An Algorithm for Preclinical Diagnosis of Alzheimer's Disease

Almost all Alzheimer's disease (AD) therapeutic trials have failed in recent years. One of the main reasons for failure is due to designing the disease-modifying clinical trials at the advanced stage of the disease when irreversible brain damage has already occurred. Diagnosis of the preclinical stage of AD and therapeutic intervention at this phase, with a perfect target, are key points to slowing the progression of the disease. Various AD biomarkers hold enormous promise for identifying individuals with preclinical AD and predicting the development of AD dementia in the future, but no single AD biomarker has the capability to distinguish the AD preclinical stage. A combination of complimentary AD biomarkers in cerebrospinal fluid (Aβ₄₂, tau, and phosphor-tau), non-invasive neuroimaging, and genetic evidence of AD can detect preclinical AD in the in-vivo ante mortem brain. Neuroimaging studies have examined region-specific cerebral blood flow (CBF) and microstructural changes in the preclinical AD brain. Functional MRI (fMRI), diffusion tensor imaging (DTI) MRI, arterial spin labeling (ASL) MRI, and advanced PET have potential application in preclinical AD diagnosis. A well-validated simple framework for diagnosis of preclinical AD is urgently needed. This article proposes a comprehensive preclinical AD diagnostic algorithm based on neuroimaging, CSF biomarkers, and genetic markers.