Evaluation of Metabolic and Synaptic Dysfunction Hypotheses of Alzheimer's Disease (AD): A Meta-Analysis of CSF Markers
Authors: Manyevitch Roni , Protas Matthew , Scarpiello Sean , Deliso Marisa , Bass Brittany , Nanajian Anthony , Chang Matthew , Thompson Stefani M. , Khoury Neil , Gonnella Rachel , Trotz Margit , Moore D. Blaine , Harms Emily , Perry George , Clunes Lucy , Ortiz Angelica , Friedrich Jan O. , Murray Ian V.J. 
Published: January 2018

Background:

Alzheimer's disease (AD) is currently incurable and a majority of investigational
drugs have failed clinical trials. One explanation for this failure may be the invalidity of hypotheses focusing
on amyloid to explain AD pathogenesis. Recently, hypotheses which are centered on synaptic and metabolic
dysfunction are increasingly implicated in AD.

Objective:

Evaluate AD hypotheses by comparing neurotransmitter and metabolite marker concentrations in
normal versus AD CSF.

Methods:

Meta-analysis allows for statistical comparison of pooled, existing cerebrospinal fluid (CSF) marker
data extracted from multiple publications, to obtain a more reliable estimate of concentrations. This method
also provides a unique opportunity to rapidly validate AD hypotheses using the resulting CSF concentration
data. Hubmed, Pubmed and Google Scholar were comprehensively searched for published English articles,
without date restrictions, for the keywords “AD”, “CSF”, and “human” plus markers selected for synaptic and
metabolic pathways. Synaptic markers were acetylcholine, gamma-aminobutyric acid (GABA), glutamine, and
glycine. Metabolic markers were glutathione, glucose, lactate, pyruvate, and 8 other amino acids. Only studies
that measured markers in AD and controls (Ctl), provided means, standard errors/deviation, and subject numbers
were included. Data were extracted by six authors and reviewed by two others for accuracy. Data were
pooled using ratio of means (RoM of AD/Ctl) and random effects meta-analysis using Cochrane Collaboration’s
Review Manager software.

Results:

Of the 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 markers of synaptic and metabolic
pathways were significantly changed in AD/controls: acetylcholine (RoM 0.36, 95% CI 0.24-0.53,
p<0.00001), GABA (0.74, 0.58-0.94, p<0.01), 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 lower levels of significance for lactate (1.2, 1.00-1.47,
p=0.05). Of note, CSF glucose and glutamate levels in AD were not significantly different than that of the controls.

Conclusion:

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 and GABAergic resistance to neurodegeneration, given observed
unchanged glutamate levels and decreased GABA levels. With regards to metabolic hypotheses, the
data supported upregulation of anaerobic glycolysis, pentose phosphate pathway (glutathione), and anaplerosis
of the tricarboxylic acid cycle using glutamate. Future applications of meta-analysis indicate the possibility of
further in silico evaluation and generation of novel hypotheses in the AD field.