# Metabolic Vulnerability and Effects of APOE in Human Neurons with Impaired Endocytic Recycling

> **NIH AG K01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2026 · $124,859

## Abstract

PROJECT SUMMARY
Neurodegenerative dementias, including Alzheimer’s disease, inflict devastating cognitive decline, for which
there is no cure. Metabolic stress is hypothesized to contribute to the development of dementia: glucose
hypometabolism is an early feature in Alzheimer’s (AD) and Parkinson’s disease (PD), and diabetes is a
substantial risk factor for developing dementia. However, how metabolic stress combines with genetic
neurodegenerative disease risk factors to lead to neuronal death is not well understood, and there are no known
ways to boost metabolic resilience in susceptible neurons. To address these knowledge gaps, we have identified
genetic targets that maintain cellular energy levels, using a unique screening paradigm that combines cutting-
edge, genetically encoded sensors for ATP, the main energy-carrying molecule in cells, with whole-genome
CRISPR-based gene manipulations. With this approach, we have identified gene pathways that have a
prominent impact on ATP levels when cells are under metabolic stress. In particular, our preliminary data
indicate that knockdown of AD/PD disease risk genes associated with endocytic recycling lead to neuronal death
specifically when glucose is scarce. One of these genes is SORL1, a risk gene that is potentially causal for AD.
SORL1 is known to interact with APOE, and the APOE4 variant is the largest genetic risk factor for AD. But the
interaction between APOE and SORL1 or the endocytic recycling pathway is not well understood. Under the
mentorship of Dr. Ken Nakamura and Dr. Robert Mahley, in collaboration with Drs. Martin Kampmann and
Thomas Graeber, and with the support of the vibrant research community and cores at the Gladstone Institutes
and UCSF, I will test the hypothesis that AD risk mutations in endocytic recycling create an energy failure and
increases the susceptibility of neurons to lipid deficits and the deleterious effects of APOE expression and
APOE4 genotype. I will investigate this hypothesis th

## Key facts

- **NIH application ID:** 11361684
- **Project number:** 5K01AG078485-05
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Neal  Bennett
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** AG
- **Fiscal year:** 2026
- **Award amount:** $124,859
- **Award type:** 5
- **Project period:** 2022-08-01T00:00:00 → 2027-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11361684

## Citation

> US National Institutes of Health, RePORTER application 11361684, Metabolic Vulnerability and Effects of APOE in Human Neurons with Impaired Endocytic Recycling (5K01AG078485-05). Retrieved via AI Analytics 2026-06-26 from https://api.ai-analytics.org/grant/nih/11361684. Licensed CC0.

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