title: Neuropathology of Autosomal Dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database.
abstract: Alzheimer disease (AD) represents a genetically heterogeneous entity. To elucidate neuropathologic features of autosomal dominant AD ([ADAD] due to PSEN1, APP, or PSEN2 mutations), we compared hallmark AD pathologic findings in 60 cases of ADAD and 120 cases of sporadic AD matched for sex, race, ethnicity, and disease duration. Greater degrees of neuritic plaque and neurofibrillary tangle formation and cerebral amyloid angiopathy (CAA) were found in ADAD (p values < 0.01). Moderate to severe CAA was more prevalent in ADAD (63.3% vs. 39.2%, p = 0.003), and persons with PSEN1 mutations beyond codon 200 had higher average Braak scores and severity and prevalence of CAA than those with mutations before codon 200. Lewy body pathology was less extensive in ADAD but was present in 27.1% of cases. We also describe a novel pathogenic PSEN1 mutation (P267A). The finding of more severe neurofibrillary pathology and CAA in ADAD, particularly in carriers of PSEN1 mutations beyond codon 200, warrants consideration when designing trials to treat or prevent ADAD. The finding of Lewy body pathology in a substantial minority of ADAD cases supports the assertion that development of Lewy bodies may be in part driven by abnormal β-amyloid protein precursor processing.
authors.affiliation: From the Mary S. Easton Center for Alzheimer's Disease Research, University of California, Los Angeles, Department of Neurology, Los Angeles, California (JMR, DWN, YZ, AN, GC, MFM, ST, HVV); Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, California (JMR); Department of Biostatistics, University of Washington, Seattle, Washington (SM); Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California (DWN, ST, HVV); Semel Institute for Neuroscience and Human Behavior, Los Angeles, California (GC,VVB); Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (SW, M-MM, EHB, DRG); Advocate Lutheran General Hospital, Park Ridge, Illinois (DRG); Department of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (DRG); Department of Pathology, University of Michigan, Ann Arbor, Michigan (AOF-H); VA Ann Arbor Healthcare System, Geriatrics Research, Education, and Clinical Center, Ann Arbor, Michigan (RLA); and Department of Neurology, University of Michigan, Ann Arbor, Michigan (RLA). john.ringman@med.usc.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Ringman
authors.affiliation: From the Mary S. Easton Center for Alzheimer's Disease Research, University of California, Los Angeles, Department of Neurology, Los Angeles, California (JMR, DWN, YZ, AN, GC, MFM, ST, HVV); Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, California (JMR); Department of Biostatistics, University of Washington, Seattle, Washington (SM); Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California (DWN, ST, HVV); Semel Institute for Neuroscience and Human Behavior, Los Angeles, California (GC,VVB); Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (SW, M-MM, EHB, DRG); Advocate Lutheran General Hospital, Park Ridge, Illinois (DRG); Department of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (DRG); Department of Pathology, University of Michigan, Ann Arbor, Michigan (AOF-H); VA Ann Arbor Healthcare System, Geriatrics Research, Education, and Clinical Center, Ann Arbor, Michigan (RLA); and Department of Neurology, University of Michigan, Ann Arbor, Michigan (RLA).
authors.forename: Sarah
authors.initials: S
authors.lastname: Monsell
authors.affiliation: From the Mary S. Easton Center for Alzheimer's Disease Research, University of California, Los Angeles, Department of Neurology, Los Angeles, California (JMR, DWN, YZ, AN, GC, MFM, ST, HVV); Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, California (JMR); Department of Biostatistics, University of Washington, Seattle, Washington (SM); Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California (DWN, ST, HVV); Semel Institute for Neuroscience and Human Behavior, Los Angeles, California (GC,VVB); Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (SW, M-MM, EHB, DRG); Advocate Lutheran General Hospital, Park Ridge, Illinois (DRG); Department of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (DRG); Department of Pathology, University of Michigan, Ann Arbor, Michigan (AOF-H); VA Ann Arbor Healthcare System, Geriatrics Research, Education, and Clinical Center, Ann Arbor, Michigan (RLA); and Department of Neurology, University of Michigan, Ann Arbor, Michigan (RLA).
authors.forename: Denise W
authors.initials: DW
authors.lastname: Ng
authors.affiliation: From the Mary S. Easton Center for Alzheimer's Disease Research, University of California, Los Angeles, Department of Neurology, Los Angeles, California (JMR, DWN, YZ, AN, GC, MFM, ST, HVV); Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, California (JMR); Department of Biostatistics, University of Washington, Seattle, Washington (SM); Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California (DWN, ST, HVV); Semel Institute for Neuroscience and Human Behavior, Los Angeles, California (GC,VVB); Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (SW, M-MM, EHB, DRG); Advocate Lutheran General Hospital, Park Ridge, Illinois (DRG); Department of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (DRG); Department of Pathology, University of Michigan, Ann Arbor, Michigan (AOF-H); VA Ann Arbor Healthcare System, Geriatrics Research, Education, and Clinical Center, Ann Arbor, Michigan (RLA); and Department of Neurology, University of Michigan, Ann Arbor, Michigan (RLA).
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: From the Mary S. Easton Center for Alzheimer's Disease Research, University of California, Los Angeles, Department of Neurology, Los Angeles, California (JMR, DWN, YZ, AN, GC, MFM, ST, HVV); Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, California (JMR); Department of Biostatistics, University of Washington, Seattle, Washington (SM); Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California (DWN, ST, HVV); Semel Institute for Neuroscience and Human Behavior, Los Angeles, California (GC,VVB); Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (SW, M-MM, EHB, DRG); Advocate Lutheran General Hospital, Park Ridge, Illinois (DRG); Department of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (DRG); Department of Pathology, University of Michigan, Ann Arbor, Michigan (AOF-H); VA Ann Arbor Healthcare System, Geriatrics Research, Education, and Clinical Center, Ann Arbor, Michigan (RLA); and Department of Neurology, University of Michigan, Ann Arbor, Michigan (RLA).
authors.forename: Andy
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: From the Mary S. Easton Center for Alzheimer's Disease Research, University of California, Los Angeles, Department of Neurology, Los Angeles, California (JMR, DWN, YZ, AN, GC, MFM, ST, HVV); Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, California (JMR); Department of Biostatistics, University of Washington, Seattle, Washington (SM); Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California (DWN, ST, HVV); Semel Institute for Neuroscience and Human Behavior, Los Angeles, California (GC,VVB); Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (SW, M-MM, EHB, DRG); Advocate Lutheran General Hospital, Park Ridge, Illinois (DRG); Department of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (DRG); Department of Pathology, University of Michigan, Ann Arbor, Michigan (AOF-H); VA Ann Arbor Healthcare System, Geriatrics Research, Education, and Clinical Center, Ann Arbor, Michigan (RLA); and Department of Neurology, University of Michigan, Ann Arbor, Michigan (RLA).
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.affiliation: From the Mary S. Easton Center for Alzheimer's Disease Research, University of California, Los Angeles, Department of Neurology, Los Angeles, California (JMR, DWN, YZ, AN, GC, MFM, ST, HVV); Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, California (JMR); Department of Biostatistics, University of Washington, Seattle, Washington (SM); Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California (DWN, ST, HVV); Semel Institute for Neuroscience and Human Behavior, Los Angeles, California (GC,VVB); Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (SW, M-MM, EHB, DRG); Advocate Lutheran General Hospital, Park Ridge, Illinois (DRG); Department of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (DRG); Department of Pathology, University of Michigan, Ann Arbor, Michigan (AOF-H); VA Ann Arbor Healthcare System, Geriatrics Research, Education, and Clinical Center, Ann Arbor, Michigan (RLA); and Department of Neurology, University of Michigan, Ann Arbor, Michigan (RLA).
authors.forename: Victoria
authors.initials: V
authors.lastname: Van Berlo
authors.affiliation: From the Mary S. Easton Center for Alzheimer's Disease Research, University of California, Los Angeles, Department of Neurology, Los Angeles, California (JMR, DWN, YZ, AN, GC, MFM, ST, HVV); Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, California (JMR); Department of Biostatistics, University of Washington, Seattle, Washington (SM); Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California (DWN, ST, HVV); Semel Institute for Neuroscience and Human Behavior, Los Angeles, California (GC,VVB); Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (SW, M-MM, EHB, DRG); Advocate Lutheran General Hospital, Park Ridge, Illinois (DRG); Department of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (DRG); Department of Pathology, University of Michigan, Ann Arbor, Michigan (AOF-H); VA Ann Arbor Healthcare System, Geriatrics Research, Education, and Clinical Center, Ann Arbor, Michigan (RLA); and Department of Neurology, University of Michigan, Ann Arbor, Michigan (RLA).
authors.forename: Mario F
authors.initials: MF
authors.lastname: Mendez
authors.affiliation: From the Mary S. Easton Center for Alzheimer's Disease Research, University of California, Los Angeles, Department of Neurology, Los Angeles, California (JMR, DWN, YZ, AN, GC, MFM, ST, HVV); Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, California (JMR); Department of Biostatistics, University of Washington, Seattle, Washington (SM); Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California (DWN, ST, HVV); Semel Institute for Neuroscience and Human Behavior, Los Angeles, California (GC,VVB); Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (SW, M-MM, EHB, DRG); Advocate Lutheran General Hospital, Park Ridge, Illinois (DRG); Department of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (DRG); Department of Pathology, University of Michigan, Ann Arbor, Michigan (AOF-H); VA Ann Arbor Healthcare System, Geriatrics Research, Education, and Clinical Center, Ann Arbor, Michigan (RLA); and Department of Neurology, University of Michigan, Ann Arbor, Michigan (RLA).
authors.forename: Spencer
authors.initials: S
authors.lastname: Tung
authors.affiliation: From the Mary S. Easton Center for Alzheimer's Disease Research, University of California, Los Angeles, Department of Neurology, Los Angeles, California (JMR, DWN, YZ, AN, GC, MFM, ST, HVV); Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, California (JMR); Department of Biostatistics, University of Washington, Seattle, Washington (SM); Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California (DWN, ST, HVV); Semel Institute for Neuroscience and Human Behavior, Los Angeles, California (GC,VVB); Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (SW, M-MM, EHB, DRG); Advocate Lutheran General Hospital, Park Ridge, Illinois (DRG); Department of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (DRG); Department of Pathology, University of Michigan, Ann Arbor, Michigan (AOF-H); VA Ann Arbor Healthcare System, Geriatrics Research, Education, and Clinical Center, Ann Arbor, Michigan (RLA); and Department of Neurology, University of Michigan, Ann Arbor, Michigan (RLA).
authors.forename: Sandra
authors.initials: S
authors.lastname: Weintraub
authors.affiliation: From the Mary S. Easton Center for Alzheimer's Disease Research, University of California, Los Angeles, Department of Neurology, Los Angeles, California (JMR, DWN, YZ, AN, GC, MFM, ST, HVV); Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, California (JMR); Department of Biostatistics, University of Washington, Seattle, Washington (SM); Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California (DWN, ST, HVV); Semel Institute for Neuroscience and Human Behavior, Los Angeles, California (GC,VVB); Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (SW, M-MM, EHB, DRG); Advocate Lutheran General Hospital, Park Ridge, Illinois (DRG); Department of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (DRG); Department of Pathology, University of Michigan, Ann Arbor, Michigan (AOF-H); VA Ann Arbor Healthcare System, Geriatrics Research, Education, and Clinical Center, Ann Arbor, Michigan (RLA); and Department of Neurology, University of Michigan, Ann Arbor, Michigan (RLA).
authors.forename: Marek-Marsel
authors.initials: MM
authors.lastname: Mesulam
authors.affiliation: From the Mary S. Easton Center for Alzheimer's Disease Research, University of California, Los Angeles, Department of Neurology, Los Angeles, California (JMR, DWN, YZ, AN, GC, MFM, ST, HVV); Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, California (JMR); Department of Biostatistics, University of Washington, Seattle, Washington (SM); Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California (DWN, ST, HVV); Semel Institute for Neuroscience and Human Behavior, Los Angeles, California (GC,VVB); Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (SW, M-MM, EHB, DRG); Advocate Lutheran General Hospital, Park Ridge, Illinois (DRG); Department of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (DRG); Department of Pathology, University of Michigan, Ann Arbor, Michigan (AOF-H); VA Ann Arbor Healthcare System, Geriatrics Research, Education, and Clinical Center, Ann Arbor, Michigan (RLA); and Department of Neurology, University of Michigan, Ann Arbor, Michigan (RLA).
authors.forename: Eileen H
authors.initials: EH
authors.lastname: Bigio
authors.affiliation: From the Mary S. Easton Center for Alzheimer's Disease Research, University of California, Los Angeles, Department of Neurology, Los Angeles, California (JMR, DWN, YZ, AN, GC, MFM, ST, HVV); Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, California (JMR); Department of Biostatistics, University of Washington, Seattle, Washington (SM); Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California (DWN, ST, HVV); Semel Institute for Neuroscience and Human Behavior, Los Angeles, California (GC,VVB); Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (SW, M-MM, EHB, DRG); Advocate Lutheran General Hospital, Park Ridge, Illinois (DRG); Department of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (DRG); Department of Pathology, University of Michigan, Ann Arbor, Michigan (AOF-H); VA Ann Arbor Healthcare System, Geriatrics Research, Education, and Clinical Center, Ann Arbor, Michigan (RLA); and Department of Neurology, University of Michigan, Ann Arbor, Michigan (RLA).
authors.forename: Darren R
authors.initials: DR
authors.lastname: Gitelman
authors.affiliation: From the Mary S. Easton Center for Alzheimer's Disease Research, University of California, Los Angeles, Department of Neurology, Los Angeles, California (JMR, DWN, YZ, AN, GC, MFM, ST, HVV); Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, California (JMR); Department of Biostatistics, University of Washington, Seattle, Washington (SM); Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California (DWN, ST, HVV); Semel Institute for Neuroscience and Human Behavior, Los Angeles, California (GC,VVB); Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (SW, M-MM, EHB, DRG); Advocate Lutheran General Hospital, Park Ridge, Illinois (DRG); Department of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (DRG); Department of Pathology, University of Michigan, Ann Arbor, Michigan (AOF-H); VA Ann Arbor Healthcare System, Geriatrics Research, Education, and Clinical Center, Ann Arbor, Michigan (RLA); and Department of Neurology, University of Michigan, Ann Arbor, Michigan (RLA).
authors.forename: Amanda O
authors.initials: AO
authors.lastname: Fisher-Hubbard
authors.affiliation: From the Mary S. Easton Center for Alzheimer's Disease Research, University of California, Los Angeles, Department of Neurology, Los Angeles, California (JMR, DWN, YZ, AN, GC, MFM, ST, HVV); Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, California (JMR); Department of Biostatistics, University of Washington, Seattle, Washington (SM); Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California (DWN, ST, HVV); Semel Institute for Neuroscience and Human Behavior, Los Angeles, California (GC,VVB); Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (SW, M-MM, EHB, DRG); Advocate Lutheran General Hospital, Park Ridge, Illinois (DRG); Department of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (DRG); Department of Pathology, University of Michigan, Ann Arbor, Michigan (AOF-H); VA Ann Arbor Healthcare System, Geriatrics Research, Education, and Clinical Center, Ann Arbor, Michigan (RLA); and Department of Neurology, University of Michigan, Ann Arbor, Michigan (RLA).
authors.forename: Roger L
authors.initials: RL
authors.lastname: Albin
authors.affiliation: From the Mary S. Easton Center for Alzheimer's Disease Research, University of California, Los Angeles, Department of Neurology, Los Angeles, California (JMR, DWN, YZ, AN, GC, MFM, ST, HVV); Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, California (JMR); Department of Biostatistics, University of Washington, Seattle, Washington (SM); Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California (DWN, ST, HVV); Semel Institute for Neuroscience and Human Behavior, Los Angeles, California (GC,VVB); Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (SW, M-MM, EHB, DRG); Advocate Lutheran General Hospital, Park Ridge, Illinois (DRG); Department of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (DRG); Department of Pathology, University of Michigan, Ann Arbor, Michigan (AOF-H); VA Ann Arbor Healthcare System, Geriatrics Research, Education, and Clinical Center, Ann Arbor, Michigan (RLA); and Department of Neurology, University of Michigan, Ann Arbor, Michigan (RLA).
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D016208:Databases, Factual / Q000706:statistics & numerical data; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D054561:National Institute on Aging (U.S.) / Q000706:statistics & numerical data; D000069338:Neuropathology; D053764:Presenilin-1 / Q000235:genetics*; D053766:Presenilin-2 / Q000235:genetics; D014481:United States / Q000453:epidemiology
chemical_list: D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2
keywords: Alzheimer disease; Amyloid plaques; Autosomal dominant; Cerebral amyloid angiopathy; Neurofibrillary tangles; Neuropathology; P267A.