Time for the systems-level integration of aging: Resilience enhancing strategies to prevent Alzheimer’s disease

Hampel, Harald; Lista, Simone; Néri, Christian; Vergallo, Andrea

doi:10.1016/j.pneurobio.2019.101662

Cited by 37 publications

(24 citation statements)

References 177 publications

(332 reference statements)

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“…In particular, despite toxic molecular pathways—such as the Aβ pathway–individuals may show normal cognitive function. Several biomarker‐based studies point at synaptic dynamics, from molecular pathways to large‐scale connectivity networks, that may underscore resilience through compensating incipient pathophysiological alterations 37–39 …”

Section: Discussionmentioning

confidence: 99%

Plasma β‐secretase1 concentrations correlate with basal forebrain atrophy and neurodegeneration in cognitively healthy individuals at risk for AD

Vergallo

Lemercier

Cavedo

et al. 2021

Alzheimer's & Dementia

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Background Increased β‐secretase 1 (BACE1) protein concentration, in body fluids, is a candidate biomarker of Alzheimer's disease (AD).We reported that plasma BACE1 protein concentrations are associated with the levels of brain amyloidβ (Αβ) accumulation in cognitively healthy individuals with subjective memory complaint (SMC). Methods In 302 individuals from the same cohort, we investigated the cross‐sectional and longitudinal association between plasma BACE1 protein concentrations and AD biomarkers of neurodegeneration (plasma t‐tau and Neurofilament light chain (NfL), fluorodeoxyglucose–positron emission tomography (FDG‐PET), brain volumes in the basal forebrain [BF], hippocampus, and entorhinal cortex). Results We report a positive longitudinal correlation of BACE1 with both NfL and t‐tau, as well as a correlation between annual BACE1 changes and bi‐annual reduction of BF volume. We show a positive association between BACE1 and FDG‐PET signal at baseline. Conclusions The association between plasma BACE1 protein concentrations and BF atrophy we found in cognitively healthy individuals with SMC corroborates translational studies, suggesting a role of BACE1 in neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Plasma β‐secretase1 concentrations correlate with basal forebrain atrophy and neurodegeneration in cognitively healthy individuals at risk for AD

Vergallo

Lemercier

Cavedo

et al. 2021

Alzheimer's & Dementia

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“…Most of the failed AD clinical trials-including trials investigating anti-inflammatory compounds-did not assess any biological in vivo identification of AD-related pathomechanistic alterations, thus preventing proof of mechanisms (157) and including a percentage of subject displaying non-AD pathophysiology (158). Therefore, robust biomarkers-drug codevelopment pipelines are strongly recommended for next-generation clinical trials (159).…”

Section: Biomarkers Of Neuroinflammation In Alzheimer's Diseasementioning

confidence: 99%

A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease

et al. 2020

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“…Emerging data encourage further analysis and characterization of specific miRNAs that may be either downregulated or upregulated aberrantly in the prodromal and preclinical phases of AD 7,8,[14][15][16] , where treatments with putative disease-modifying effect are more likely to be effective [17][18][19] .…”

Section: Introductionmentioning

confidence: 99%

MiRNA-15b and miRNA-125b are associated with regional Aβ-PET and FDG-PET uptake in cognitively normal individuals with subjective memory complaints

Vergallo

Zhao²,

Lemercier³

et al. 2021

Transl Psychiatry

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There is substantial experimental evidence for dysregulation of several microRNA (miRNA) expression levels in Alzheimer’s disease (AD). MiRNAs modulate critical brain intracellular signaling pathways and are associated with AD core pathophysiological mechanisms. First, we conducted a real-time quantitative PCR-based pilot study to identify a set of brain-enriched miRNAs in a monocentric cohort of cognitively normal individuals with subjective memory complaints, a condition associated with increased risk of AD. Second, we investigated the impact of age, sex, and the Apolipoprotein E ε4 (APOE ε4) allele, on the identified miRNA plasma concentrations. In addition, we explored the cross-sectional and longitudinal association of the miRNAs plasma concentrations with regional brain metabolic uptake using amyloid-β (Aβ)-positron emission tomography (Aβ-PET) and 18F-fluorodeoxyglucose-PET (18F-FDG-PET). We identified a set of six brain-enriched miRNAs—miRNA-125b, miRNA-146a, miRNA-15b, miRNA-148a, miRNA-26b, and miRNA-100. Age, sex, and APOE ε4 allele were not associated with individual miRNA abundance. MiRNA-15b concentrations were significantly lower in the Aβ-PET-positive compared to Aβ-PET-negative individuals. Furthermore, we found a positive effect of the miRNA-15b*time interaction on regional metabolic 18F-FDG-PET uptake in the left hippocampus. Plasma miRNA-125b concentrations, as well as the miRNA-125b*time interaction (over a 2-year follow-up), were negatively associated with regional Aβ-PET standard uptake value ratio in the right anterior cingulate cortex. At baseline, we found a significantly negative association between plasma miRNA-125b concentrations and 18F-FDG-PET uptake in specific brain regions. In an asymptomatic at-risk population for AD, we show significant associations between plasma concentrations of miRNA-125b and miRNA-15b with core neuroimaging biomarkers of AD pathophysiology. Our results, coupled with existing experimental evidence, suggest a potential protective anti-Aβ effect of miRNA-15b and a biological link between miRNA-125b and Aβ-independent neurotoxic pathways.

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Time for the systems-level integration of aging: Resilience enhancing strategies to prevent Alzheimer’s disease

Cited by 37 publications

References 177 publications

Plasma β‐secretase1 concentrations correlate with basal forebrain atrophy and neurodegeneration in cognitively healthy individuals at risk for AD

Plasma β‐secretase1 concentrations correlate with basal forebrain atrophy and neurodegeneration in cognitively healthy individuals at risk for AD

A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease

MiRNA-15b and miRNA-125b are associated with regional Aβ-PET and FDG-PET uptake in cognitively normal individuals with subjective memory complaints

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