USING CSF MARKERS TO VALIDATE METABOLIC AND SYNAPTIC DYSFUNCTION HYPOTHESES OF ALZHEIMER’S DISEASE (AD): META-ANALYSIS

Alzheimer's disease (AD) is currently incurable and a majority of investigational drugs have failed clinical trials. One explanation for this failure is the invalidity of some hypotheses explaining AD pathogenesis. Recently, hypotheses centered on synaptic and metabolic dysfunction are increasingly implicated in AD. Importantly, these hypotheses can readily be validated using neurotransmitter and metabolite biomarkers. Meta-analysis allows for statistical comparison of existing CSF biomarker data extracted from multiple publications, providing a unique opportunity to rapidly validate AD hypotheses in silico. Pubmed and Google Scholar were comprehensively searched for published English articles, without date restrictions, for the keywords “AD”, “CSF”, and “human” plus biomarkers selected for synaptic and metabolic pathways. Synaptic biomarkers were acetylcholine, GABA, glutamine, and glycine. Metabolic biomarkers were glutathione, glucose, lactate, pyruvate, and 8 other amino acids. Only studies that measured biomarkers in both AD and controls, provided means, standard errors/deviation, and subject numbers were included. Data were extracted by six authors and checked by two for accuracy. The data were transformed to log ratio of the means (AD/Control) and analyzed by the random effects model in the meta-analysis software (Cochrane Review Manager). Of 435 identified publications, after exclusion and removal of duplicates, 35 articles were included comprising a total of 605 AD patients and 585 controls. The following biomarkers for synaptic and metabolic pathways were significantly changed in AD/controls: acetylcholine (average ratio 0.36, 95% CI 0.24–0.53, p<0.00001), GABA (0.68, 0.54–0.85, p<0.0008), pyruvate (0.48, 0.24–0.94, p=0.03), glutathione (1.11, 1.01–1.21, p=0.03), alanine (1.10, 0.98–1.23, p=0.09), and lactate (1.17, 0.98–1.39, p=0.09). This study provides proof of concept for the use of meta-analysis validation of AD hypotheses, specifically via robust evidence for the cholinergic hypothesis of AD. Our data disagree with the other synaptic hypotheses of glutamate excitotoxicity (normal glutamate) and GABAergic resistance to neurodegeneration (decreased GABA levels). With regards to metabolic hypotheses, the data supported upregulation of anaerobic glycolysis, pentose phosphate pathway (glutathione), and TCA anaplerosis (several metabolites involved). Future applications of meta-analysis indicate the possibility of further in silico evaluation and generation of novel hypotheses in the AD field.