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In Autosomal Dominant Inheritance Jsp Fid
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August 30, 2012 N Engl J Med 2012; 367:795-804
DOI: 10.1056/NEJMoa1202753
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.
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.
Concentrations of amyloid-beta (AΞ²) 42 in the CSF appeared to decline 25 years before expected symptom onset. AΞ² 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 MiniβMental 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.
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 . opens in new tab .)
Alzheimer's disease is the most common cause of dementia and is currently estimated to affect more than 5 million people in the United States, with an expected increase to 13 million by the year 2050. The typical clinical presentation is progressive loss of memory and cognitive function, ultimately leading to a loss of independence and causing a heavy personal toll on the patient and the family. The costs of care of patients with Alzheimer's disease in 2010 were estimated at more than $172 billion in the United States, an annual cost that is predicted to increase to a trillion dollars by 2050 unless disease-modifying treatments are developed. 1
Alzheimer's disease has been hypothesized to begin decades before the first symptoms manifest. 2-4 Thus, longitudinal studies of Alzheimer's disease biomarkers take many years to show the full pathologic cascade of events that lead to dementia. Furthermore, trials of disease-modifying treatment require large numbers of patients over extended periods owing to the slow progression of cognitive symptoms. 5,6 Therefore, well-validated biomarkers of Alzheimer's disease processes are needed to improve the design of clinical trials, develop more effective therapeutics, and offer the opportunity for prevention trials. 7
On the basis of the amyloid hypothesis, 8 amyloid-beta (AΞ²) is currently the most common disease-modifying target. Recent research indicates that the targeting of amyloidosis in familial amyloid polyneuropathy improves clinical outcomes. 9-11 However, the order and timing of amyloidosis and other Alzheimer's disease processes that lead to clinical dementia are not well understood. We hypothesized that autosomal dominant Alzheimer's disease and the more common late-onset Alzheimer's disease 12 have similar pathophysiological features. Although autosomal dominant Alzheimer's disease accounts for a relatively small proportion (approximately 1%) of cases of Alzheimer's disease, increasing evidence 13 suggests that it overlaps with sporadic Alzheimer's disease. Mutations in one of three genes ( APP, PSEN1, and PSEN2 ) have been identified that cause alterations in AΞ² processing and lead to Alzheimer's disease with complete penetrance. The age at clinical onset of autosomal dominant Alzheimer's disease is similar between generations 14 and is affected mostly by the mutation type and background family genetics. 15 We compared a wide range of pathophysiological markers between mutation carriers and noncarriers as a function of the parental age at onset in order to evaluate the cascade of events that lead to dementia. Clinical, cognitive, imaging, and biochemical measures were compared between mutation carriers and noncarriers in the first large international cohort of families with autosomal dominant Alzheimer's disease.
Participants at risk for carrying a mutation for autosomal dominant Alzheimer's disease were enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study at 1 of 10 sites. Each participant was a member of a pedigree with a known mutation for autosomal dominant Alzheimer's disease. DIAN participants are assessed at baseline and in subsequent years with comprehensive clinical, cognitive, imaging, and biochemical assessments. Data from all 128 participants who were enrolled and who had completed baseline assessments between January 26, 2009, and the first data-cutoff point (April 28, 2011) went through quality-control checks and were included in the analysis (see the Methods section in the Supplementary Appendix , available with the full text of this article at NEJM.org). All participants provided written informed consent or assent with proxy consent. All study procedures were approved by the Washington University Human Research Protection Office and the local institutional review boards of the participating sites. All authors vouch for the accuracy of the data and the fidelity of the study to the protocol (available at NEJM.org).
Participants underwent clinical assessments of cognitive change with the use of the Clinical Dementia Rating (CDR) 16 scale, with CDR 0 indicating normal cognitive function, CDR 0.5 very mild impairment, and CDR 1 mild impairment. The DIAN assessments ascertained family history of Alzheimer's disease and medical history, and participants underwent a physical examination, including a neurologic evaluation (see the study protocol). Clinicians who performed the asses
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