Decreased levels of guanosine 3′, 5′‐monophosphate (c GMP ) in cerebrospinal fluid ( CSF ) are associated with cognitive decline and amyloid pathology in A lzheimer's disease

Aims Levels of the cyclic nucleotides guanosine 3′, 5′‐monophosphate (c GMP ) or adenosine 3′, 5′‐monophosphate (c AMP ) that play important roles in memory processes are not characterized in A lzheimer's disease ( AD ). The aim of this study was to analyse the levels of these nucleotides in cerebrospinal fluid ( CSF ) samples from patients diagnosed with clinical and prodromal stages of AD and study the expression level of the enzymes that hydrolyzed them [phosphodiesterases ( PDE s)] in the brain of AD patients vs. controls. Methods For c GMP and c AMP CSF analysis, the cohort (n = 79) included cognitively normal participants (subjective cognitive impairment), individuals with stable mild cognitive impairment or AD converters (s MCI and c MCI ), and mild AD patients. A high throughput liquid chromatography–tandem mass spectrometry method was used. Interactions between CSF c GMP or c AMP with mini–mental state examination ( MMSE ) score, CSF A β (1–42) and CSF p‐tau were analysed. For PDE 4, 5, 9 and 10 expression analysis, brains of AD patients vs. controls (n = 7 and n = 8) were used. Results c GMP , and not c AMP levels, were significantly lower in the CSF of patients diagnosed with mild AD when compared with nondemented controls. CSF levels of c GMP showed a significant association with MMSE ‐diagnosed clinical dementia and with CSF biomarker A β 42 in AD patients. Significant increase in PDE 5 expression was detected in temporal cortex of AD patients compared with that of age‐matched healthy control subjects. No changes in the expression of others PDE s were detected. Conclusions These results support the potential involvement of c GMP in the pathological and clinical development of AD . The c GMP reduction in early stages of AD might participate in the aggravation of amyloid pathology and cognitive decline.