Correlation Between Urine Formaldehyde and Cognitive Abilities in the Clinical Spectrum of Alzheimer’s Disease

Abstract

Urine-based formaldehyde has been reported to be a potential biomarker for Alzheimer’s disease (AD). However, there is a lack of research about the correlation between urine formaldehyde and cognitive abilities in the clinical spectrum of AD, especially the preclinical period. The relationship of urine formaldehyde with APOE genotype, brain Aβ status and plasma pathological markers in AD are also not clear. This study intends to explore the correlation between urine formaldehyde and cognitive abilities throughout the AD continuum, to evaluate the role of APOE genotype and Aβ accumulation on urine formaldehyde, and further to clarify the relationship between urine formaldehyde level and AD plasma pathological markers. We recruited 72 cognitively normal controls (NC), 110 subjective cognitive decline (SCD), 140 objectively defined subtle cognitive decline (Obj-SCD), 171 mild cognitive impairment (MCI) and 136 AD dementia participants. Next, we collected the data of clinical materials, neuropsychological examination, APOE genotyping, urine formaldehyde concentration, 18F-florbetapir PET imaging and plasma biomarkers. Compared with NC, Obj-SCD and MCI groups, the level of urine formaldehyde was found to be significantly upregulated in SCD group. In addition, the level of urine formaldehyde was significantly higher in AD group compared to both NC and MCI groups. Further subgroup analysis showed that, the level of urine formaldehyde was higher in APOE ε4+ subgroup compared to APOE ε4– subgroup in both NC and AD groups. There was no difference in urine formaldehyde level between the brain Aβ+ subgroup and Aβ– subgroup in each group. In addition, regression analysis showed urine formaldehyde level was correlated with gender, plasma Aβ42 and p-Tau181/T-tau. The dynamic change of urine formaldehyde in the AD continuum could be used as a potential biomarker, and combined with comprehensive cognitive evaluation could become a useful method to distinguish SCD from NC and Obj-SCD, and to distinguish MCI from AD.

Association of N-nitrosodimethylamine exposure with cognitive impairment based on the clues of mice and humans

“…Chinese investigators have demonstrated that formaldehyde is associated with de cits in human cognition, such that there is a correlation between urine formaldehyde and cognitive abilities throughout the AD continuum (i.e., formaldehyde levels in AD > MCI > early cognitive decline). Urine formaldehyde levels also correlated with gender, plasma Aβ 42 and p-Tau181/T-tau (markers of AD) (Wang Y, et al 2022).…”

Is liquid biopsy mature enough for the diagnosis of Alzheimer’s disease?

“…For example, the levels of formaldehyde and 8-hydroxy-2deoxyguanosine (8-OHdG) can be used to access the status of formaldehyde metabolism and oxidative DNA damage, respectively. They were significantly higher in the urine of AD patients compared to cognitively normal controls (Pena-Bautista et al, 2019;Wang et al, 2022). AD would interact with osteoporosis during its progression.…”

Systematic evaluation of urinary formic acid as a new potential biomarker for Alzheimer’s disease

“…Formaldehyde is considered a “trigger” of AD, meaning that capturing dynamic changes in formaldehyde can greatly help diagnose early AD ( Tong et al, 2017 ). Our previous study explored the possibility of urinary formaldehyde as a potential biomarker for the early diagnosis of AD and obtained some positive results ( Wang et al, 2022 ). Formic acid is a metabolic product of formaldehyde and can be excreted in the form of formate ( Bruckner et al, 2008 ; Kageyama et al, 2008 ; Burgos-Barragan et al, 2017 ; Liu et al, 2017 ).…”

“…All participants took standardized neuropsychological tests, including the Mini-Mental State Examination (MMSE) 10.3389/fnagi.2022.1046066 (Katzman et al, 1988), Montreal Cognitive Assessment-Basic (MoCA-B) (Huang et al, 2018), the Chinese version of Addenbrooke's Cognitive Examination III (ACE-III) (Pan et al, 2022), and the Shape Trial Test (SST), Auditory Verbal Learning Test (AVLT) (Considine et al, 2017), Animal Fluency Test (AFT), and other tests which involved memory, language, attention, executive function, and visuospatial ability. Welltrained assessors conducted neuropsychological tests on all participants in Mandarin and recorded detailed clinical data.…”

“…In recent years, abnormal formaldehyde metabolism has been recognized as one of the essential features of age-related cognitive impairment ( Yu et al, 2014 ; He, 2017 ). Our previous study reported a correlation between urinary formaldehyde levels and cognitive function, suggesting that urinary formaldehyde is a potential biomarker for the early diagnosis of AD ( Wang et al, 2022 ). Formaldehyde plays a vital role in cellular metabolism and is involved in one-carbon metabolism, providing carbon for synthesizing and modifying biological compounds such as DNA, RNA, and amino acids ( Li et al, 2021 ; Morellato et al, 2021 ).…”