# Targeting Endosomal dysfunction as a new source of biomarkers for Alzheimer's disease

> **NIH AG R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2026 · $398,575

## Abstract

Endosomal dysfunction is a well-accepted cell biological feature in Alzheimer’s disease (AD). However,
biomarkers reflecting endosomal traffic defects are still lacking. Current imaging and cerebrospinal fluid (CSF)
AD biomarkers focus primarily on the histopathology of the disease—that is, biomarkers that are linked to
neurofibrillary tangles and amyloid plaques. This proposal is designed to expand this focus to develop
biomarkers of the ‘cell biology’ of AD. Such biomarkers could potentially accelerate drug discovery, as
therapeutic interventions are currently being developed that target endosomal trafficking defects in AD.
 Genetic and cell biology studies have previously linked the endosomal trafficking assembly Retromer to
AD pathology. Most notable are deficiencies and rare mutations in retromer’s core protein, VPS35, and
retromer’s receptor, SORL1. Depletion of either VPS35 or SORL1 mimics the core cytopathology in AD, enlarged
endosomes in neurons, with concomitant mis-trafficking of endosomal cargoes.
In an effort to characterize defects in the endocytic pathway resulting from retromer dysfunction, we recently
completed a proteomic screen of CSF of VPS35 knock-out (KO) mice and control littermates. Among the proteins found elevated in the CSF of VPS35 KO mice were well established β-secretase BACE1 substrates, includingAPP (Amyloid Precursor Protein); APLP1/2 (Amyloid Beta Precursor Like Proteins 1 and 2); and CHL1 (Neuralcell adhesion molecule L1-like protein). Two of these proteins --APLP1 and CHL1-- were further validated inmouse CSF, and human CSF from cognitively healthy participants and prodromal AD patients. Collectively, our studies suggest BACE1 substrates as potential biomarkers of retromer-dependent endosomal dysfunction.
However, since VPS35 is implicated in other neurodegenerative disorders, including Parkinson’s disease (PD),
these new biomarkers may not be specific to AD. Therefore, relying on these exciting findings, but moving
towards the d

## Key facts

- **NIH application ID:** 11239773
- **Project number:** 5R01AG071868-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Sabrina  Alves Simoes Spassov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** AG
- **Fiscal year:** 2026
- **Award amount:** $398,575
- **Award type:** 5
- **Project period:** 2022-03-15T00:00:00 → 2026-12-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11239773

## Citation

> US National Institutes of Health, RePORTER application 11239773, Targeting Endosomal dysfunction as a new source of biomarkers for Alzheimer's disease (5R01AG071868-05). Retrieved via AI Analytics 2026-05-16 from https://api.ai-analytics.org/grant/nih/11239773. Licensed CC0.

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