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Original Investigation |

Phenotypic Similarities Between Late-Onset Autosomal Dominant and Sporadic Alzheimer Disease A Single-Family Case-Control Study

Gregory S. Day, MD, MSc, FRCPC1,2; Erik S. Musiek, MD, PhD1,2; Catherine M. Roe, PhD1,2; Joanne Norton, MSN, RN, PMHCNS-BC1,3; Alison M. Goate, DPhil1,2,3; Carlos Cruchaga, PhD1,3; Nigel J. Cairns, PhD, FRCPath1,2,4; John C. Morris, MD1,2
[+] Author Affiliations
1The Charles F. and Joanne Knight Alzheimer Disease Research Center, St Louis, Missouri
2Department of Neurology, Washington University School of Medicine, St Louis, Missouri
3Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri
4Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri
JAMA Neurol. 2016;73(9):1125-1132. doi:10.1001/jamaneurol.2016.1236.
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Importance  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.

Objective  To use a family with late-onset ADAD caused by a presenilin 1 (PSEN1) gene mutation to mitigate the potential confound of age when comparing ADAD and LOAD.

Design, Setting, and Participants  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 PSEN1 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.

Main Outcomes and Measures  Planned comparison of clinical characteristics between cohorts, including age at symptom onset, associated symptoms and signs, rates of progression, and disease duration.

Results  Of the PSEN1 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]; P = .29), presenting symptoms (memory loss in 7 of 7 mutation carriers [100%] vs 958 of 1063 individuals with LOAD [90.1%]; P ≥ .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]; P = .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]; P = .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) (P = .03). Three of 12 noncarriers (25%) from the PSEN1 A79V family are potential phenocopies as they also developed AD dementia (median age at onset, 76.0 years).

Conclusions and Relevance  In this family, the amyloidogenic PSEN1 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.

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Figure.
Scatterplots of Disease Age at Onset, Duration, and Progression

Age at symptom onset (A), duration of symptomatic dementia (B), and rate of dementia progression (C) in sporadic late-onset Alzheimer disease (LOAD) and A79V family members with dementia. Data from participants with LOAD from the National Alzheimer Coordinating Center are shown as boxplots (n = 1115 in A and B; n = 837 in C). The distribution of dementia age at onset, disease duration (years), and rate of dementia progression (annualized change in Clinical Dementia Rating–Sum of Boxes [CDR-SB]) are shown through scatterplots for individual cases (n = 7 in A; n = 5 in B and C).

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