Moving fluid biomarkers for Alzheimer’s disease from research tools to routine clinical diagnostics

Zetterberg, Henrik; Blennow, Kaj

doi:10.1186/s13024-021-00430-x

Cited by 140 publications

(138 citation statements)

References 62 publications

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“…The definitive diagnosis could only be confirmed post-mortem by identifying the main AD hallmarks which are the extracellular accumulation of amyloid-β (Aβ) peptides and the hyperphosphorylation of intracellular tau protein leading to senile plaque and neurofibrillary tangle (NFT) formation, respectively, in the brain [ 1 , 2 ]. More recently, several guidelines indicate the quantification of Aβ 42 , total tau (t-tau) and tau phosphorylated at threonine 181 (p-tau) in blood samples and in the cerebrospinal fluid (CSF) as indicators for AD clinical diagnosis [ 3 , 4 , 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

The Controversial Role of 24-S-Hydroxycholesterol in Alzheimer’s Disease

et al. 2021

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The development of Alzheimer’s disease (AD) is influenced by several events, among which the dysregulation of cholesterol metabolism in the brain plays a major role. Maintenance of brain cholesterol homeostasis is essential for neuronal functioning and brain development. To maintain the steady-state level, excess brain cholesterol is converted into the more hydrophilic metabolite 24-S-hydroxycholesterol (24-OHC), also called cerebrosterol, by the neuron-specific enzyme CYP46A1. A growing bulk of evidence suggests that cholesterol oxidation products, named oxysterols, are the link connecting altered cholesterol metabolism to AD. It has been shown that the levels of some oxysterols, including 27-hydroxycholesterol, 7β-hydroxycholesterol and 7-ketocholesterol, significantly increase in AD brains contributing to disease progression. In contrast, 24-OHC levels decrease, likely due to neuronal loss. Among the different brain oxysterols, 24-OHC is certainly the one whose role is most controversial. It is the dominant oxysterol in the brain and evidence shows that it represents a signaling molecule of great importance for brain function. However, numerous studies highlighted the potential role of 24-OHC in favoring AD development, since it promotes neuroinflammation, amyloid β (Aβ) peptide production, oxidative stress and cell death. In parallel, 24-OHC has been shown to exert several beneficial effects against AD progression, such as preventing tau hyperphosphorylation and Aβ production. In this review we focus on the current knowledge of the controversial role of 24-OHC in AD pathogenesis, reporting a detailed overview of the findings about its levels in different AD biological samples and its noxious or neuroprotective effects in the brain. Given the relevant role of 24-OHC in AD pathophysiology, its targeting could be useful for disease prevention or slowing down its progression.

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Section: Introductionmentioning

confidence: 99%

The Controversial Role of 24-S-Hydroxycholesterol in Alzheimer’s Disease

et al. 2021

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“…However, other changes in total tau and phosphorylated tau, and neurodegeneration, occur subsequently in the disease course, suggesting that future research should examine how driving behaviours predict the presence of abnormalities in other CSF biomarkers such as tau, phosphorylated tau181, phosphorylated tau217, and neurofilament light. Furthermore, recent advances in the development of plasma AD biomarkers have led to newly available blood tests for abnormality of AD-related proteins [ 42 ], and these blood tests may ultimately become widely used in clinical practice to diagnose AD. Machine learning methods like those used here should also be applied to determining the optimal combination of driving behaviours to identify and predict blood-based AD diagnoses.…”

Section: Discussion/conclusionmentioning

confidence: 99%

GPS driving: a digital biomarker for preclinical Alzheimer disease

et al. 2021

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Background Alzheimer disease (AD) is the most common cause of dementia. Preclinical AD is the period during which early AD brain changes are present but cognitive symptoms have not yet manifest. The presence of AD brain changes can be ascertained by molecular biomarkers obtained via imaging and lumbar puncture. However, the use of these methods is limited by cost, acceptability, and availability. The preclinical stage of AD may have a subtle functional signature, which can impact complex behaviours such as driving. The objective of the present study was to evaluate the ability of in-vehicle GPS data loggers to distinguish cognitively normal older drivers with preclinical AD from those without preclinical AD using machine learning methods. Methods We followed naturalistic driving in cognitively normal older drivers for 1 year with a commercial in-vehicle GPS data logger. The cohort included n = 64 individuals with and n = 75 without preclinical AD, as determined by cerebrospinal fluid biomarkers. Four Random Forest (RF) models were trained to detect preclinical AD. RF Gini index was used to identify the strongest predictors of preclinical AD. Results The F1 score of the RF models for identifying preclinical AD was 0.85 using APOE ε4 status and age only, 0.82 using GPS-based driving indicators only, 0.88 using age and driving indicators, and 0.91 using age, APOE ε4 status, and driving. The area under the receiver operating curve for the final model was 0.96. Conclusion The findings suggest that GPS driving may serve as an effective and accurate digital biomarker for identifying preclinical AD among older adults.

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“…These two groups of biomarkers can be less invasive but continue to be expensive and hard to include in routine clinical practice. So, to try a more accessible approach, recent studies focus on circulating biomarkers as the next promising tool in the diagnostic area [ 50 , 51 ]. The easier way to assess patients’ samples for biomarkers study is through the blood.…”

Section: Diagnostic Tools For Alzheimer’s Diseasementioning

confidence: 99%

New RNA-Based Breakthroughs in Alzheimer’s Disease Diagnosis and Therapeutics

2021

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Dementia is described as the fifth leading cause of death worldwide and Alzheimer’s disease (AD) is recognized as the most common, causing a huge impact on health costs and quality of patients’ lives. The main hallmarks that are commonly associated with the pathologic process are amyloid deposition, pathologic Tau phosphorylation and neurodegeneration. It is still unclear how these events are linked to the disease progression, due to the complex pathologic mechanisms. Nevertheless, several hypotheses have been proposed for a better understanding of AD. The AD diagnosis is performed by using a combination of several tools to detect β-amyloid peptide (Aβ) deposits and modifications in cognitive performance, sometimes being expensive and invasive. In the treatment field, there is still an absence of effective treatments to delay or stop the progression of the disease, with most of the approved drugs used to relieve symptoms, and all of them with significant adverse side effects. Considering all limitations, the need to establish new and more effective diagnostic and therapeutic strategies becomes clear. This review aims not only to describe the disease and its impact but also to collect the currently available diagnostic and therapeutic strategies, highlighting new promising RNA-based strategies for AD.

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Moving fluid biomarkers for Alzheimer’s disease from research tools to routine clinical diagnostics

Cited by 140 publications

References 62 publications

The Controversial Role of 24-S-Hydroxycholesterol in Alzheimer’s Disease

The Controversial Role of 24-S-Hydroxycholesterol in Alzheimer’s Disease

GPS driving: a digital biomarker for preclinical Alzheimer disease

New RNA-Based Breakthroughs in Alzheimer’s Disease Diagnosis and Therapeutics

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