Mapping Alzheimer's disease heterogeneity with molecular imaging biomarkers

BACKGROUND: Alzheimer's disease (AD) is neuropathologically defined by the buildup of misfolded proteins such as extracellular amyloid-β (Aβ) and intracellular tau neurofibrillary tangles. AD also extends beyond these pathological processes, and additional mechanisms such as synaptic dysfunction, microglial activity, astrocytic neuroinflammation play an important role as biomarkers of AD progression. In vivo evaluation and quantification of these molecular processes are possible with positron emission tomography (PET) imaging. As disease-modifying therapies are entering clinical use, biomarkers' importance for early diagnosis and longitudinal monitoring of the disease increases. RESULTS: Aβ is the earliest signature of AD which can be measured with PET imaging, followed by tau-PET positivity, which is highly specific and central for staging and longitudinal monitoring. FDG-PET continues to serve as a gold standard for detecting neurodegeneration, challenged by emerging dual-phase PET protocols for amyloid and tau imaging, which integrate perfusion as a measure of neurodegeneration and pathology information in a single session, enhancing diagnostic efficiency. Synaptic density imaging reveals early synaptic loss linked to cognitive performance and decline. Neuroinflammation tracers can visualize microglial and astrocytic activation, contributing to disease onset and progression. Novel PET tracers targeting alpha-synuclein and TDP-43 show great promise for detecting co-pathologies which can contribute to AD clinical heterogeneity. CONCLUSION: PET imaging has advanced the field by enabling visualization of AD-related changes and providing measurable outcomes for clinical trials and disease-modifying therapies. Imaging of related pathologies can further improve diagnostic accuracy and provide important insights into disease heterogeneity. Moving forward, integrating multiple PET biomarkers into personalized diagnostic approaches will be crucial.