Common metabolic, environmental, and molecular mechanisms underlying neurodevelopmental and neurodegenerative disorders

Abstract

Several neurodevelopmental disorders and neurodegenerative diseases share common pathogenic mechanisms that unfold across the lifespan, blurring the distinction between the two nosological entities. Environmental factors, particularly those shaping metabolic health during critical developmental time windows, have emerged as key modulators of long-term brain liabilities. This review critically evaluates the experimental, epidemiological, and mechanistic evidence linking early-life metabolic and environmental insults with the establishment of latent vulnerability. We propose that this status may remain clinically silent for decades until activated by aging and cumulative stressors, ultimately leading to neurodegeneration. Specifically, we analyze how early metabolic alterations disrupt mitochondrial function, redox signaling, synaptogenesis, and glial programming, particularly in microglia, thereby shaping long-term neuroinflammatory tone and dysfunctional neural circuit maturation. The review highlights the role of the α7 nicotinic acetylcholine receptor (α7nAChR) as a strategic molecular bridge onto which metabolic and inflammatory signals converge. We further discuss how early dysregulatory stressors manifest later in life as dysmetabolism, vascular impairment, and defective energy sensing, all of which accelerate neurodegenerative pathophysiological processes. This life-course perspective reframes these disorders as a continuum and highlights critical prophylactic and/or therapeutic opportunities through early nutritional, metabolic, and environmental interventions.