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Peripheral transcriptomic biomarkers for early detection of sporadic Alzheimer disease?

ABSTRACT: Alzheimer disease (AD) is the major epidemic of the 21st century, its prevalence rising along with improved human longevity. Early AD diagnosis is key to successful treatment, as currently available therapeutics only allow small benefits for diagnosed AD patients. By contrast, future therapeutics, including those already in preclinical or clinical trials, are expected to afford neuroprotection prior to widespread brain damage and dementia. Brain imaging technologies are developing as promising tools for early AD diagnostics, yet their high cost limits their utility for screening at-risk populations. Blood or plasma transcriptomics, proteomics, and/or metabolomics may pave the way for cost-effective AD risk screening in middle-aged individuals years ahead of cognitive decline. This notion is exemplified by data mining of blood transcriptomics from a published dataset. Consortia blood sample collection and analysis from large cohorts with mild cognitive impairment followed longitudinally for their cognitive state would allow the development of a reliable and inexpensive early AD screening tool.

SUBMITTER: Hadar A

PROVIDER: S-EPMC6436957 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Peripheral transcriptomic biomarkers for early detection of sporadic Alzheimer disease?

Hadar Adva A Gurwitz David D

Dialogues in clinical neuroscience 20181201 4

Alzheimer disease (AD) is the major epidemic of the 21<sup>st</sup> century, its prevalence rising along with improved human longevity. Early AD diagnosis is key to successful treatment, as currently available therapeutics only allow small benefits for diagnosed AD patients. By contrast, future therapeutics, including those already in preclinical or clinical trials, are expected to afford neuroprotection prior to widespread brain damage and dementia. Brain imaging technologies are developing as ...[more]

PMID: 30936769

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Project description:Short-term memory dysfunction is a key early feature of Alzheimer's disease (AD). Psychiatric patients may be at higher risk for memory dysfunction and subsequent AD due to the negative effects of stress and depression on the brain. We carried out longitudinal within-subject studies in male and female psychiatric patients to discover blood gene expression biomarkers that track short term memory as measured by the retention measure in the Hopkins Verbal Learning Test. These biomarkers were subsequently prioritized with a convergent functional genomics approach using previous evidence in the field implicating them in AD. The top candidate biomarkers were then tested in an independent cohort for ability to predict state short-term memory, and trait future positive neuropsychological testing for cognitive impairment. The best overall evidence was for a series of new, as well as some previously known genes, which are now newly shown to have functional evidence in humans as blood biomarkers: RAB7A, NPC2, TGFB1, GAP43, ARSB, PER1, GUSB, and MAPT. Additional top blood biomarkers include GSK3B, PTGS2, APOE, BACE1, PSEN1, and TREM2, well known genes implicated in AD by previous brain and genetic studies, in humans and animal models, which serve as reassuring de facto positive controls for our whole-genome gene expression discovery approach. Biological pathway analyses implicate LXR/RXR activation, neuroinflammation, atherosclerosis signaling, and amyloid processing. Co-directionality of expression data provide new mechanistic insights that are consistent with a compensatory/scarring scenario for brain pathological changes. A majority of top biomarkers also have evidence for involvement in other psychiatric disorders, particularly stress, providing a molecular basis for clinical co-morbidity and for stress as an early precipitant/risk factor. Some of them are modulated by existing drugs, such as antidepressants, lithium and omega-3 fatty acids. Other drug and nutraceutical leads were identified through bioinformatic drug repurposing analyses (such as pioglitazone, levonorgestrel, salsolidine, ginkgolide A, and icariin). Our work contributes to the overall pathophysiological understanding of memory disorders and AD. It also opens new avenues for precision medicine- diagnostics (assement of risk) as well as early treatment (pharmacogenomically informed, personalized, and preventive).

Project description:ObjectiveTo measure CSF levels of biomarkers reflecting microglia and astrocytes activation, neuroinflammation, and cerebrovascular changes and study their associations with the core biomarkers of Alzheimer disease (AD) pathology (β-amyloid [Aβ] and tau), structural imaging correlates, and clinical disease progression over time.MethodsThe study included cognitively unimpaired elderly (n = 508), patients with mild cognitive impairment (MCI, n = 256), and patients with AD dementia (n = 57) from the longitudinal Swedish BioFINDER cohort. CSF samples were analyzed for YKL-40, interleukin (IL)-6, IL-7, IL-8, IL-15, IP-10, monocyte chemoattractant protein 1, intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), placental growth factor, and fms-related tyrosine kinase 1 (Flt-1). MRI data were available from 677 study participants. Longitudinal clinical assessments were conducted in control individuals and patients with MCI (mean follow-up 3 years, range 1-6 years).ResultsCSF levels of YKL-40, ICAM-1, VCAM-1, IL-15, and Flt-1 were increased during the preclinical, prodromal, and dementia stages of AD. High levels of these biomarkers were associated with increased CSF levels of total tau, with the associations, especially for YKL-40, being stronger in Aβ-positive individuals. The results were similar for associations between phosphorylated tau and YKL-40, ICAM-1, and VCAM-1. High levels of the biomarkers were also associated with cortical thinning (primarily in the precuneus and superior parietal regions) and with subsequent cognitive deterioration in patients without dementia as measured with Mini-Mental State Examination (YKL-40) and Clinical Dementia Rating Sum of Boxes (YKL-40, ICAM-1, VCAM-1 and IL-15). Finally, higher levels of CSF YKL-40, ICAM-1, and Flt-1 increased risk of development of AD dementia in patients without dementia.ConclusionsNeuroinflammation and cerebrovascular dysfunction are early events occurring already at presymptomatic stages of AD and contribute to disease progression.

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Peripheral transcriptomic biomarkers for early detection of sporadic Alzheimer disease?

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Peripheral transcriptomic biomarkers for early detection of sporadic Alzheimer disease?

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