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

Abstract

IntroductionThe accumulation of endogenous formaldehyde is considered a pathogenic factor in Alzheimer’s disease (AD). The purpose of this study was to investigate the relationship between urinary formic acid and plasma biomarkers in AD.Materials and methodsFive hundred and seventy-four participants were divided into five groups according to their diagnosis: 71 with normal cognitive (NC), 101 with subjective cognitive decline (SCD), 131 with cognitive impairment without mild cognitive impairment (CINM), 158 with mild cognitive impairment (MCI), and 113 with AD.ResultsWith the progression of the disease, urinary formic acid levels showed an overall upward trend. Urinary formic acid was significantly correlated with Mini-Mental State Examination (MMSE) scores, the Chinese version of Addenbrooke’s Cognitive Examination III (ACE-III) scores, and Montreal Cognitive Assessment-Basic (MoCA-B) time. The areas under the receiver operating characteristic curves (AUC) of urinary formic acid in distinguishing NC from AD was 0.797, which was similar to that of plasma neurofilament light chain (NfL; AUC = 0.768) and better than other plasma biomarkers (Aβ40, Aβ42, Aβ42/Aβ40, T-tau, P-tau181, and P-tau181/T-tau). We also found that using urinary formic acid and formaldehyde levels could improve the accuracy of using plasma biomarkers to determine AD disease stage.DiscussionOur study revealed the possibility of urinary formic acid as a potential novel biomarker for the early diagnosis of AD.

Whole-body metabolic modelling reveals microbiome and genomic interactions on reduced urine formate levels in Alzheimer’s disease

“…The use of urine metabolomics, as a non-invasively collectable biofluid, in the context of AD and the identification of early markers of AD could be crucial to developing successful therapies 36 , 37 . Notably, urinary formate has been already suggested as a new potential biomarker for Alzheimer’s disease by an independent study 14 . As a final breakdown product of human and microbial metabolism, formate is typically found in human urine 38 .…”

“…Moreover, changes in gut microbial metabolites, such as primary and secondary bile acids (BAs), have been reported to correlate with mild cognitive impairment and AD dementia 11 , 12 . In particular, gut microbiome contributes up to 50% of formic acid human production 13 and urinary formic acid levels have been recently suggested as non-invasive and cost-effective urinary biomarkers analysis in case of AD 14 .…”

Breakthroughs in Alzheimer’s Research: A Path to a More Promising Future?

“…These findings might result in affordable testing for the early detection of AD. 20 If additional research confirms that urine formic acid may detect cognitive loss, then making this kind of testing (non-invasive and affordable) accessible to the general public would be a game changer in the fight against AD. One study examined the differences between people with and without AD using post-mortem brain tissue from both groups.…”

A Transfer Hydrogenation Approach to Activity-Based Sensing of Formate in Living Cells

“…One-carbon metabolism plays a central role in regulating cellular metabolism and epigenetics, but aberrations in one-carbon cycles are associated with the progression of serious diseases, including diabetes, chronic liver and heart diseases, neurodegenerative diseases, and cancer. − In this context, formate is a primary one-carbon unit that is produced, utilized, and regulated within one-carbon metabolic cycles and is essential for sustaining amino acid (serine, glycine, methionine) and nucleotide (purine/thymidylate) biosynthesis, as well as redox, energy, and epigenetic homeostasis. − In mammals, formate concentrations normally reside in range of 10–100 μM in blood and can rise to above 1 mM within cells; moreover, its levels can fluctuate greatly between healthy and diseased states. , Indeed, increased formate overflow is a potential biomarker for neurodegenerative Alzheimer’s disease and a hallmark of oxidative stress in cancer . In one striking clinical study, formate was posited as a potential biomarker for esophageal cancer progression, with the observation that formate levels progressively increased in esophageal tumors relative to normal mucosae from Stage I (8.45×) to Stage II (13.51×) to Stage III (14.84×) to Stage IV (21.48×) …”

“…1−5 In mammals, formate concentrations normally reside in range of 10−100 μM in blood 1 and can rise to above 1 mM within cells; 6 moreover, its levels can fluctuate greatly between healthy and diseased states. 4,5 Indeed, increased formate overflow is a potential biomarker for neurodegenerative Alzheimer's disease 7 and a hallmark of oxidative stress in cancer. 8 In one striking clinical study, formate was posited as a potential biomarker for esophageal cancer progression, with the observation that formate levels progressively increased in esophageal tumors relative to normal mucosae from Stage I (8.45×) to Stage II (13.51×) to Stage III (14.84×) to Stage IV (21.48×).…”