU group demonstrated more anxiety and depression, and more negative effects of the COVID-19 pandemic, compared to age-matched controls. They also demonstrated a steep deterioration of quality of life compared to younger adults with PKU. These last results confounded age with the effects of the pandemic, since only the older participants were tested during the COVID-19 pandemic, but taken together, results consistently point to AwPKU being less resilient to age and other life stressors affecting wellbeing. Regarding cognition, the older PKU group demonstrated significantly worse performance than the younger group, and within the middle-age groups, the effect of age was stronger in the PKU group than in the control, even though this was not statistically significant. In contrast, size of impairment relative to an age-matched control group was numerically smaller in older, middle-age PKU group. We discuss possible methodological confounders related to this last result. Our study points to the challenges of using cross-sectional results to track performance across the lifespan and to the need to acquire more corroborating evidence before concluding there is no accelerating brain aging in PKU.