Phenotypic Similarities Between Late-Onset Autosomal Dominant and Sporadic Alzheimer Disease
Authors: Gregory S. Day, Erik S. Musiek, Catherine M. Roe, Joanne Norton, Alison M. Goate, Carlos Cruchaga, Nigel J. Cairns, John C. Morris
Journal: JAMA Neurology (2016)

<h3>Importance</h3> The amyloid hypothesis posits that disrupted β-amyloid homeostasis initiates the pathological process resulting in Alzheimer disease (AD). Autosomal dominant AD (ADAD) has an early symptomatic onset and is caused by single-gene mutations that result in overproduction of β-amyloid 42. To the extent that sporadic late-onset AD (LOAD) also results from dysregulated β-amyloid 42, the clinical phenotypes of ADAD and LOAD should be similar when controlling for the effects of age. <h3>Objective</h3> To use a family with late-onset ADAD caused by a presenilin 1 (<i>PSEN1</i>) gene mutation to mitigate the potential confound of age when comparing ADAD and LOAD. <h3>Design, Setting, and Participants</h3> This case-control study was conducted at the Knight Alzheimer Disease Research Center at Washington University, St Louis, Missouri, and other National Institutes of Aging–funded AD centers in the United States. Ten<i>PSEN1 </i>A79V mutation carriers from multiple generations of a family with late-onset ADAD and 12 noncarrier family members were followed up at the Knight Alzheimer Disease Research Center (1985-2015) and 1115 individuals with neuropathologically confirmed LOAD were included from the National Alzheimer Coordinating Center database (September 2005-December 2014). Data analysis was completed in January 2016, including Knight Alzheimer Disease Research Center patient data collected up until the end of 2015. <h3>Main Outcomes and Measures</h3> Planned comparison of clinical characteristics between cohorts, including age at symptom onset, associated symptoms and signs, rates of progression, and disease duration. <h3>Results</h3> Of the<i>PSEN1 </i>A79V carriers in the family with late-onset ADAD, 4 were female (57%); among those with LOAD, 529 were female (47%). Seven mutation carriers (70%) developed AD dementia, while 3 were yet asymptomatic in their seventh and eighth decades of life. No differences were observed between mutation carriers and individuals with LOAD concerning age at symptom onset (mutation carriers: mean, 75 years [range, 63-77 years] vs those with LOAD: mean, 74 years [range, 60-101 years];<i>P</i> = .29), presenting symptoms (memory loss in 7 of 7 mutation carriers [100%] vs 958 of 1063 individuals with LOAD [90.1%];<i>P</i> ≥ .99) and duration (mutation carriers: mean, 9.9 years [range, 2.3-12.8 years] vs those with LOAD: 9 years [range, 1-27 years];<i>P</i> = .73), and rate of progression of dementia (median annualized change in Clinical Dementia Rating–Sum of Boxes score, mutation carriers: 1.2 [range, 0.1-3.3] vs those with LOAD: 1.9 [range, −3.5 to 11.9];<i>P</i> = .73). Early emergence of comorbid hallucinations and delusions were observed in 57% of individuals with ADAD (4 of 7) vs 19% of individuals with LOAD (137 of 706) (<i>P</i> = .03). Three of 12 noncarriers (25%) from the<i>PSEN1 </i>A79V family are potential phenocopies as they also developed AD dementia (median age at onset, 76.0 years). <h3>Conclusions and Relevance</h3> In this family, the amyloidogenic<i>PSEN1 </i>A79V mutation recapitulates the clinical attributes of LOAD. Previously reported clinical phenotypic differences between individuals with ADAD and LOAD may reflect age- or mutation-dependent effects.