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The Molecular and Neuropathological Consequences of Genetic Risk for Alzheimer's Dementia.

ABSTRACT: Alzheimer's dementia commonly impacts the health of older adults and lacks any preventative therapy. While Alzheimer's dementia risk has a substantial genetic component, the specific molecular mechanisms and neuropathologies triggered by most of the known genetic variants are unclear. Resultantly, they have shown limited influence on drug development portfolios to date. To facilitate our understanding of the consequences of Alzheimer's dementia susceptibility variants, we examined their relationship to a wide range of clinical, molecular and neuropathological features. Because the effect size of individual variants is typically small, we utilized a polygenic (overall) risk approach to identify the global impact of Alzheimer's dementia susceptibility variants. Under this approach, each individual has a polygenic risk score (PRS) that we related to clinical, molecular and neuropathological phenotypes. Applying this approach to 1,272 individuals who came to autopsy from one of two longitudinal aging cohorts, we observed that an individual's PRS was associated with cognitive decline and brain pathologies including beta-amyloid, tau-tangles, hippocampal sclerosis, and TDP-43, MIR132, four proteins including VGF, IGFBP5, and STX1A, and many chromosomal regions decorated with acetylation on histone H3 lysine 9 (H3K9Ac). While excluding the APOE/TOMM40 region (containing the single largest genetic risk factor for late-onset Alzheimer's dementia) in the calculation of the PRS resulted in a slightly weaker association with the molecular signatures, results remained significant. These PRS-associated brain pathologies and molecular signatures appear to mediate genetic risk, as they attenuated the association of the PRS with cognitive decline. Notably, the PRS induced changes in H3K9Ac throughout the genome, implicating it in large-scale chromatin changes. Thus, the PRS for Alzheimer's dementia (AD-PRS) showed effects on diverse clinical, molecular, and pathological systems, ranging from the epigenome to specific proteins. These convergent targets of a large number of genetic risk factors for Alzheimer's dementia will help define the experimental systems and models needed to test therapeutic targets, which are expected to be broadly effective in the aging population that carries diverse genetic risks for Alzheimer's dementia.

SUBMITTER: Tasaki S

PROVIDER: S-EPMC6187226 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The Molecular and Neuropathological Consequences of Genetic Risk for Alzheimer's Dementia.

Tasaki Shinya S Gaiteri Chris C Mostafavi Sara S De Jager Philip L PL Bennett David A DA

Frontiers in neuroscience 20181008

Alzheimer's dementia commonly impacts the health of older adults and lacks any preventative therapy. While Alzheimer's dementia risk has a substantial genetic component, the specific molecular mechanisms and neuropathologies triggered by most of the known genetic variants are unclear. Resultantly, they have shown limited influence on drug development portfolios to date. To facilitate our understanding of the consequences of Alzheimer's dementia susceptibility variants, we examined their relation ...[more]

PMID: 30349450

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Project description:BackgroundMechanical ventilation is strongly associated with cognitive decline after critical illness. This finding is particularly evident among older individuals who have pre-existing cognitive impairment, most commonly characterized by varying degrees of cerebral amyloid-β accumulation, neuroinflammation, and blood-brain barrier dysfunction. We sought to test the hypothesis that short-term mechanical ventilation contributes to the neuropathology of cognitive impairment by (i) increasing cerebral amyloid-β accumulation in mice with pre-existing Alzheimer's disease pathology, (ii) increasing neurologic and systemic inflammation in wild-type mice and mice with pre-existing Alzheimer's disease pathology, and (iii) increasing hippocampal blood-brain barrier permeability in wild-type mice and mice with pre-existing Alzheimer's disease pathology.MethodsWe subjected double transgenic Alzheimer's disease (APP/PSEN1) and wild-type mice to mechanical ventilation for 4 h and compared to non-mechanically ventilated Alzheimer's disease model and wild-type mice. Cerebral soluble/insoluble amyloid-β1-40/amyloid-β1-42 and neurological and systemic markers of inflammation were quantified. Hippocampal blood-brain barrier permeability was quantified using a novel methodology that enabled assessment of small and large molecule permeability across the blood-brain barrier.ResultsMechanical ventilation resulted in (i) a significant increase in cerebral soluble amyloid-β1-40 (p = 0.007) and (ii) significant increases in neuroinflammatory cytokines in both wild-type and Alzheimer's disease mice which, in most cases, were not reflected in the plasma. There were (i) direct correlations between polymorphonuclear cells in the bronchoalveolar fluid and cerebral soluble amyloid-β1-40 (p = 0.0033), and several Alzheimer's disease-relevant neuroinflammatory biomarkers including cerebral TNF-α and IL-6; (iii) significant decreases in blood-brain barrier permeability in mechanically ventilated Alzheimer's disease mice and a trend towards increased blood-brain barrier permeability in mechanically ventilated wild-type mice.ConclusionsThese results provide the first evidence that short-term mechanical ventilation independently promotes the neuropathology of Alzheimer's disease in subjects with and without pre-existing cerebral Alzheimer's disease pathology. Future studies are needed to further clarify the specific mechanisms by which this occurs and to develop neuroprotective mechanical ventilation strategies that mitigate the risk of cognitive decline after critical illness.

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Dataset Information

The Molecular and Neuropathological Consequences of Genetic Risk for Alzheimer's Dementia.

Publications

The Molecular and Neuropathological Consequences of Genetic Risk for Alzheimer's Dementia.

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