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Blood Biomarkers for Memory: Towards Early Detection of Risk for Alzheimer Disease, Pharmacogenomics, and Repurposed Drugs

ABSTRACT: Short-memory dysfunction is a key early feature of Alzheimer Disease. Psychiatric patients may be at higher risk for memory dysfunction and subsequent Alzheimer 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 identify blood gene expression biomarkers that track short term memory as measured by the retention measure in the Hopkins Verbal Learning Test. These biomarkers were prioritized with a convergent functional genomics approach using previous evidence in the field implicating them in Alzheimer Disease. The top candidate biomarkers were tested in an independent cohort for ability to predict state short-term memory, and trait future positive neuropsychological testing for cognitive impairment

ORGANISM(S): Homo sapiens

PROVIDER: GSE127711 | GEO | 2020/04/01

REPOSITORIES: GEO

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Project description:GenADA is a multi-site collaborative study, involving GlaxoSmithKline Inc and nine medical centres in Canada, to develop a dataset containing 1000 Alzheimer's disease patients and 1000 ethnically-matched controls in order to associate DNA sequence (allelic) variations in candidate genes with Alzheimer's disease phenotypes. The study consists of both retrospective and prospective components, that is, patients with an existing diagnosis of Alzheimer's disease as well as newly diagnosed patients were enrolled in the study. Thus, clinical data was retrospectively or prospectively obtained on Day 1 of entry into GenADA. Where possible, biological relatives with Alzheimer's (up to third degree relationship such as cousins) and unaffected siblings of AD cases were also recruited. Note that recruitment numbers for biological relatives were lower than expected and genotypic data has not been submitted to dbGap for these subjects. The purpose of this study is: <ul> <li>To identify DNA sequence variations (genotype) in candidate genes that are associated with the clinical symptoms and behavioural features of Alzheimer's disease (phenotype), which differ between study participants with and without the disease.</li> <li>To identify other genotype-phenotype associations in cognitively impaired study participants such as age of onset, family history, rate of cognitive decline, patterns of behavioural/psychiatric non-cognitive symptoms factors, response to treatment co-morbid conditions, and risks/exposure.</li> </ul> The final subject recruitment for this study included 875 Alzheimer's disease patients, 850 ethnically-matched controls, and 37 family members. GenADA LONG is a longitudinal assessment to the original GenADA study. Eligible subjects were recruited from five of the nine memory clinics that participated in the GenADA study. Mild to moderate AD participants, a matched subset of controls, and biological related siblings (both affected and unaffected) or other blood relatives affected with AD, were initially examined a minimum of 12 months from recruitment into the original GenADA study, then at two further intervals of 12 and 18 months after time of entry into GenADA LONG. This enables an evaluation of the disease progression in AD patients and a determination of whether controls show evidence of cognitive decline. The overall goal of this extension study is to identify genetic differences and environmental influences that modulate the age of onset of the disease, the course of the disease, and/or biomarkers for neurodegenerative processes. Three of the five memory clinics that participated in the GenADA LONG study recruited eligible patients into GenADA Imaging. A concurrent neuroimaging sub-study was conducted at three of the five memory clinics participating in GenADA LONG. Eligible AD cases with mild to moderate AD, who were recruited into the original GenADA study and participated in the GenADA LONG extension study, were enrolled. Additionally, controls that showed signs of cognitive decline, as part of the assessment in GenADA LONG, were imaged at baseline, 12 and 18 month scanning intervals. The objective of this study is to find genes that: affect changes in AD brain volume measure by magnetic resonance in order to investigate how well change in brain volume predicts other key clinical measures in AD, such as neurodegenerative scales; that correlate changes in brain volume for other genotype-phenotype associations in cognitively impaired study participants; and that correlate with other clinically applicable magnetic resonance measures of pathology that can be conducted at the same time as structural volume measures, and are complementary to the volume measures. The ultimate aim of this research is to obtain a better understanding and definition of Alzheimer's Disease in order to develop new improved medicines.

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Blood Biomarkers for Memory: Towards Early Detection of Risk for Alzheimer Disease, Pharmacogenomics, and Repurposed Drugs

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