Biomarker Changes in Alzheimer Disease
Alzheimer disease (AD) is the most common cause of dementia and currently affects about 5 million Americans. By 2050, this number is expected to increase to 13 million.
Because AD, which typically presents as progressive loss of memory and cognitive function, has been hypothesized to begin decades before the first symptoms manifest, longitudinal studies of AD biomarkers take many years to show the full pathologic cascade of events that lead to dementia. Because of this, among other reasons, well-validated biomarkers of AD processes are needed to improve the design of clinical trials, develop more effective therapeutics, and offer the opportunity for prevention trials. Mutations in 1 of 3 genes (APP, PSEN1, and PSEN2) have been identified as causing alterations in amyloid-beta (Aβ) processing and leading to AD with complete penetrance.
In the Dominantly Inherited Alzheimer Network (DIAN) study, a prospective longitudinal study [N Engl J Med. doi:10.1056/NEJMoa1202753], investigators from Washington University analyzed families with autosomal dominant AD. A total of 128 participants at risk for carrying a mutation for autosomal dominant AD were enrolled in the study at 1 of 10 sites. Each participant was a member of a pedigree with a known mutation for autosomal dominant AD. All participants were assessed at baseline and in subsequent years with comprehensive clinical, cognitive, imaging, and biochemical assessments.
Data from all 128 participants, who were enrolled and completed baseline assessments between January 26, 2009, and the first data-cutoff point (April 28, 2011), were included in the study. Participants underwent clinical assessments of cognitive change with the use of the Clinical Dementia Rating (CDR) scale, with CDR 0 indicating normal cognitive function, CDR 0.5 indicating very mild impairment, and CDR 1 indicating mild impairment. The DIAN assessments ascertained family history of AD and medical history, and participants underwent a physical examination, including neurologic evaluation.
Patients’ test scores on the Mini-Mental State Examination (MMSE), a measure of general cognitive function, and Story A from the Logical Memory subtest of the Wechsler Memory Scale-Revised, a measure of episodic memory, were recorded. Subjects also underwent volumetric magnetic resonance imaging (MRI), and biochemical analyses of cerebrospinal fluid (CSF) and blood were performed. Clinical impairment was measured using the Clinical Dementia Rating-Sum of Boxes (CDR-SOB), with scores ranging from 0 (cognitive normality) to 18 (maximal cognitive impairment).
As expected with an autosomal dominant inheritance pattern, approximately 50% of the asymptomatic participants were mutation carriers. There were no significant differences in the presence of an APOE ε4 allele or sex between asymptomatic mutation carriers and noncarriers. The mean (±SD) age of parental onset of symptoms was 45.7±6.8 years. The DIAN parental age of symptom onset was correlated with the age of symptom onset for symptomatic offspring (Pearson correlation coefficient, 0.56; P<.001). Significant differences in CDR-SOB scores were detected between mutation carriers and noncarriers 5 years before expected symptom onset.
Noncarriers had stable CDR-SOB scores of 0 throughout the relative age range, whereas carriers had increasing CDR-SOB scores at higher values of estimated years from expected symptom onset. In this cohort, participants had a CDR rating of mild dementia (CDR 1) at a mean of 3.3±5.3 years after the parent’s age of symptom onset.
Significant differences in MMSE scores between mutation carriers and noncarriers were detected at assessments performed 5 years before expected symptom onset; carriers had decreasing MMSE scores at higher values of estimated years from expected symptom onset. Compared to noncarriers, there was significant cognitive impairment in mutation carriers. Increased atrophy of bilateral hippocampi was detected in mutation carriers 15 years before expected symptom onset.
A significant decrease in cerebral metabolism in the precuneus was detected in mutation carriers 10 years before expected symptom onset. In mutation carriers, levels of tau in the CSF were increased 15 years before expected symptom onset. The decrease by half in Aβ42 in the CSF and the increase in tau in the CSF were similar in magnitude to those typically observed in late-onset sporadic AD.
