Browsing by Subject "Autosomal-dominant Alzheimer's disease"

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    Circular RNA detection identifies circPSEN1 alterations in brain specific to autosomal dominant Alzheimer's disease
    (BMC, 2022-03-04) Chen, Hsiang‑Han; Eteleeb, Abdallah; Wang, Ciyang; Fernandez, Maria Victoria; Budde, John P.; Bergmann, Kristy; Norton, Joanne; Wang, Fengxian; Ebl, Curtis; Morris, John C.; Perrin, Richard J.; Bateman, Randall J.; McDade, Eric; Xiong, Chengjie; Goate, Alison; Farlow, Martin; Chhatwal, Jasmeer; Schofield, Peter R.; Chui, Helena; Harari, Oscar; Cruchaga, Carlos; Ibanez, Laura; Dominantly Inherited Alzheimer Network; Neurology, School of Medicine
    Background: Autosomal-dominant Alzheimer's disease (ADAD) is caused by pathogenic mutations in APP, PSEN1, and PSEN2, which usually lead to an early age at onset (< 65). Circular RNAs are a family of non-coding RNAs highly expressed in the nervous system and especially in synapses. We aimed to investigate differences in brain gene expression of linear and circular transcripts from the three ADAD genes in controls, sporadic AD, and ADAD. Methods: We obtained and sequenced RNA from brain cortex using standard protocols. Linear counts were obtained using the TOPMed pipeline; circular counts, using python package DCC. After stringent quality control (QC), we obtained the counts for PSEN1, PSEN2 and APP genes. Only circPSEN1 passed QC. We used DESeq2 to compare the counts across groups, correcting for biological and technical variables. Finally, we performed in-silico functional analyses using the Circular RNA interactome website and DIANA mirPath software. Results: Our results show significant differences in gene counts of circPSEN1 in ADAD individuals, when compared to sporadic AD and controls (ADAD = 21, AD = 253, Controls = 23-ADADvsCO: log2FC = 0.794, p = 1.63 × 10-04, ADADvsAD: log2FC = 0.602, p = 8.22 × 10-04). The high gene counts are contributed by two circPSEN1 species (hsa_circ_0008521 and hsa_circ_0003848). No significant differences were observed in linear PSEN1 gene expression between cases and controls, indicating that this finding is specific to the circular forms. In addition, the high circPSEN1 levels do not seem to be specific to PSEN1 mutation carriers; the counts are also elevated in APP and PSEN2 mutation carriers. In-silico functional analyses suggest that circPSEN1 is involved in several pathways such as axon guidance (p = 3.39 × 10-07), hippo signaling pathway (p = 7.38 × 10-07), lysine degradation (p = 2.48 × 10-05) or Wnt signaling pathway (p = 5.58 × 10-04) among other KEGG pathways. Additionally, circPSEN1 counts were able to discriminate ADAD from sporadic AD and controls with an AUC above 0.70. Conclusions: Our findings show the differential expression of circPSEN1 is increased in ADAD. Given the biological function previously ascribed to circular RNAs and the results of our in-silico analyses, we hypothesize that this finding might be related to neuroinflammatory events that lead or that are caused by the accumulation of amyloid-beta.
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    Higher systolic blood pressure in early-mid adulthood is associated with poorer cognitive performance in those with a dominantly inherited Alzheimer’s Disease mutation but not in non-carriers. Results from the DIAN study
    (Wiley, 2023) Xu, Ying; Aung, Htein Linn; Bateman, Randall J.; Brooks, William S.; Chhatwal, Jasmeer; Day, Gregory S.; Fagan, Anne M.; Farlow, Martin R.; Gordon, Brian; Kehoe, Patrick G.; Levin, Johannes; Mori, Hiroshi; Morris, John C.; Wharton, Whitney; Humburg, Peter; Schofield, Peter R.; Peters, Ruth; Dominantly Inherited Alzheimer Network (DIAN); Neurology, School of Medicine
    Background: The Dominantly Inherited Alzheimer Network (DIAN) is a longitudinal observational study that collects data on cognition, blood pressure (BP), and other variables from autosomal-dominant Alzheimer's disease mutation carriers (MCs) and non-carrier (NC) family members in early to mid-adulthood, providing a unique opportunity to evaluate BP and cognition relationships in these populations. Method: We examined cross-sectional and longitudinal relationships between systolic and diastolic BP and cognition in DIAN MC and NC. Results: Data were available from 528 participants, who had a mean age of 38 (SD = 11) and were 42% male and 61% MCs, at a median follow-up of 2 years. Linear-multilevel models found only cross-sectional associations in the MC group between higher systolic BP and poorer performance on language (β = -0.181 [-0.318, -0.044]), episodic memory (-0.212 [-0.375, -0.049]), and a composite cognitive measure (-0.146 [-0.276, -0.015]). In NCs, the relationship was cross-sectional only and present for language alone. Discussion: Higher systolic BP was cross-sectionally but not longitudinally associated with poorer cognition, particularly in MCs. BP may influence cognition gradually, but further longitudinal research is needed.