L-α-GPC in Cognitive Decline: Mechanisms and Clinical Evidence in Neurodegenerative Disorders.
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Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and vascular dementia are characterized by progressive neuronal loss, synaptic dysfunction, and cognitive decline. Despite the widespread use of symptomatic treatments, including acetylcholinesterase inhibitors and dopaminergic agents, these disorders remain incurable and lack disease-modifying therapies. L-α-Glycerylphosphorylcholine (L-α-GPC), a naturally occurring choline-containing phospholipid, has attracted interest for its dual roles as a precursor to acetylcholine biosynthesis and a modulator of neuroprotective signaling pathways. This narrative review summarizes current preclinical and clinical evidence regarding the mechanistic and clinical relevance of L-α-GPC in neurodegenerative disorders associated with cognitive impairment. Preclinical studies suggest that L-α-GPC can cross the blood-brain barrier, enhance cholinergic neurotransmission, upregulate neurotrophic factors such as brain-derived neurotrophic factor (BDNF), and modulate inflammatory responses, including those involving the α7 nicotinic acetylcholine receptor pathway. In animal models, L-α-GPC has been associated with improved cognitive performance, reduced neuroinflammation, and attenuation of amyloid-β and tau-related pathological features. Clinical studies have reported potential benefits of L-α-GPC, either as monotherapy or in combination with agents such as donepezil, in patients with AD, vascular dementia, mild cognitive impairment (MCI), and PD-related cognitive decline. However, the interpretation of these findings should be cautious because the available evidence remains heterogeneous, with notable variability in study design, dosage regimens, treatment duration, and outcome measures. Further well-designed, large-scale randomized controlled trials, together with biomarker-based assessments, are needed to clarify the therapeutic relevance and optimal clinical application of L-α-GPC in cognitive decline and neurodegenerative disorders. Overall, current evidence indicates that L-α-GPC may represent a promising adjunctive approach, although more robust validation is still required.