a, (left) Representative G-quadruplex tetrad structure with Hoogsteen base pairing stabilized by a cation at the center. (right) G-quadruplex structure with stacked tetrads. b, Demographics table for individuals included in this study. c, Immunofluorescence showing BG4 staining (red) in brain sections of human hippocampus from four control individuals of increasing age ranging 30-91 years old (Case 15, 13, and 8, respectively) all with Braak stage 0. d, Correlation of percent area covered by BG4 fluorescence in the outer-molecular layer versus age of individual.

a, Immunofluorescence showing BG4 staining (red) in brain sections of human hippocampus with increasing Braak stage (1-6) associated with AD severity (Case 16, 11, 10, and 8, respectively). All scale bars are 300 µm. b, Correlation of percent area BG4 coverage in the outer molecular layer versus severity of Braak stage. c, Quantification of percent area BG4 coverage by population with E2/E3 and E3/E3 versus E3/E4 and E4/E4 APOE alleles.

Cellular types and localization of rG4s, all scale bars are 50 µm. a, Immunofluorescence showing BG4 staining patterns (red) in human hippocampal tissue of case 17, a 53-year-old individual with Braak stage 1.5, and case 4, a 79-year-old individual with Braak stage 5 AD pathology (right). Cell nuclei stained with DAPI (blue). b, Co-stain of rRNA (left, yellow green) and BG4 (right, red), in the hippocampal CA4 region, an 80-year old individual with early stage tauopathy, demonstrating significant but not complete overlap between BG4 and rRNA. c, BG4 staining (red) with cell type markers (green) of oligodendrocytes (SOX10, case 8), neurons (NEUN, case 4), microglia (IBA1, case 18) and astrocytes (GFAP, case 18). BG4 is most prevalent in oligodendrocytes, neurons, and astrocytes. BG4 does not strongly colocalize with microglia (IBA1).

Colocalization of rG4s with p-tau and neurodegeneration model.

a, Immunofluorescence of human hippocampus from 2 older AD individuals (case 8 and case 21)showing BG4 (red), DAPI (blue), and p-tau (green). b, Proposed model relating chronic rG4 formation and protein aggregation in aging and neurodegeneration.