Mar 13, 2025
Tau and depression: A systematic review and Meta-analysis
- 1Faculdade de Medicina de São José do Rio Preto
Protocol Citation: Juliano Flávio Rubatino Rodrigues 2025. Tau and depression: A systematic review and Meta-analysis. protocols.io https://dx.doi.org/10.17504/protocols.io.q26g7mqw8gwz/v1
License: This is an open access protocol distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Protocol status: Working
We use this protocol and it's working
Created: March 10, 2025
Last Modified: March 13, 2025
Protocol Integer ID: 124155
Abstract
Objectives: The tau protein is essential for stabilizing microtubules. Changes in its phosphorylation are identified in many neurodegenerative diseases, such as frontotemporal dementia and Alzheimer's disease. The hyperphosphorylation of the tau protein is linked to various factors, including stress, which has a substantial impact on depressive illness. The present study aimed to systematically review studies that describe the association between tau protein and depression.
Design: The present study used the PRISMA statement 2020 as the inclusion criterion for articles describing tau protein in individuals with depression. The exclusion criterion was the lack of comparison of tau protein levels with individuals without depression.
Results: A total of 138 papers were identified, of which 21 were ultimately included. Associations have been found between tau protein and depression. In one study, participants with elevated tau had 1.42 times more chance of being depressed. Meta analyses demonstrated no statistical difference in tau values in people with depression compared to controls.
Conclusions: The association between tau protein and depression seems uncertain. More studies with adequate sampling are necessary to improve understanding of this vital question.
Protocol to systematic reviey
Protocol to systematic reviey
This systematic review followed this protocol.
Protocol
Protocol
1. Introduction:
The tau protein is essential for stabilizing microtubules, which transport nutrients in neurons. Negative phosphorylation regulates tau's interaction with microtubules. Mutations in the MAPT gene can impair this process, leading to neurofibrillary aggregates (1). Hyperphosphorylation of tau protein has been linked to numerous diseases such as diabetes, Parkinson's disease, Huntington's disease, Pick's disease, etc (2). Alzheimer's disease is the best-documented disease in which tau protein plays a pathophysiological role (3). The neuronal damage caused by the tau protein starts with its hyperphosphorylation. Several factors contribute to an imbalance between the elements that promote tau hyperphosphorylation and those that facilitate its dephosphorylation. Most hyperphosphorylation promoters hyperactivate glycogen synthase kinase-3b (GSK-3b) and inhibit PP2A phosphatase, promoting an imbalance between phosphorylation mechanisms (4). Hyperphosphorylated tau protein accumulates in neurofilaments and destabilizes microtubules with consequent neuronal atrophy and death. GSK-3b may serve as a critical junction connecting the mechanisms of tau hyperphosphorylation and the onset of depression. By delving into the physiopathology of stress, we can gain valuable insights that could enhance preventive measures against neurodegenerative diseases in older adults.
2. Objective:
This review aims to provide a comprehensive exploration of the current literature, focusing specifically on
the connection between alterations in tau protein levels and the experience of depressive symptoms. By systematically identifying and analyzing relevant studies, we seek to illuminate the complex interplay between tau protein dynamics and mood disorders, highlighting the implications for understanding how these biological changes may contribute to the onset and progression of depression.
3. Methods:
3.1. Study design
This study proposes to investigate the tau
protein associated with depression. This systematic review follows the PRISMA methodology (5) with two parallel reviews.
After review, a meta-analysis will proceed.
3.2. Selection
criteria
The question (PECOS) under study
was: Do individuals (P) exposed to high levels of Tau protein (E), compared to
individuals with normal levels of Tau protein (C), exhibit a higher prevalence
of depression (O)? Case-control studies and other kinds of study that
discriminate between the control group and case of depression(S) were selected,
with the inclusion criterion for articles describing tau protein in individuals
with depression and the exclusion criterion being the lack of comparison of tau
protein levels with individuals without depression.
To be eligible,
studies had to meet the following criteria: They had to include a paper that
reported cardiovascular disease in individuals with Alzheimer’s. We excluded
every study that did not describe a possible association between cardiovascular
disease and Alzheimer's. Three authors systematically searched, read titles and
abstracts, and shared the findings of the eligible papers. Some cardiovascular
risk factors, such as diabetes and dyslipidemia, were not included as
cardiovascular disease. Studies that did not distinguish Alzheimer's disease
from other dementias, other vascular diseases not related to heart disease, and
simple comments were excluded.
3.3. Search Strategy
Following the PRISMA, the defined
papers’ titles and abstracts are eligible and non-restricted languages without
time limits. Furthermore, it was systematically identified by searching
electronic databases Embase
[Emtree - Major Focus Exp.], Pubmed [Mesh Terms], and Lilacs - Complete
collection of the Virtual Health Library [Title/abstracts], in April 2024.
3.4. Data
extraction
The data will be
extracted into two tables describing insomnia-related factors. Factors
associated with insomnia in the two parallel reviews will be compared through
exploratory factor analysis to identify and extract commonalities.
Data extraction will be performed independently by two reviewers (JFRR
and LPR) using a pre-piloted, standardized data extraction form. Discrepancies
will be resolved through discussion and consensus or with arbitration by a
third reviewer (GMAF).
3.6. Analysis
One hundred and thirty-eight articles were found, eighteen of which were
repeated. One was written in Spanish, one in German, four in Mandarin, and the
others in English. All were read in full by one of the authors, and two read all abstracts. The two co-authors
who read all the abstracts agreed to exclude 42 articles that did not meet the
inclusion criteria and to read the four articles written in Chinese with the
help of AI Chat. The author, who read all the articles in full, agreed
with excluding 42 articles and noted the inappropriateness of another 57,
including 21 for data extraction.
Statistical analyses were
performed using SPSS version 29.
Dissemination
The findings of this systematic review will be
disseminated through:
·
Publication in a peer-reviewed, internationally recognized journal indexed in PUBMED. We will target journals with a focus on sleep,
psychiatry, neurology, or public health.
·
Preprint server deposition. We will consider
posting a preprint of the manuscript on a recognized preprint server (e.g.,
medRxiv, bioRxiv) to facilitate rapid dissemination of findings.
·
Conference presentations. We will present the
findings at relevant national and international conferences.
·
Lay summaries. We will prepare lay summaries of the findings
for dissemination to patient advocacy groups and the general public.
References
References
1. Zheng H, Sun H, Cai Q, Tai HC. The Enigma of Tau Protein Aggregation: Mechanistic Insights and Future Challenges. Int J Mol Sci. 2024;25(9):4969.
2. Goedert M, Spillantini MG. Ordered Assembly of Tau Protein and Neurodegeneration. In: Takashima A, editor. Tau Biology. 1184. Singapore Springer; 2019. p. 3-21.
3. Watanabe H, Bagarinao E, Yokoi T, Yamaguchi H, Ishigaki S, Mausuda M, et al. Tau Accumulation and Network Breakdown in Alzheimer's Disease. In: Takashima A, editor. Tau Biology. 1184. Singapore: Springer; 2019. p. 231-40.
4. Gratuze M, Joly-Amado A, Buee L, Vieau D, Blum D. Tau, Diabetes and Insulin. In: Takashima A, editor. Tau Biology. 1184. Singapore: Springer; 2019. p. 259-87.
5. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev. 2021;10.