Current research status of blood biomarkers in Alzheimer’s disease: Diagnosis and prognosis

Alzheimer’s disease (AD), which mainly occurs in the elderly, is a neurodegenerative disease with a hidden onset, which leads to progressive cognitive and behavioral changes. The annually increasing prevalence rate and number of patients with AD exert great pressure on the society. No effective disease-modifying drug treatments are available; thus, there is no cure yet. The disease progression can only be delayed through early detection and drug assistance. Therefore, the importance of exploring associated biomarkers for the early diagnosis and prediction of the disease progress is highlighted. The National Institute on Aging— Alzheimer’s Association (NIA-AA) proposed A/T/N diagnostic criteria in 2018, including Aβ42, p-tau, t-tau in cerebrospinal fluid (CSF), and positron emission tomography (PET). However, the invasiveness of lumbar puncture for CSF assessment and non-popularity of PET have prompted researchers to look for minimally invasive, easy to collect, and cost-effective biomarkers. Therefore, studies have largely focused on some novel molecules in the peripheral blood. This is an emerging research field, facing many obstacles and challenges while achieving some promising results.     

Circadian and sleep dysfunction in Alzheimer’s disease

Alzheimer's disease (AD) is a devastating and irreversible cognitive impairment and the most common type of dementia. Along with progressive cognitive impairment, dysfunction of the circadian rhythms also plays a pivotal role in the progression of AD. A mutual relationship among circadian rhythms, sleep, and AD has been well-recommended. The etiopathogenesis of the disturbances of the circadian system and AD share some general features that also unlock the outlook of observing them as a mutually dependent pathway. Indeed, the burden of amyloid β (Aβ), neurofibrillary tangles (NFTs), neuroinflammation, oxidative stress, and dysfunction of circadian rhythms may lead to AD. Aging can alter both sleep timings and quality that can be strongly disrupted in AD. Increased production of Aβ and reduced Aβ clearance are caused by a close interplay of Aβ, sleep disturbance and raised wakefulness. Besides Aβ, the impact of tau pathology is possibly noteworthy to the sleep deprivation found in AD. Hence, this review is focused on the primary mechanistic complexities linked to disruption of circadian rhythms, sleep deprivation, and AD. Furthermore, this review also highlights the potential therapeutic strategies to abate AD pathogenesis.     

Cystatin C in aging and in Alzheimer’s disease

Under normal conditions, the function of catalytically active proteases is regulated, in part, by their endogenous inhibitors, and any change in the synthesis and/or function of a protease or its endogenous inhibitors may result in inappropriate protease activity. Altered proteolysis as a result of an imbalance between active proteases and their endogenous inhibitors can occur during normal aging, and such changes have also been associated with multiple neuronal diseases, including Amyotrophic Lateral Sclerosis (ALS), rare heritable neurodegenerative disorders, ischemia, some forms of epilepsy, and Alzheimer’s disease (AD). One of the most extensively studied endogenous inhibitor is the cysteine-protease inhibitor cystatin C (CysC). Changes in the expression and secretion of CysC in the brain have been described in various neurological disorders and in animal models of neurodegeneration, underscoring a role for CysC in these conditions. In the brain, multiple in vitro and in vivo findings have demonstrated that CysC plays protective roles via pathways that depend upon the inhibition of endosomal-lysosomal pathway cysteine proteases, such as cathepsin B (Cat B), via the induction of cellular autophagy, via the induction of cell proliferation, or via the inhibition of amyloid-β (Aβ) aggregation. We review the data demonstrating the protective roles of CysC under conditions of neuronal challenge and the protective pathways induced by CysC under various conditions. Beyond highlighting the essential role that balanced proteolytic activity plays in supporting normal brain aging, these findings suggest that CysC is a therapeutic candidate that can potentially prevent brain damage and neurodegeneration.     

Retinal biomarkers in Alzheimer’s disease and mild cognitive impairment: A systematic review and meta-analysis

BackgroundRetinal changes may reflect the pathophysiological processes in the central nervous system and can be assessed by imaging modalities non-invasively. We aim to localize candidate retinal biomarkers in Alzheimer’s disease (AD), mild cognitive impairment (MCI), and preclinical AD.MethodsWe systematically searched PubMed, EMBASE, Scopus, and Web of Science from inception to January 2021 for observational studies that investigated retinal imaging and electrophysiological markers in AD, MCI, and preclinical AD. Between-groups standardized mean differences (SMDs) with 95 % confidence intervals were computed using random-effects models.ResultsOf 19,727 citations identified, 126 articles were eligible for inclusion. Compared with healthy controls, the thickness of peripapillary retinal nerve fiber layer (pRNFL; SMD = -0.723, p < 0.001), total macular (SMD = -0.612, p < 0.001), and subfoveal choroid (SMD = -0.888, p < 0.001) were significantly reduced in patients with AD. Compared with healthy controls, patients with MCI also had lower thickness of pRNFL (SMD = -0.324, p < 0.001), total macular (SMD = -0.302, p < 0.001), and subfoveal choroid (SMD = -0.462, p = 0.020). Other candidate biomarkers included the optic nerve head morphology, retinal amyloid deposition, microvascular morphology and densities, blood flow, and electrophysiological markers.ConclusionsRetinal structural, vascular, and electrophysiological biomarkers hold great potential for the diagnosis, prognosis and risk assessment of AD and MCI. These biomarkers warrant further development in the future, especially in diagnostic test accuracy and longitudinal studies.     

Prospective biomarkers of Alzheimer’s disease: A systematic review and meta-analysis

ObjectiveAlzheimer’s disease (AD) involves a series of pathological changes and some biomarkers were reported to assist in monitoring and predicting disease progression before the emergence of clinical symptoms. We aimed to identify prospective biomarkers and quantify their effect on AD progression.MethodsPubMed, EMBASE and Web of Science databases were searched for prospective cohort studies published up to October 2021. Eligible studies were included, and the available data were extracted. Meta-analyses were conducted based on random-effect models. Relative risk (RR) with 95% confidence interval (CI) was adopted as the final effect size.ResultsTotally 48,769 articles were identified, of which 84 studies with 20 prospective biomarkers were included in meta-analyses. In the present study, 15 biomarkers were associated with AD progression, comprising CSF Aβ42 (RR=2.49, 95%CI=1.68–3.69), t-tau (RR=1.88, 95%CI=1.49–2.37), p-tau (RR=1.74, 95%CI=1.37–2.21), tau/Aβ42 ratio (RR=5.11, 95%CI=2.01–13.00); peripheral blood Aβ42/Aβ40 (RR=1.26, 95%CI=1.05–1.51), t-tau (RR=1.33, 95%CI=1.08–1.64), NFL (RR=1.75, 95%CI=1.07–2.87); whole, left and right hippocampal volume (HV) (whole: RR=1.65, 95%CI=1.39–1.95; left: RR=2.60, 95%CI=1.02–6.64; right: RR=1.43, 95%CI=1.23–1.66), entorhinal cortex (EC) volume (RR=1.69, 95%CI=1.24–2.30), medial temporal lobe atrophy (MTA) (RR=1.52, 95%CI=1.33–1.74), 18 F-FDG PET (RR=2.24, 95%CI=1.29–3.89), 11 C-labeled Pittsburgh Compound B PET (11 C-PIB PET) (RR=3.91, 95%CI=1.06–14.41); APOE ε4 (RR=2.16, 1.83–2.55). A total of 70 articles were included in the qualitative review, in which 61 biomarkers were additionally associated with AD progression.ConclusionCSF Aβ42, t-tau, p-tau, tau/Aβ42; peripheral blood t-tau, Aβ42/Aβ40, NFL; whole, left and right HV, EC volume, MTA, 18 F-FDG PET, 11 C-PIB PET; APOE ε4 may be promising prospective biomarkers for AD progression.     

Alzheimer’s disease and disseminated mycoses

Alzheimer’s disease (AD) is characterized by the presence in the brain of amyloid plaques and neurofibrillary tangles that provoke neuronal cell death, vascular dysfunction and inflammatory processes. In the present work, we have analyzed the existence of fungal infection in AD patients. A number of tests have been carried out in blood serum, including the detection of antibodies against several yeast species and fungal proteins, and also the presence of fungal (1,3)-β-glucan. Results from this analysis indicate that there is disseminated fungal infection in the majority of AD patients tested. Of interest, several AD patients contain high levels of fungal polysaccharides in peripheral blood, reflecting that disseminated fungal infection occurs in these patients. Together, these results suggest the presence of disseminated mycoses in blood serum from AD patients. To our knowledge these findings represent the first evidence that fungal infection is detectable in blood samples in AD patients. The possibility that this may represent a risk factor or may contribute to the etiological cause of AD is discussed.     

APOE mediated neuroinflammation and neurodegeneration in Alzheimer’s disease

Neuroinflammation is a central mechanism involved in neurodegeneration as observed in Alzheimer’s disease (AD), the most prevalent form of neurodegenerative disease. Apolipoprotein E4 (APOE4), the strongest genetic risk factor for AD, directly influences disease onset and progression by interacting with the major pathological hallmarks of AD including amyloid-β plaques, neurofibrillary tau tangles, as well as neuroinflammation. Microglia and astrocytes, the two major immune cells in the brain, exist in an immune-vigilant state providing immunological defense as well as housekeeping functions that promote neuronal well-being. It is becoming increasingly evident that under disease conditions, these immune cells become progressively dysfunctional in regulating metabolic and immunoregulatory pathways, thereby promoting chronic inflammation-induced neurodegeneration. Here, we review and discuss how APOE and specifically APOE4 directly influences amyloid-β and tau pathology, and disrupts microglial as well as astroglial immunomodulating functions leading to chronic inflammation that contributes to neurodegeneration in AD.     

Vascular risk factors and Alzheimer’s disease

Vascular factors are now established risk factors for cognitive decline, both for dementia and its two main subtypes: Alzheimer’s disease (AD) and vascular dementia. Their impact likely goes beyond causing an increase in concurrent vascular pathology, since they have been associated with increasing the risk of degenerative Alzheimer (plaque and tangle) pathology, either by increasing its rate of formation or reducing elimination from the brain, or a mixture of the two. A comprehensive series of reviews published in BMC Medicine, investigates the relationship between AD and cardiovascular diseases and risk factors from a clinical, pathological and therapeutic perspective. Whilst links between vascular factors and AD have clearly been demonstrated at both the clinical and pathological level, the nature of the relationship remains to be fully established and there is a lack of high quality treatment studies examining the extent to which vascular risk modification alters AD disease course. Further longitudinal mechanistic and therapeutic studies are required, especially to determine whether treatment of vascular risk can prevent or delay the onset of AD and/or reduce its rate of clinical progression.     

Selective neuronal vulnerability in Alzheimer’s disease

Alzheimer's disease (AD) is defined by a deficiency in specific behavioural and/or cognitive domains, pointing to selective vulnerabilities of specific neurons from different brain regions. These vulnerabilities can be compared across neuron subgroups to identify the most vulnerable neuronal types, regions, and time points for further investigation. Thus, the relevant organizational frameworks for brain subgroups will hold great values for a clear understanding of the progression in AD. Presently, the neuronal vulnerability has yet urgently required to be elucidated as not yet been clearly defined. It is suggested that cell-autonomous and non-cell-autonomous mechanisms can affect the neuronal vulnerability to stressors, and in turn modulates AD progression. This review examines cell-autonomous and non-cell-autonomous mechanisms that contribute to the neuronal vulnerability. Collectively, the cell-autonomous mechanisms seem to be the primary drivers responsible for initiating specific stressor-related neuronal vulnerability with pathological changes in certain brain areas, which then utilize non-cell-autonomous mechanisms and result in subsequent progression of AD. In summary, this article has provided a new perspective on the preventative and therapeutic options for AD.     

Parkinson’s disease and Alzheimer’s disease: a Mendelian randomization study

Background

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the top two common neurodegenerative diseases in elderly. Recent studies found the α-synuclein have a key role in AD. Although many clinical and pathological features between AD and PD are shared, the genetic association between them remains unclear, especially whether α-synuclein in PD genetically alters AD risk.

Results

We did not obtain any significant result (OR?=?0.918, 95% CI: 0.782–1.076, P?=?0.291) in MR analysis between PD and AD risk. In MR between α-synuclein in PD with AD risk, we only extracted rs356182 as the IV through a strict screening process. The result indicated a significant association based on IVW method (OR?=?0.638, 95% CI: 0.485–0.838, P?=?1.20E-03). In order to examine the robustness of the IVW method, we used other three complementary analytical methods and also obtained consistent results.

Conclusion

The overall PD genetic risk factors did not predict AD risk, but the α-synuclein susceptibility genetic variants in PD reduce the AD risk. We believe that our findings may help to understand the association between them, which may be useful for future genetic studies for both diseases.

     

β-amyloid oligomers and cellular prion protein in Alzheimer’s disease

Prefibrillar oligomers of the β-amyloid peptide (Aβ) are recognized as potential mediators of Alzheimer’s disease (AD) pathophysiology. Deficits in synaptic function, neurotoxicity, and the progression of AD have all been linked to the oligomeric Aβ assemblies rather than to Aβ monomers or to amyloid plaques. However, the molecular sites of Aβ oligomer action have remained largely unknown. Recently, the cellular prion protein (PrP^C) has been shown to act as a functional receptor for Aβ oligomers in brain slices. Because PrP^C serves as the substrate for Creutzfeldt–Jakob Disease (CJD), these data suggest mechanistic similarities between the two neurodegenerative diseases. Here, we review the importance of Aβ oligomers in AD, commonalities between AD and CJD, and the newly emergent role of PrP^C as a receptor for Aβ oligomers.     

Influence of genetic and cardiometabolic risk factors in Alzheimer’s disease

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder. Cardiometabolic and genetic risk factors play an important role in the trajectory of AD. Cardiometabolic risk factors including diabetes, mid-life obesity, mid-life hypertension and elevated cholesterol have been linked with cognitive decline in AD subjects. These potential risk factors associated with cerebral metabolic changes which fuel AD pathogenesis have been suggested to be the reason for the disappointing clinical trial results. In appreciation of the risks involved, using search engines such as PubMed, Scopus, MEDLINE and Google Scholar, a relevant literature search on cardiometabolic and genetic risk factors in AD was conducted. We discuss the role of genetic as well as established cardiovascular risk factors in the neuropathology of AD. Moreover, we show new evidence of genetic interaction between several genes potentially involved in different pathways related to both neurodegenerative process and cardiovascular damage.     

Ghrelin in Alzheimer’s disease: Pathologic roles and therapeutic implications

Ghrelin, which has many important physiological roles, such as stimulating food intake, regulating energy homeostasis, and releasing insulin, has recently been studied for its roles in a diverse range of neurological disorders. Despite the several functions of ghrelin in the central nervous system, whether it works as a therapeutic agent for neurological dysfunction has been unclear. Altered levels and various roles of ghrelin have been reported in Alzheimer’s disease (AD), which is characterized by the accumulation of misfolded proteins resulting in synaptic loss and cognitive decline. Interestingly, treatment with ghrelin or with the agonist of ghrelin receptor showed attenuation in several cases of AD-related pathology. These findings suggest the potential therapeutic implications of ghrelin in the pathogenesis of AD. In the present review, we summarized the roles of ghrelin in AD pathogenesis, amyloid beta (Aβ) homeostasis, tau hyperphosphorylation, neuroinflammation, mitochondrial deficit, synaptic dysfunction and cognitive impairment. The findings from this review suggest that ghrelin has a novel therapeutic potential for AD treatment. Thus, rigorously designed studies are needed to establish an effective AD-modifying strategy.     

Why do Alzheimer’s disease and Parkinson’s disease target the same neurons?

The puzzle is to explain how cerebral involvement in the sporadic forms of Alzheimer’s disease (AD) and Parkinson’s disease (PD) can target the same population of vulnerable neurons. These neurons are poorly-myelinated projection neurons, lack of myelin being associated with high metabolic demand, high oxygen consumption, and high baseline oxidative stress. Yet the two diseases are clearly separable, with different intracellular markers, different risk factors, and different patterns of subcortical involvement.A theory is developed to show how two different pathophysiologies can preferentially affect the same neurons. In the case of AD, the hypothesis is as follows: the so-called vascular risk factors of AD, which include hypertension, diabetes, hyperlipidemia, and smoking, are all associated with increased systemic extracellular oxidative stress. High extracellular oxidative stress synergizes with high baseline intracellular oxidative stress to cause the disease. In the case of PD, mitochondrial failure associated with normal aging leads to diminished energy production and increased leakage of reactive oxygen species from mitochondria, a process which preferentially targets neurons with high baseline oxidative stress. In one case, the extra oxidative stress comes from outside the cell and, in the other case, it comes from inside the cell, i.e. from mitochondria. There is also evidence that neurofibrillary tangles are a protective mechanism against extracellular oxidative stress and that α-synuclein is a marker for mitochondrial failure. The basic pathophysiological difference is that AD is caused by oxidative stress alone, whereas PD is caused by oxidative stress plus failure of energy production.