Molecular timeline of preclinical Alzheimers disease: why Autosomal Dominant Alzheimers Disease (ADAD) matters
JNNP - Current Issue Published 13 Oct 2026 Relevancy: 47%
When the causal mutation is known, the challenge shifts from identifying disease origins to defining its detectable beginning. For decades, the study of Alzheimer’s disease has been framed by a deceptively simple question: when does the disease begin? In autosomal dominant Alzheimer’s disease (ADAD), the causal event is known. Pathogenic variants in amyloid precursor protein (APP) and presenilin 1 (PSEN1) are present from conception, establishing a lifelong predisposition to disease. Yet knowing the cause does not reveal when the disease becomes biologically manifest. The distinction is important: the causal event and the earliest detectable manifestation of disease are not necessarily the same phenomenon. ADAD offers a rare opportunity to investigate the interval between them. Belder et al 1 exploit one of the most informative natural experiments in human neurodegeneration. Unlike sporadic Alzheimer’s disease, where multiple biological processes converge and temporal inference remains challenging, ADAD provides a genetically anchored...
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