# Nerve growth factor (NGF) metabolic dysfunction as a marker of cognitive decline in autosomal dominant Alzheimer's disease

> **NIH NIH RF1** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $1,969,396

## Abstract

PROJECT SUMMARY
 Alzheimer’s disease (AD) progresses slowly over several decades preceding its clinical diagnosis, at
which point the brain compromise is most likely irreversible. Consequently, there is a growing realization that
future therapeutic interventions should be applied at earlier AD preclinical stages with the assistance of reliable
and accessible biomarkers signaling such “clinically silent” stages. The nerve growth factor (NGF) metabolic
pathway has been found to be disrupted in postmortem brain samples along the continuum of AD, starting at
preclinical stages. The brain’s NGF metabolism is compromised in non-cognitively impaired (NCI) individuals
with incipient AD pathology, but not in NCI individuals devoid of AD pathology. Importantly, in Down syndrome
(DS) individuals, also known to develop AD dementia, the brain’s NGF dysmetabolism is reflected in plasma and
cerebrospinal fluid (CSF) at asymptomatic stages.
 We propose the hypothesis that changes in proteins related to NGF metabolism in plasma and CSF
should assist in the early detection of preclinical AD. This hypothesis will be tested in individuals carrying
familial AD mutations, as this patient population undergoes a predictable disease course, that limits the
heterogeneity and comorbidity characteristic of sporadic AD. We propose to study the levels of NGF pathway
proteins in biofluids from carriers and non-carriers of pathogenic mutations in the presenilin1 (PSEN1) gene,
causing autosomal dominant early-onset Alzheimer's disease. NGF metabolism related putative biomarkers of
preclinical AD will be correlated with established biomarkers of Aβ (amyloid) and tau, brain structure, and
cognitive assessments in cross-sectional and longitudinal analyses. Towards this objective we have assembled
an ambitious research project involving an international collaboration between Massachusetts General
Hospital/Harvard Medical School (Boston, USA), University of Antioquia (Medellin, Colombia) and McGill
University (Montreal, Canada).
 Given that NGF metabolism-related proteins are altered in DS individuals at preclinical AD stages, we
are confident that this multidisciplinary study will yield novel biomarkers, which should assist in the identification
of individuals at preclinical AD stages in the general population. Towards such goals, we have outlined the
following aims: 1) To determine whether baseline abnormalities in the NGF metabolic pathway biomarkers, as
measured in plasma and CSF, can distinguish cognitively unimpaired PSEN1 mutation carriers from non-
carriers, and whether such NGF biomarkers are differentially associated with baseline brain volume and cognitive
performance; 2) To evaluate the extent to which changes in the NGF metabolic biomarkers improves prediction
of future cognitive decline, neurodegeneration, and clinical progression over and above predictions based only
on established biomarkers (e.g. amyloid markers) and baseline cognitive measures in PSEN1 mutation carr...

## Key facts

- **NIH application ID:** 10447866
- **Project number:** 1RF1AG077627-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** David Fernando Aguillon
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,969,396
- **Award type:** 1
- **Project period:** 2022-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447866

## Citation

> US National Institutes of Health, RePORTER application 10447866, Nerve growth factor (NGF) metabolic dysfunction as a marker of cognitive decline in autosomal dominant Alzheimer's disease (1RF1AG077627-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10447866. Licensed CC0.

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