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Cited by 99Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchIntracerebral and Subarachnoid Hemorrhage Research

Neuropathology of Autosomal Dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database

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Ringman, John M., Monsell, Sarah, Ng, Denise W., Zhou, Yan, Nguyen, Andy, Coppola, Giovanni, Van Berlo, Victoria, Mendez, Mario F. +8 more·2016·Journal of Neuropathology & Experimental Neurology
DOI 10.1093/jnen/nlv028PMC PMC4934612
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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.

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  • Human PSEN1 mutation carriers have notable BBB breakdown and cerebrovascular dysfunction including cerebellar amyloid angiopathy and CAA, disrupted meningeal, subpial, and cortical arterioles, degeneration of pericytes and SMCs, cerebral perivascular amyloid deposits, and diminished FDG transport across the BBB in an early asymptomatic stage.

    “Human PSEN1 mutation carriers have notable BBB breakdown and cerebrovascular dysfunction including cerebellar amyloid angiopathy and CAA (143, 183, 274, 280, 354, 389, 440, 500, 544, 573, 639, 668); disrupted meningeal, subpial, and cortical arterioles (274, 389, 440); degeneration of pericytes and SMCs (573); cerebral perivascular amyloid deposits (25, 274, 289, 354, 573, 668); and diminished FDG”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [500]

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References 56 · Cited by 99

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  1. [1]Hardy J Selkoe DJ The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics Science 2002 297 353 356 12130773
  2. [3]Xia D Watanabe H Wu B Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer’s disease Neuron 2015 85 967 981 25741723 PMC4358812
  3. [4]Reitz C Tokuhiro S Clark LN SORCS1 alters amyloid precursor protein processing and variants may increase Alzheimer’s disease risk Ann Neurol 2011 69 47 64 21280075 PMC3086759
  4. [7]Bell RD Sagare AP Friedman AE Transport pathways for clearance of human Alzheimer’s amyloid β-peptide and apolipoproteins E and J in the mouse central nervous system J Cereb Blood Flow Metab 2007 27 909 918 17077814 PMC2853021
  5. [8]Tanzi RE Moir RD Wagner SL Clearance of Alzheimer’s Aβ peptide: The many roads to perdition Neuron 2004 43 605 608 15339642
  6. [11]Ringman JM Gylys KH Medina LD Biochemical, neuropathological, and neuroimaging characteristics of early-onset Alzheimer’s disease due to a novel PSEN1 mutation Neurosci Lett 2011 487 287 292 21094210 PMC3034479
  7. [12]Ishii K Lippa C Tomiyama T Distinguishable effects of presenilin-1 and APP717 mutations on amyloid plaque deposition Neurobiol Aging 2001 22 367 376 11378241
  8. [13]Gómez-Isla T Growdon WB McNamara MJ The impact of different presenilin 1 and presenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer’s disease brain: Evidence for other phenotype-modifying factors Brain 1999 122 1709 1719 10468510
  9. [16]Viswanathan A Greenberg SM Cerebral amyloid angiopathy in the elderly Ann Neurol 2011 70 871 880 22190361 PMC4004372
  10. [17]Rosand J Hylek EM O’Donnell HC Warfarin-associated hemorrhage and cerebral amyloid angiopathy: A genetic and pathologic study Neurology 2000 55 947 951 11061249
  11. [18]Weller RO Boche D Nicoll JA Microvasculature changes and cerebral amyloid angiopathy in Alzheimer’s disease and their potential impact on therapy Acta Neuropathol 2009 118 87 102 19234858
  12. [20]Mirra SS Heyman A McKeel D The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease Neurology 1991 41 479 486 2011243
  13. [21]Beekly DL Ramos EM Lee WW The National Alzheimer’s Coordinating Center (NACC) database: The Uniform Data Set Alzheimer Dis Assoc Disord 2007 21 249 258 17804958
  14. [22]McKhann G Drachman D Folstein M Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease Neurology 1984 34 939 944 6610841
  15. [23]Ringman JM Sachs MC Zhou Y Clinical predictors of severe cerebral amyloid angiopathy and influence of APOE genotype in persons with pathologically verified Alzheimer disease JAMA Neurol 2014 71 878 883 24797962 PMC4101018
  16. [25]Bird TD Lampe TH Nemens EJ Familial Alzheimer’s disease in American descendants of the Volga Germans: Probable genetic founder effect Ann Neurol 1988 23 25 31 3345066
  17. [26]Hutton M Busfield F Wragg M Complete analysis of the presenilin-1 gene in early onset Alzheimer’s disease Neuroreport 1996 7 801 805 8733749
  18. [27]Kowalska A Wender M Florczak J Molecular genetics of Alzheimer’s disease: Presenilin 1 gene analysis in a cohort of patients from the Poznan region J Appl Genet 2003 44 231 234 12817569
  19. [28]Guerreiro RJ Baquero M Blesa R Genetic screening of Alzheimer’s disease genes in Iberian and African samples yields novel mutations in presenilins and APP Neurobiol Aging 2010 31 725 731 18667258 PMC2850052
  20. [29]Yescas P Huertas-Vazquez A Villarreal-Molina MT Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing early-onset Alzheimer’s disease in Mexican families Neurogenetics 2006 7 195 200 16628450
  21. [30]Murrell J Ghetti B Cochran E The A431E mutation in PSEN1 causing familial Alzheimer’s disease originating in Jalisco State, Mexico: An additional fifteen families Neurogenetics 2006 7 277 279 16897084 PMC3378247
  22. [31]Athan ES Williamson J Ciappa A A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families JAMA 2001 286 2257 2263 11710891
  23. [33]Arnold SE Hyman BT Flory J The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer’s disease Cereb Cortex 1991 1 103 116 1822725
  24. [34]Uchihara T Pretangles and neurofibrillary changes: Similarities and differences between AD and CBD based on molecular and morphological evolution Neuropathology 2014 34 571 577 24612177
  25. [35]Lucke-Wold BP Turner RC Logsdon AF Linking traumatic brain injury to chronic traumatic encephalopathy: Identification of potential mechanisms leading to neurofibrillary tangle development J Neurotrauma 2014 31 1129 1138 24499307 PMC4089022
  26. [36]Delacourte A David JP Sergeant N The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer’s disease Neurology 1999 52 1158 1165 10214737
  27. [37]Portelius E Andreasson U Ringman JM Distinct cerebrospinal fluid amyloid β peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer’s disease Mol Neurodegener 2010 5 2 20145736 PMC2818651
  28. [38]Pera M Alcolea D Sanchez-Valle R Distinct patterns of APP processing in the CNS in autosomal-dominant and sporadic Alzheimer disease Acta Neuropathol 2013 125 201 213 23224319 PMC3623032
  29. [39]Miravalle L Calero M Takao M Amino-terminally truncated Abeta peptide species are the main component of cotton wool plaques Biochemistry 2005 44 10810 10821 16086583
  30. [40]Suarez-Calvet M Belbin O Pera M Autosomal-dominant Alzheimer’s disease mutations at the same codon of amyloid precursor protein differentially alter Aβ production J Neurochem 2014 128 330 339 24117942
  31. [41]Vinters HV Gilbert JJ Cerebral amyloid angiopathy: Incidence and complications in the aging brain. II. The distribution of amyloid vascular changes Stroke 1983 14 924 928 6658996
  32. [42]Rovelet-Lecrux A Hannequin D Raux G APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy Nat Genet 2006 38 24 26 16369530
  33. [43]Belza MG Urich H Cerebral amyloid angiopathy in Down’s syndrome Clin Neuropathol 1986 5 257 260 2949903
  34. [44]Nilsberth C Westlind-Danielsson A Eckman CB The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Aβ protofibril formation Nat Neurosci 2001 4 887 893 11528419
  35. [45]Hawkes CA Jayakody N Johnston DA Failure of perivascular drainage of β-amyloid in cerebral amyloid angiopathy Brain Pathol 2014 24 396 403 24946077 PMC8029317
  36. [46]Zheng L Vinters HV Mack WJ Cerebral atherosclerosis is associated with cystic infarcts and microinfarcts but not Alzheimer pathologic changes Stroke 2013 44 2835 2841 23887837 PMC4049465
  37. [47]Leverenz JB Fishel MA Peskind ER Lewy body pathology in familial Alzheimer disease: Evidence for disease- and mutation-specific pathologic phenotype Arch Neurol 2006 63 370 376 16533963 PMC1892620
  38. [49]Clinton LK Blurton-Jones M Myczek K Synergistic Interactions between Abeta, tau, and alpha-synuclein: Acceleration of neuropathology and cognitive decline J Neurosci 2010 30 7281 7289 20505094 PMC3308018
  39. [50]Bachhuber T Katzmarski N McCarter JF Inhibition of amyloid-β plaque formation by α-synuclein Nat Med 2015 21 802 807 26099047
  40. [51]Sepulveda-Falla D Matschke J Bernreuther C Deposition of hyperphosphorylated tau in cerebellum of PS1 E280A Alzheimer’s disease Brain Pathol 2011 21 452 463 21159009 PMC8094246
  41. [52]Smith EE Schneider JA Wardlaw JM Cerebral microinfarcts: The invisible lesions Lancet Neurol 2012 11 272 282 22341035 PMC3359329

Authors
Ringman, J. M., Monsell, S., Ng, D. W., Zhou, Y., Nguyen, A., Coppola, G., Van Berlo, V., Mendez, M. F., Tung, S., Weintraub, S., Mesulam, M.-M., Bigio, E. H., Gitelman, D. R., Fisher-Hubbard, A. O., Albin, R. L., & Vinters, H. V.
Affiliations
University of Southern California (US)
ORCID
Venue
Journal of Neuropathology & Experimental Neurology
Publisher
Oxford University Press (OUP)
Published
2016-02-17
Volume
75
Issue
3
Pages
284-290
ISSN
  • 0022-3069 (ISSN-L)
  • 1554-6578
DOI
10.1093/jnen/nlv028
PMC
PMC4934612
OpenAlex
W2324271630
Cited by
99
References
56
Citations by year
2026: 5 · 2025: 13 · 2024: 9 · 2023: 7 · 2022: 9 · 2021: 15 · 2020: 16 · 2019: 10 · 2018: 7 · 2017: 5 · 2016: 3
FWCI
6.71
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Neuropathology & Experimental Neurology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • Eli Lilly and Company
  • Biogen
  • National Institutes of Health (1ul1rr033176-01, UL1TR001422)
  • National Institute on Aging (P30AG010129, P30AG010133, P30AG028383, P30AG012300, P50AG005133, U01AG016976, P50AG005131, P50AG005138, P50AG016570, P50-AG 16570, P30AG010124, P50AG016573, P30AG008017, P30AG010161, P30AG008051, P50AG008702, P50AG033514, P30AG035982, P50AG005681, P50AG005142, P30AG019610, P50AG005146, P30AG013846, P50AG005136, P50AG005134, U19AG032438, P30AG013854, P50AG025688, U01AG051218, P50AG023501, P50AG016574)
  • National Center for Research Resources (UL1-RR-033176, M01RR000865, 1UL1RR033176)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
Keywords
autosomal dominant Alzheimer's disease, PSEN1 mutations, APP mutations, PSEN2 mutations, cerebral amyloid angiopathy, neuritic plaques, neurofibrillary tangles, Lewy bodies, genetic heterogeneity
MeSH terms
Neuropathology, Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Female, Humans, Male, Middle Aged, Mutation, United States, Databases, Factual, Amyloid beta-Protein Precursor, Presenilin-1, Presenilin-2, National Institute on Aging (U.S.)

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