Heterogeneity of Alzheimer’s disease: consequence for drug trials?

Devi, Gayatri; Scheltens, Philip

doi:10.1186/s13195-018-0455-y

Cited by 93 publications

(67 citation statements)

References 15 publications

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“…The heterogeneous nature of AD ( 32 ), as a complex neurodegenerative disease affecting multiple biological pathways and processes during onset and progression ( 33 ), represents one major hurdle for AD drug discovery and development. Another hurdle, but simultaneously an opportunity, includes the length of time over which AD develops.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive characterization of Alzheimer’s disease by circulating, cell-free messenger RNA next-generation sequencing

Toden¹,

Zhuang²,

Acosta³

et al. 2020

Sci. Adv.

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The lack of accessible noninvasive tools to examine the molecular alterations occurring in the brain limits our understanding of the causes and progression of Alzheimer’s disease (AD), as well as the identification of effective therapeutic strategies. Here, we conducted a comprehensive profiling of circulating, cell-free messenger RNA (cf-mRNA) in plasma of 126 patients with AD and 116 healthy controls of similar age. We identified 2591 dysregulated genes in the cf-mRNA of patients with AD, which are enriched in biological processes well known to be associated with AD. Dysregulated genes included brain-specific genes and resembled those identified to be dysregulated in postmortem AD brain tissue. Furthermore, we identified disease-relevant circulating gene transcripts that correlated with the severity of cognitive impairment. These data highlight the potential of high-throughput cf-mRNA sequencing to evaluate AD-related pathophysiological alterations in the brain, leading to precision healthcare solutions that could improve AD patient management.

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Section: Discussionmentioning

confidence: 99%

Noninvasive characterization of Alzheimer’s disease by circulating, cell-free messenger RNA next-generation sequencing

Toden¹,

Zhuang²,

Acosta³

et al. 2020

Sci. Adv.

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“…The implication is therefore that stratification on MBI symptoms enriches samples for individuals with preclinical or prodromal disease, creating a more etiologically homogenous sample. Deeper phenotyping including fluid imaging and longitudinal follow up with detailed neuropsychology and clinical outcomes will be required to confirm this hypothesis, which could have important implications for clinical trials where cohort heterogeneity has been identified as a major concern [44].…”

Section: Discussionmentioning

confidence: 99%

Genetic risk for Alzheimer disease, cognition and Mild Behavioral Impairment in healthy older adults

Creese¹,

Brooker²,

Aarsland³

et al. 2020

Preprint

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BACKGROUND: Mild Behavioral Impairment (MBI) is a neuropsychiatric syndrome describing later-life emergent apathy, mood/anxiety symptoms, impulse dyscontrol, social inappropriateness and psychosis that are not attributable to psychiatric diagnoses. MBI is an at-risk state for incident cognitive decline and dementia, and is associated with dementia biomarkers including amyloid beta; and neurofilament light. Thus, MBI may be an early clinical marker of neurodegenerative disease. In this study, we hypothesized that stratification by MBI in a cognitively normal sample would moderate the signal between Alzheimer disease (AD) genetic risk and cognition. METHODS: Genetic, cognitive and MBI data was available for 3,126 PROTECT study participants over 50 without dementia. A general cognitive composite score was constructed based on scores on paired associates learning, digit span, self-ordered search and verbal reasoning. MBI was assessed using the MBI Checklist. Polygenic scores for AD were split by tertile (representing low, medium and high risk) and the sample was stratified by MBI into those with no symptoms and those with any symptoms. RESULTS: AD genetic risk was associated with poorer cognition in the MBI strata only (MBI: F(2,1746)=4.95, p=0.007; no MBI: F(2,1366)=0.72, p=0.49). The mean difference between low and high genetic risk groups was significant (p=0.005) and the standardised effect size in the MBI sample was higher than in the whole sample. CONCLUSIONS: These findings justify MBI screening to enrich samples with at-risk individuals, and underscore the importance of late-life neuropsychiatric symptoms in cognitive ageing.

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“…Gene editing techniques are increasingly used in drug discovery research, [ 302 ], particularly when the genetic cause(s) of disease is known. However, with the recognition that late-life sporadic neurodegenerative diseases frequently have more than one contributing pathology, identifying a single molecular therapeutic target whose manipulation is efficacious in all affected individuals may not be straightforward [ 303 ]. Additionally, and as highlighted in previous sections, given the diverse roles of tau in the human brain, complete MAPT knockdown has been approached cautiously.…”

Section: Tau-directed Therapeuticsmentioning

confidence: 99%

Tauopathies: Deciphering Disease Mechanisms to Develop Effective Therapies

Silva

Haggarty

2020

IJMS

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Tauopathies are neurodegenerative diseases characterized by the pathological accumulation of microtubule-associated protein tau (MAPT) in the form of neurofibrillary tangles and paired helical filaments in neurons and glia, leading to brain cell death. These diseases include frontotemporal dementia (FTD) and Alzheimer’s disease (AD) and can be sporadic or inherited when caused by mutations in the MAPT gene. Despite an incredibly high socio-economic burden worldwide, there are still no effective disease-modifying therapies, and few tau-focused experimental drugs have reached clinical trials. One major hindrance for therapeutic development is the knowledge gap in molecular mechanisms of tau-mediated neuronal toxicity and death. For the promise of precision medicine for brain disorders to be fulfilled, it is necessary to integrate known genetic causes of disease, i.e., MAPT mutations, with an understanding of the dysregulated molecular pathways that constitute potential therapeutic targets. Here, the growing understanding of known and proposed mechanisms of disease etiology will be reviewed, together with promising experimental tau-directed therapeutics, such as recently developed tau degraders. Current challenges faced by the fields of tau research and drug discovery will also be addressed.

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Heterogeneity of Alzheimer’s disease: consequence for drug trials?

Cited by 93 publications

References 15 publications

Noninvasive characterization of Alzheimer’s disease by circulating, cell-free messenger RNA next-generation sequencing

Noninvasive characterization of Alzheimer’s disease by circulating, cell-free messenger RNA next-generation sequencing

Genetic risk for Alzheimer disease, cognition and Mild Behavioral Impairment in healthy older adults

Tauopathies: Deciphering Disease Mechanisms to Develop Effective Therapies

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