Alzheimer's Disease Pathologies Affect Dopaminergic Neural Mechanisms of Memory

Aging is accompanied by the disruption of multiple neural systems including alteration in dopamine neurotransmission as well as through the accumulation of neuropathology. Despite broad appreciation that complex mental function relies on integration across systems, there is a general lack of understanding of how multiple age- and disease-related brain features interact to drive variation in performance. To address this gap, we used positron emission tomography in male and female humans to examine independent and combined impacts of dopamine synthesis capacity ([¹⁸F]Fluoro-L-m-tyrosine) and Alzheimer's disease (AD)-related pathology (amyloid-β: [¹¹C]Pittsburgh Compound B; tau: [¹⁸F]Flortaucipir) on memory for rewarding events, which we assessed using functional magnetic resonance imaging (n = 80 young and older adults). We specifically probed dopamine synthesis capacity given evidence that it is upregulated in older age and may impart resilience to age-related neural losses. In young adults, higher dopamine synthesis capacity was associated with superior overall memory and greater temporal lobe activation. In older adults, neither dopamine nor AD pathology independently predicted memory performance, though higher dopamine synthesis capacity was associated with memory biases for stimuli associated with rewards rather than losses. Instead, we observed interactions between dopamine synthesis and pathology whereby only older adults with minimal pathology showed preservation of positive dopamine-memory associations. In contrast to resilience accounts, the presence of AD pathology disrupted and even reversed relationships between dopamine synthesis, memory, and temporal lobe activation. These results suggest that AD pathological processes acutely alter the mechanisms by which elevated dopamine synthesis supports optimal memory performance.