Background: Altered brain energy metabolism is implicated in Alzheimer's disease (AD). Limited and conflicting studies on brain pH changes, indicative of metabolic alterations associated with neural activity, warrant a comprehensive investigation into their relevance in this neurodegenerative condition. Furthermore, the relationship between these pH changes and established AD neuropathological evaluations, such as Braak staging, remains unexplored. Methods: We conducted quantitative meta-analyses on postmortem brain and cerebrospinal fluid pH in patients with AD and non-AD controls, using publicly available demographic data. We collected raw pH data from studies in the NCBI GEO, PubMed, and Google Scholar databases. Results: Our analysis of 17 datasets (457 patients and 315 controls) using a random-effects model showed a significant decrease in brain and cerebrospinal fluid pH in patients compared to controls (Hedges' g = -0.54, p < 0.0001). This decrease remained significant after considering postmortem interval, age at death, and sex. Notably, pH levels were negatively correlated with Braak stage, indicated by the random-effects model of correlation coefficients from 15 datasets (292 patients and 159 controls) (adjusted r = -0.26, p < 0.0001). Furthermore, brain pH enhanced the discriminative power of the APOEϵ4 allele, the most prevalent risk gene for AD, in distinguishing patients from controls in a meta-analysis of four combined datasets (95 patients and 87 controls). Conclusions: The significant decrease in brain pH in AD underlines its potential role in disease progression and diagnosis. This decrease, potentially reflecting neural hyperexcitation, could enhance our understanding of neurodegenerative pathology and aid in developing diagnostic strategies.

The authors have declared no competing interest.

This work was supported by MEXT Promotion of Distinctive Joint Research Center Program Grant Number JPMXP0618217663 and JSPS KAKENHI Grant Number JP20H00522.

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