Genetic risk score for Alzheimer's aligns with observed lysosomal damage in human brain
University of Washington researchers combined 14 genetic variants known to act in endosomes and lysosomes into a single score that predicted diagnosis and disease severity in two independent donor cohorts.
The score was evaluated in 293 donors from their own cohort and 27,399 donors from the ADSP sequencing project, with the assessment released on 11 September. In both groups it forecast postmortem‑confirmed pathology diagnosis and severity.
In cortical slices, individuals with a high risk score showed more damaged endosomes in neurons and increased lysosomal aggregates in microglia, independent of disease stage.
Genome‑wide studies link DNA variants to genes indirectly; early suspects include APOE, CLU, PICALM, BIN1 and SORL1, many of which function in the endosome‑lysosome system. Loss of such genes causes endosome swelling, a phenotype also seen in mild cognitive impairment and Down syndrome before amyloid plaques appear.
The team hypothesized that combining risk variants would bridge statistical diagnosis to actual organelle damage; a new preprint released on 11 September tested this idea in human tissue.
RNA sequencing of 150,000 single nuclei revealed that a high risk score shifts gene expression in multiple brain cell types toward DNA‑damage response pathways while suppressing protein‑maintenance and energy‑metabolism programs, with the effect reversing across disease progression.
For BIN1 and CLU, gene activity flips in a manner similar to earlier reports for a CLU risk variant; comparable logic was previously demonstrated for the SORL1 gene.
The study remains postmortem; future longitudinal work with biomarkers and direct gene
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September 19, 2026 9
