To investigate catecholaminergic alterations in the medial frontal gyrus (MFG) in Alzheimer’s disease (AD) patients, including a case with TDP-43 pathology, with a focus on norepinephrine (NE) and dopamine (DA) signaling. Postmortem MFG tissue from five human donors, one with AD, one with AD and TDP-43 co-pathology (AD-TDP43), one preclinical AD, and two controls, was analyzed using high-performance liquid chromatography. Concentrations of NE, DA, and their primary metabolites (MHPG, DOPAC, HVA) were measured to assess neurotransmitter levels and turnover ratios. Elevated MHPG levels were observed only in AD and AD-TDP43 patients, despite unchanged NE concentrations, indicating increased NE turnover. DA levels were also selectively elevated in AD and AD-TDP43 brains only. Possible impaired DA metabolism appeared consistent with reduced DOPAC/DA and HVA/DA ratios and DA turnover. Catecholaminergic dysfunction, marked by increased NE turnover and elevated DA levels, characterizes both AD and AD-TDP43 pathology in the MFG, implicating catecholamine imbalance in disease mechanisms. By revealing a selective increase in NE turnover and DA levels in the medial frontal lobe, these data may help to clarify the neurochemical imbalance linking cortical to subcortical neurodegeneration, such as that of the locus coeruleus and ventral tegmental area, to catecholamine innervation of the frontal cortex.

Alzheimer’s disease (AD) is increasingly recognized as a disorder not only of cognition but also of motivation and emotional regulation. Apathy and anhedonia often precede memory deficits, implicating early dysfunction in reward-related circuits. This study investigated whether chronic infusion of palmitoylethanolamide (PEA), a lipid-derived PPARα agonist, could restore motivational behavior and dendritic plasticity in the Tg2576 mouse model of AD. The motivational behavior of mice that received sustained-release PEA pellets for 6 months was assessed by using the conditioned place preference (CPP) paradigm. Morphological and molecular analyses were conducted in the entorhinal cortex (EC), dentate gyrus (DG), and prefrontal cortex (PFC). In Tg2576 mice, PEA significantly rescued CPP performance, increased basal dendritic spines in WT mice in the EC, and both basal and apical dendritic expression in EC and DG from Tg2576 mice, and upregulated the expression of both PPAR-α and brain-derived neurotrophic factor (BDNF) in the PFC. Interestingly, the BDNF increase occurred even in the absence of baseline deficits, suggesting a trophic-enhancement effect. These findings suggest that the PEA-PPARα-BDNF axis may be a potential mechanism for restoring motivation and synaptic integrity in an AD-like mouse model. Lipid-based neuromodulation may therefore offer novel therapeutic routes for addressing non-cognitive symptoms and affective circuitopathy in neurodegenerative diseases.