A systematic review and meta-analysis of pteridines in mild cognitive impairment and Alzheimer's disease

BackgroundAlterations in specific pteridine metabolites, particularly neopterin, biopterin, and tetrahydrobiopterin have been reported in mild cognitive impairment, Alzheimer's disease, and other types of dementia. However, the available evidence regarding such alterations has not been comprehensively and critically appraised.MethodsWe systematically reviewed studies reporting the concentrations of biopterin, tetrahydrobiopterin, and neopterin in different biological fluids in patients with mild cognitive impairment, Alzheimer's disease or other types of dementia, and healthy controls. Electronic databases were searched from inception to 29 February 2024.ResultsOverall, there were no significant differences in plasma/serum concentrations of neopterin between patients with mild cognitive impairment, Alzheimer's disease, or other types of dementia, when grouped together, and healthy controls after adjusting for publication bias (11 studies, standard mean difference, SMD = 0.20, 95% CI -0.02 to 0.41, p = 0.076). In meta-regression and subgroup analysis, the effect size was significantly associated with age, number of participants, study continent, presence of mild cognitive impairment, presence of Alzheimer's disease, analytical method, and assessment of serum vs. plasma. One study reported higher urine neopterin in patients with Alzheimer's disease vs. controls whereas another study reported non-significant between-group differences in cerebrospinal neopterin. The cerebrospinal fluid concentrations of biopterin were significantly lower in patients with Alzheimer's disease vs. controls (two studies, SMD = -0.75, 95% CI -1.23 to -0.27, p = 0.002; I2 = 0.0%, p = 0.46). One study showed non-significant between-group differences in plasma biopterin whereas another study showed higher concentrations of urine biopterin in patients with Alzheimer's disease. Our search did not identify studies investigating tetrahydrobiopterin.ConclusionOur study showed no significant differences in circulating neopterin between patients with mild cognitive impairment, Alzheimer's disease, or other types of dementia, when grouped together, and healthy controls. The significant associations observed between the effect size and mild cognitive impairment and Alzheimer's disease in subgroup analysis warrant further investigation. (PROSPERO registration number: CRD42024523478).