BACKGROUND The order and magnitude of pathologic processes in Alzheimer’s disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer’s disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant’s age at baseline assessment and the parent’s age at the onset of symptoms of Alzheimer’s disease to calculate the estimated years from expected symptom onset (age of the participant minus parent’s age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS Concentrations of amyloid-beta (Aβ)42 in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini–Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS We found that autosomal dominant Alzheimer’s disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer’s disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer’s disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.)

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Alzheimer’s disease is associated with reduced β-amyloid clearance from the brain

Diagnosing Alzheimer's disease is challenging, partly due to the closely related pathological features shared with other neurodegenerative diseases. Presently, a definite diagnosis of Alzheimer's disease can only be established by post mortem pathological examination focusing on two main pathological hallmarks: (i) amyloid plaques consisting of aggregated amyloid beta (Aβ) peptides, and (ii) neurofibrillary tangles made of abnormally phosphorylated tau protein.In living individuals, Alzheimer's disease diagnosis relies on two main approaches: (i) imaging of the accumulation of tau tangles and Aβ plaques in the brain using positron emission tomography (PET), and (ii) measuring brain-specific biochemical changes in CSF reflecting tau and Aβ pathophysiology. However, tau PET is expensive and only available in specialised medical centres. In 1995, our group developed two immunoassays for quantifying tau in CSF, one for measuring pathological tau phosphorylated at threonine-181 (p-tau181) and the other for the neuronal injury marker "total tau." These assays, targeting mid-region tau species, were subsequently developed into commercial kit assays, and have recently been approved by the United States Food and Drugs Administration to support diagnosis and candidate drug testing.The assays have been used in hundreds of published independent clinical studies. In reviewing