# Are neurodegenerative diseases late-onset neurodevelopmental disorders? Tracing the developmental origins of neuronal vulnerability

## TL;DR

This paper suggests that neurodegenerative diseases may originate from early developmental issues, not just aging, and proposes a new way to prevent and treat them.

## Contribution

The paper reframes neurodegeneration as a late-onset neurodevelopmental disorder, emphasizing developmental origins and early-life risk factors.

## Key findings

- Neurodegenerative diseases may stem from early-life developmental misprogramming.
- Shared developmental commonalities across neurological disorders suggest early predispositions to later degeneration.
- Human-specific developmental features and 3D organoid modeling reveal unique vulnerabilities to neurodegeneration.

## Abstract

Neurodegenerative diseases are traditionally viewed as age-associated conditions, characterized by distinct biochemical, cellular, and clinical features. However, emerging evidence suggests that their origins may trace back to much earlier stages of life. In this review, we synthesize insights from molecular genetics, developmental neurobiology, and systems neuroscience to examine the hypothesis that selective neuronal vulnerability can arise from developmental misprogramming. We explore how early-life processes—ranging from neurogenesis to synaptic maturation and circuit formation—can imprint long-lasting susceptibilities that manifest as degeneration decades later. Crucially, we highlight that many neurological disorders share early developmental commonalities that may predispose individuals to neurodegenerative vulnerability later in life. This is most apparent in familial forms of these diseases but may also emerge through embryonic or perinatal interactions with environmental or polygenic risk factors. Furthermore, we emphasize the importance of human-specific developmental features, which not only advance our understanding of brain formation but also reveal unique vulnerabilities to neurodegenerative diseases—insights that are increasingly accessible through advances in 3D organoid modeling. Together, these perspectives support a conceptual reframing of neurodegeneration as a late-onset neurodevelopmental disorder. This shift opens promising avenues for early diagnosis, prevention, and precision therapeutics, redirecting focus from late-stage intervention to fostering developmental resilience.