Molecular timeline of preclinical Alzheimers disease: why Autosomal Dominant Alzheimers Disease (ADAD) matters

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17 Oct 2026 0 comments

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 al1 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...