Gambling rarely stands alone: clustered addictive behaviours and socioeconomic vulnerability in adolescents.

Neurotransmitters play a crucial role in regulating synaptic signaling and neuronal network dynamics, making them essential to understanding both healthy brain aging and the pathogenesis of age-related neurological and psychiatric disorders (; ). Across the lifespan, these systems follow nonlinear and region-specific trajectories that reshape excitatory–inhibitory balance (), alter metabolic coupling between neurons and glia (), and modify the computational capacity of cortical and subcortical circuits (). MRS and PET reveal age-related declines in GABA and glutamate within the anterior cingulate, hippocampus, and striatum, accompanied by progressive reductions in cholinergic tone and more subtle dopaminergic and serotonergic shifts (; ; ; ; ; ; ; ). These changes influence working memory, executive control, and episodic memory long before clinical impairment emerges, positioning neurotransmitter dynamics as early determinants of cognitive aging rather than downstream consequences of structural decline (; ). Understanding these neurochemical trajectories, therefore, provides a mechanistic foundation for distinguishing adaptive remodeling from pathological degeneration across aging brains (). These dynamics manifest through distinct neurotransmitter systems, each of which follows a characteristic aging trajectory that shapes cognition and vulnerability to disease. Among all neurotransmitters, the GABAergic and glutamatergic systems exhibit the most pronounced age-related alterations and provide the most robust evidence for region-specific decline (; ; ). Nonlinear, region-specific changes in neurotransmitter levels occur during normal aging and in age-related neurological and psychiatric conditions (; ; ). Magnetic resonance spectroscopy and PET persistently reveal decreases in GABA, the primary inhibitory neurotransmitter in the human nervous system, and glutamate, the primary excitatory neurotransmitter, in the anterior cingulate, hippocampus, and striatum as well as a gradual decrease in acetylcholine of about 3.7% per decade (; ; ). After controlling for atrophy, this reduction in GABA persists, indicating a genuine decrease in GABA concentration in brain tissue rather than a consequence of cortical atrophy (). GABA concentrations are also associated with cognitive performance (; ), which remains significant even after controlling for factors such as age and education (; ). Simultaneous decreases in glutamate also occur (). Unchanged GABA concentrations accompanied by decreased glutamate concentrations occur in patients with Alzheimer’s disease () and increased GABA/glutamate ratios are associated with higher amyloid-beta levels in healthy, elderly patients (). Cholinergic and dopaminergic pathways also exhibit distinct aging patterns, and their combined disruption directly contributes to cognitive decline and network instability (; ; ). Significant cholinergic and glutamatergic losses take place in the hippocampus, posterior cingulate, and dorsolateral prefrontal cortex in Alzheimer’s disease (; ). Widespread loss of cholinergic terminals in the neocortex and hippocampus occurs in early-onset disease (). In late-onset disease, reductions are usually limited to the temporal cortex and hippocampus. Terminal deficits are extensive in patients with severe dementia (). Although a reduction in GABA typically occurs, paradoxical elevations in GABA are also reported in patients with advanced Alzheimer’s. Although results vary across cohorts, cerebral MRS and fMRI reveal a negative correlation between GABA levels and cognitive scores (). These converging, paradoxical findings underscore the need for more precise, multimodal imaging to better characterize the changing GABA concentrations in Alzheimer’s disease.