Biomarker Analysis in Autosomal Dominant Alzheimer’s Disease

Autosomal dominant Alzheimer’s disease (ADAD) arises from highly penetrant mutations in genes encoding amyloid precursor protein or presenilin enzymes, leading to an almost inevitable progression to dementia by midlife. Unlike sporadic Alzheimer’s disease, the age of onset in ADAD can be predicted within families, allowing the systematic mapping of biomarker changes from a presymptomatic phase through to clinical decline. Core biomarkers include measures of amyloid-β accumulation, tau pathology, synaptic dysfunction and regional brain atrophy. Fluid assays of cerebrospinal fluid (CSF) and blood reveal changes in peptide ratios and phosphorylated tau long before cognitive symptoms emerge. Multimodal neuroimaging—combining positron emission tomography for amyloid and tau ligands with structural and functional magnetic resonance imaging—charts the temporal sequence of amyloid deposition, tau spread, network disruption and grey matter loss. Recent efforts have also highlighted cases of extreme resilience, in which individuals harbour pathogenic mutations yet remain cognitively intact into late adulthood, pinpointing protective molecular pathways that may inform therapeutic strategies. The detailed biomarker trajectories defined in ADAD not only guide secondary prevention trials within this rare population but also illuminate the earliest events in more common, age-related Alzheimer’s disease.

Research from Nature Portfolio

Recent studies have described an individual carrying a rare gain-of-function variant in the RELN gene who, despite a pathogenic presenilin mutation and heavy amyloid burden, showed minimal tau pathology and preserved cognition until well beyond the expected onset age. Functional investigations in knockin models indicate that enhanced Reelin signalling can attenuate tau phosphorylation, offering a novel resilience mechanism against neurodegeneration. In parallel, an international consortium has released an extensive PET and MRI dataset from families with dominantly inherited Alzheimer’s, capturing longitudinal amyloid and tau ligand binding alongside volumetric and connectivity measures. This resource delineates the preclinical cascade—beginning with amyloid accumulation, followed by entorhinal tau, neocortical tau, hippocampal atrophy and eventual cognitive decline—and provides a standardised framework for future interventional studies.

Biomarker Analysis in Autosomal Dominant Alzheimer’s Disease publication trend

The graph below shows the total number of articles in biomarker analysis in autosomal dominant alzheimer’s disease across all publications each year (not limited to Nature Index journals).

Technical terms

Autosomal dominant Alzheimer’s disease: A hereditary form of Alzheimer’s caused by mutations in APP, PSEN1 or PSEN2, leading to early-onset dementia.

Biomarker: A measurable biological indicator—molecular, imaging or physiological—used to detect or monitor disease processes.

Amyloid-β: A peptide that aggregates into extracellular plaques, central to Alzheimer’s pathology.

Tau: A microtubule-associated protein that forms intracellular neurofibrillary tangles when abnormally phosphorylated.

Positron emission tomography (PET): A nuclear imaging technique employing radiolabelled tracers to visualise molecular pathology in vivo.

Magnetic resonance imaging (MRI): A non-invasive imaging method using magnetic fields and radio waves to visualise brain structure and function.

Cerebrospinal fluid (CSF): The fluid surrounding the brain and spinal cord, sampled to measure soluble biomarkers of neurodegeneration.

References

1. Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man. Nature Medicine (2023).
2. Positron emission tomography and magnetic resonance imaging methods and datasets within the Dominantly Inherited Alzheimer Network (DIAN). Nature Neuroscience (2023).
3. Resistant and Resilient mutations in protection against familial Alzheimer’s disease: learning from nature. Molecular Neurodegeneration (2023).
4. Shared and unique effects of ApoEε4 and pathogenic gene mutation on cognition and imaging in preclinical familial Alzheimer’s disease. Alzheimer's Research & Therapy (2023).