By Yoonah Kang, Neurobiology, Physiology, and Behavior ’24

Author Bio : I am a third year student studying Neurobiology, Physiology, and Behavior. I always enjoyed biology in middle school and high school. I became interested in neurobiology through the AP psychology class in high school because I really enjoyed the section about the biology behind psychological phenomena. This paper was originally written for the UWP 104F class, writing in health professions. I was interested in Alzheimer’s Disease because it is a disease that affects many people around the world, but there is still no cure/treatment for it. While reading articles about Alzheimer’s, I found out that the best course for longevity is early diagnosis which allows for early intervention. So I focused on a way that can allow for easier ways to diagnose patients. I hope the readers understand that Alzheimer’s is very complex, and there is still a lot to learn, but also there has been a lot of research to further our knowledge about AD.

Introduction:

As the population over 65 years of age increases, the prevalence of Alzheimer’s Disease in the United States is projected to triple to 14 million by 2060 [1]. Alzheimer’s disease (AD) is a progressive neurodegenerative disease that begins with mild memory loss and can ultimately lead to death. It is characterized by the accumulation of amyloid-β and tau neurofibrillary tangles in the brain [2]. These characteristics can be measured to determine the onset of Alzheimer’s at earlier stages. Currently, treatments only delay the onset and progression of symptoms. Early diagnosis is important because it identifies the disease before it causes irreversible damage and improves treatment efficacy. Early diagnosis can also aid research for new drugs that reverse the pathological effects of AD before it becomes irreversible. It is possible to detect biomarkers involved in AD early because “neurodegenerative processes … start up to 20-30 years before symptom onset” [3].

Aggregation of Tau proteins is a major distinguishing feature of AD. Neurofibrillary tangles (i.e. tau protein aggregates) inside neuronal axons block transport of nutrients and disturbs essential functions, which leads to damage and destruction of neurons in the brain [4]. Under normal conditions, Tau proteins are highly soluble (able to be dissolved) and are directly attached to microtubules to support the intracellular transport of proteins and organelles. In the brains of AD patients, Tau proteins are hyperphosphorylated and dissociate from microtubules, which “initiates the conformational change from natively unfolded tau into [insoluble] paired helical filament tau inclusions (protein aggregates) and neurofibrillary tangles” [5]. The dissociation of Tau proteins from microtubules leads to instability and breakdown of microtubules, which leads to neuronal dysfunction. 

Currently, the evaluation of cerebrospinal fluid biomarkers (CSF) and positron emission tomography (PET) scans are widely used as diagnostic criteria for AD. The presence of the three main CSF biomarkers, Aβ42, T-tau, and P-tau, are established as diagnostic criteria for AD [6]. For example, a patient suspected of having AD may get their tau-PET or CSF p-tau checked to confirm diagnosis. However, drawing blood and evaluating blood biomarkers is less invasive than CSF biomarkers, which require a lumbar puncture, and are more cost-effective than PET scans. Retrieving biomarkers via blood is also more accessible at hospitals and local clinics because it does not require specialized instruments. This literature review focuses on the detection of abnormally high concentrations of tau proteins in blood to diagnose Alzheimer’s disease. 

Methodology:

I used the UC Davis library website to access the databases PubMed and APA PsycInfo. I searched a combination of the following terms: “Alzheimer’s”, “Alzheimer’s Disease”, “blood biomarker”, “blood”, “biomarker”, “tau”, “diagnosis”, “early diagnosis”, “literature review”, and “meta-study”. I chose articles between 2014 to 2022 because research of tau blood biomarkers is a recent field with new advances each year. 

Initially, I chose articles with titles such as “fluid biomarkers in diagnosis of Alzheimer’s” to understand the overall use of biomarkers in diagnosing AD. Reading meta-studies about blood biomarkers helped narrow my topic to tau proteins in blood. Afterwards, I skimmed literature reviews to find sections about tau proteins. I also read articles that specifically focused on tau proteins and their use in diagnosis of Alzheimer’s. I read titles and abstracts to rule out articles that only included biomarkers such as CSF biomarkers, microRNA, platelets, apolipoprotein B, or amyloid β peptides.

Results and Discussion:

Biomarkers that originate from the brain, such as tau proteins, are present at low concentrations in the systemic blood circulation because of the blood-brain barrier, which filters molecules moving in and out of the brain. However, in the 2021 article “Blood Biomarkers in Alzheimer’s Disease”, Miren Altuna-Azkargorta and Maite Mendioroz-Iriarte point out that “researchers have described blood-brain barrier dysfunction in patients with AD.” This dysfunction allows passage of molecules between the CSF and blood [3]. Brain protein concentration is low in blood because components of blood are complex and contain various other proteins and proteases, which mix with and hydrolyze (break down) proteins from the brain [7]. Therefore, more sensitive instruments are required to measure tau protein levels accurately and consistently.

However, there is an ongoing debate on the plausibility of t-tau in blood being used to diagnose AD. Lei Feng et al.’s 2021 article, “Current Research Status of Blood Biomarkers in Alzheimer’s Disease: Diagnosis and Prognosis,” reviews the various biomarkers in blood for AD diagnosis. In the section about t-tau proteins, they state that “t-tau may lack diagnostic specificity for AD because of its elevation [in concentration] in a series of pathologies, such as epilepsy and corticobasal degeneration” [7]. Another article, “Review: Tau in Biofluids – Relation to Pathology, Imaging and Clinical Features”, written by Henrick Zetterberg in 2017, is skeptical of blood plasma t-tau proteins because they lack specificity for AD and have a shorter half-life than CSF t-tau [8]. Since levels of t-tau are elevated for other neurodegenerative diseases, these tests may yield a false positive result for AD.

However, Bob Olsson et al. are hopeful about the prospects of plasma t-tau being used to diagnose AD. In their 2017 meta-analysis, “CSF and Blood Biomarkers for the Diagnosis of Alzheimer’s Disease: a Systematic Review and Meta-analysis,” they perform a systematic review of eleven research papers that assess t-tau in blood, including a total of 271 AD patients and 394 controls. With the combined data, the authors conclude that there is a significant difference in t-tau levels in blood between AD patients and control. Even though this association between elevated t-tau levels and AD has been found, Olsson et al. admit that there is large variation among the few studies available. Therefore, more studies must be done to establish a clearer association between t-tau and AD [6].

In 2016, Niklas Mattsson et al. published “Plasma Tau in Alzheimer Disease”, which looks at a total of 1284 participants between two cohorts: BioFINDER, which is in Sweden, and ADNI, located in the United States and Canada. The authors compare levels of tau proteins in blood plasma between patients with AD, patients with mild cognitive impairment (MCI), and people with normal cognition. With the cohort of patients in the ADNI program, the researchers found that there was an increase in plasma tau in AD patients, but they were not able to replicate these results with the BioFINDER cohort [9]. Varying results between the cohorts can suggest that association between plasma tau and AD is low, but it should be noted that this study was carried out across different locations with different handling protocols, inclusion criteria and technologies [9]. These confounding variables may have affected the results of this study.

Recent studies using ultrasensitive immunoassay methods show more promising results for detecting tau proteins. Leian Chen et al.’s article, “Plasma Tau Proteins for the Diagnosis of Mild Cognitive Impairment and Alzheimer’s Disease: a Systematic Review and Meta-analysis,” reviews 56 studies and summarize which technologies are effective at detecting an elevation in tau protein concentration, from people with normal cognition to MCI to AD patients. They find that immunomagnetic reduction technique (IMR) and Single molecule array (Simoa) assay methods detect differences in p-tau181, p-tau217, and p-tau231 levels across all three groups [2]. More specifically, blood “p-tau217 [is] more sensitive than p-tau181 and p-tau231 … because p-tau217 is more tightly related to the formation of Aβ plaques in the brain” [2], which is a distinguishing feature of AD. IMR is also consistent in detecting differences in t-tau levels between normal, MCI, and AD groups [2]. This shows that new technologies are starting to show more consistency in data reproduction of blood biomarkers, which prior research lacked. However, elevated plasma p-tau181 and p-tau217 levels are also found in other diseases like chronic kidney disease, hypertension, myocardial infarction, and stroke [2] – similar to tests for t-tau. Future research could focus on differentiating p-tau protein levels indicated by AD versus other diseases.

Two articles observe p-tau181 for early diagnosis of AD. Joyce R. Chong et al. wrote the article, “Blood-based High Sensitivity Measurements of Beta-amyloid and Phosphorylated Tau as Biomarkers of Alzheimer’s Disease: A Focused Review on Recent Advances,” in 2021, and it looks at studies that observe p-tau181 using Simoa immunoassay platform. They find that plasma p-tau181 can “differentiate between AD and non-AD neurodegenerative diseases” because it is associated with other AD-specific pathologies such as “NFT burden, grey matter atrophy, hippocampal atrophy, cortical atrophy brain, metabolic dysfunction and cognitive impairment” [10]. The study also reports that “the earliest increases in plasma p-tau181 occurred shortly before PET and CSF Aβ markers reached abnormal levels” [10]. Another article, written by Syed Haris Omar and John Preddy in 2020, titled “Advantages and Pitfalls in Fluid Biomarkers for Diagnosis of Alzheimer’s Disease,” looks at a study that used IMR to observe p-tau181. Omar and Preddy conclude that plasma p-tau181 can differentiate between AD and cognitive decline due to age because there is an increase in the ratio of p-tau181 to t-tau from control to patients with mild AD: 14.4% and 19.5%, respectively [11]. Therefore, developing more accurate detection methods of plasma p-tau181 may allow for earlier diagnosis of AD than current diagnosis procedures, which uses PET scans and CSF biomarkers, because it is an AD specific biomarker. 

Even though plasma tau currently cannot be used to diagnose Alzheimer’s Disease, recent studies show promising use in preclinical settings. In 2022, Rik Ossenkoppele et al. published the article “Tau Biomarkers in Alzheimer’s Disease: Towards Implementation in Clinical Practice and Trials.” Ossenkoppele et al. looked at tau pathology identified through PET, CSF, and plasma. The authors recommend using plasma p-tau as a “screening method to identify preclinical Alzheimer’s disease among cognitively unimpaired individuals,” but a “positive result should be confirmed using tau-PET or CSF p-tau” [5]. In “Plasma Tau Association with Brain Atrophy in Mild Cognitive Impairment and Alzheimer’s Disease,” Kacie D. Deters and her colleagues also highlight plasma tau’s use as a screening tool rather than a diagnostic tool for “cognitively normal or mildly symptomatic older adults” [12]. Currently, there is more research confirming the reliability of tau-PET and CSF p-tau in diagnosing AD compared to plasma tau. However, PET scans and collecting CSF samples for all patients suspected to have AD is not cost-effective and may not be available in clinical settings without special instruments to perform these tests. Since collecting blood samples is easier, checking for plasma p-tau in the pre-clinical phase can narrow down the patients who will need the more invasive procedures.

Conclusion:

The research on plasma tau proteins is new and has made significant progress in the past decade, but more research must be done on this topic. A more uniform way of measuring tau proteins must be established so studies can be replicated and yield similar results. Because these are recent advances, longitudinal studies are much needed. The progress of tau proteins in blood should be monitored in patients with AD to observe their effects in disease progression. In the near future, research on tau proteins can be used to develop drugs to treat AD.