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Aging is associated with declines in multiple components of the dopamine system including loss of dopamine-producing neurons, atrophy of the dopamine system’s cortical targets, and reductions in the density of dopamine receptors. Countering these patterns, dopamine synthesis appears to be stable or elevated in older age. We tested the hypothesis that elevation in dopamine synthesis in aging reflects a compensatory response to neuronal loss rather than a nonspecific monotonic shift in older age. We measured individual differences in striatal dopamine synthesis capacity in cognitively normal older adults using [18F]Fluoro-l-m-tyrosine positron emission tomography cross-sectionally and tested relationships with longitudinal reductions in cortical thickness and working memory decline beginning up to 13 years earlier. Consistent with a compensation account, older adults with the highest dopamine synthesis capacity were those with greatest atrophy in posterior parietal cortex. Elevated dopamine synthesis capacity was not associated with successful maintenance of working memory performance overall, but had a moderating effect such that higher levels of dopamine synthesis capacity reduced the impact of atrophy on cognitive decline. Together, these findings support a model by which upregulation of dopamine synthesis represents a mechanism of cognitive resilience in aging.

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BackgroundSerotonin‐producing raphe nuclei are sites of age and Alzheimer’s disease‐related alterations in structure and function.MethodWe used [18F]Fluoro‐m‐tyrosine ([18F]FMT) positron emission tomography (PET) to measure serotonin synthesis capacity in younger (mean age = 22.08, n = 62) and older adults (mean age = 77.8, n = 49). [18F]FMT net tracer influx (Ki) was higher in older adults in both the dorsal and median raphe nuclei (both p < 0.001). To examine the functional relevance of higher raphe [18F]FMT Ki in older adults, we tested relationships with β‐amyloid status as defined by [11C]Pittburgh compound B ([11C]PiB) PET, retrospective longitudinal declines in cortical thickness, and retrospective longitudinal changes in depression symptoms measured using the geriatric depression scale (GDS).Result[11C]PiB positive (n=14) older adults showed trend‐level elevation in dorsal and median raphe [18F]FMT Ki relative to [11C]PiB negative older adults (n = 35; both p < 0.09). Higher dorsal raphe [18F]FMT Ki was associated with decreasing cortical thickness over time in the banks of the superior temporal sulcus (BanksSTS) (Monte Carlo, p < 0.05, r = ‐0.513), consistent with the interpretation that serotonin synthesis may be upregulated in response to neural losses. Decreasing cortical thickness was also associated with increasing GDS. We did not find evidence that higher dorsal raphe [18F]FMT Ki had a beneficial impact on affective function. Instead, interaction analyses revealed relationships between atrophy and increasing GDS were strongest in individuals with highest dorsal raphe [18F]FMT Ki (t = ‐2.056, p = 0.049; adjusting for age, sex, and [11C]PiB status).ConclusionTogether, these findings suggest serotonin synthesis capacity increases with age, and appears to signal poor aging trajectories. Most elevated serotonin synthesis capacity was associated with greatest cortical atrophy and drove relationships between atrophy and worsening depressive symptoms over time.