Clinical and Biomarker Changes in Dominantly Inherited Alzheimer’s Disease

By Randall J. Bateman, C. Xiong, T. Benzinger, Anne M. Fagan, A. Goate, Nick C Fox, Daniel S. Marcus, Nigel J. Cairns, Xianyun Xie, Tyler M. Blazey and 18 more. New England Journal of Medicine, 2012

3,500 citations recorded by the source corpus.

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.)

Subfields: Neurology, Physiology, Psychiatry and Mental health

View Paper: https://www.semanticscholar.org/paper/f9e95e5b9f5f5f7439a49c2f9832d72c680590a1

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Neurology

In Physiology

In Psychiatry and Mental health

Citations in the corpus

Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer’s Disease (2014, background): “The carrier study was conducted at 170 sites in the United States from December 2007 through April 2012, and the noncarrier study was conducted at 218 sites in the United States (195 sites), Canada (17), Germany (4), and Austria (2) from December 2007 through June 2012.”
NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease (2018, neutral): “Consequently, a widely held view is that amyloid biomarkers represent the earliest evidence of AD neuropathologic change currently detectable in living persons [9,11,72,103,104].”
Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup (2024, positive): “146,147 Therefore,theapproachtodetermining A + versus A − may need special consideration in ADAD and DSAD.”
2020 Alzheimer's disease facts and figures (2020, background): “8 million in 2020),A2 rather than the prevalence estimates derived by the model itself; (3) estimates of inflation and excess cost growth reflect the most recent relevant estimates from the cited sources (Centers for Medicare & Medicaid Services [CMS] actuaries and the Congressional Budget Office); ”
2013 Alzheimer's disease facts and figures (2013, neutral): “This decreased glucose metabolism is followed by impairment of a type of memory called episodic memory, and then a worsening of cognitive skills, called global cognitive impairment [20].”