Genetic Heterogeneity in Alzheimer Disease and Implications for Treatment Strategies

Current Neurology and Neuroscience Reports

Volumn 14, Issue 11, 2014, Pages

  Ringman, John M ^a   Goate, Alison ^b   Masters, Colin L ^c   Cairns, Nigel J ^b   Danek, Adrian ^d   Graff Radford, Neill ^e   Ghetti, Bernardino ^f   Morris, John C ^b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c UNIVERSITY OF MELBOURNE   (Australia)

^d UNIVERSITY OF MUNICH   (Germany)

^e MAYO CLINIC   (United States)

^f INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Alzheimer s disease; Amyloid precursor protein; Apolipoprotein E; Genetic; Heterogeneity; Presenilin

Indexed keywords

AMYLOID PRECURSOR PROTEIN; APOLIPOPROTEIN E4; BAPINEUZUMAB; BEXAROTENE; GAMMA SECRETASE INHIBITOR; PRESENILIN 1; PRESENILIN 2; MEMBRANE PROTEIN; PSEN1 PROTEIN, HUMAN; PSEN2 PROTEIN, HUMAN;

ALZHEIMER DISEASE; APOE GENE; APP GENE; AUTOSOMAL DOMINANT INHERITANCE; COLOMBIAN; DOWN SYNDROME; DRUG EFFICACY; FAMILY; GENE MUTATION; GENETIC HETEROGENEITY; HOMOZYGOTE; HUMAN; PHENOTYPE; PSEN1 GENE; PSEN2 GENE; REVIEW; ANIMAL; GENETICS; PATHOPHYSIOLOGY;

ALZHEIMER DISEASE; AMYLOID BETA-PROTEIN PRECURSOR; ANIMALS; GENETIC HETEROGENEITY; HUMANS; MEMBRANE PROTEINS; PRESENILIN-1; PRESENILIN-2;

EID: 84919665907     PISSN: 15284042     EISSN: 15346293     Source Type: Journal    
DOI: 10.1007/s11910-014-0499-8     Document Type: Review

References (93)

1. Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR. An English translation of Alzheimer's 1907 paper, "Uber eine eigenartige Erkankung der Hirnrinde". Clin Anat. 1995;8:429–31.
2. Katzman R. Alzheimer's disease. N Engl J Med. 1986;314:964–73.
3. Gatz M, Reynolds CA, Fratiglioni L, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006;63:168–74.
4. Lowenberg K, Waggoner RW. Familial organic psychosis (Alzheimer's type). Arch Neurol Psychiatry. 1934;31:737–54.
5. St George-Hyslop PH, Haines JL, Farrer LA, et al. Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous disorder. Nature. 1990;347:194–7.
6. Ringman JM, Coppola G. New genes and new insights from old genes: update on Alzheimer disease. Continuum (Minneap Minn). 2013;19:358–71.
7. Cruchaga C, Karch CM, Jin SC, et al. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature. 2014;505:550–4.
8. Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. JAMA. 1997;278:1349–56.
9. Ringman JM. What the study of persons at risk for familial Alzheimer's disease can tell us about the earliest stages of the disorder: a review. J Geriatr Psychiatry Neurol. 2005;18:228–33.
10. Morris JC, Aisen PS, Bateman RJ, et al. Developing an international network for Alzheimer research: the Dominantly Inherited Alzheimer Network. Clin Investig (Lond). 2012;2:975–84.
11. Ryman DC, Acosta-Baena N, Aisen PS, et al. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology. 2014;83:253–60. In this study, investigators in the Dominantly Inherited Alzheimer Network quantified differences in the age of symptom onset across ADAD subtypes.
12. Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012;367:795–804.
13. Levy E, Carman MD, Fernandez-Madrid IJ, et al. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science. 1990;248:1124–6.
14. Masters CL, Multhaup G, Simms G, Pottgiesser J, Martins RN, Beyreuther K. Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer's disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J. 1985;4:2757–63.
15. Glenner GG, Wong CW. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984;120:885–90.
16. Kang J, Lemaire HG, Unterbeck A, et al. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987;325:733–6.
17. Wong CW, Quaranta V, Glenner GG. Neuritic plaques and cerebrovascular amyloid in Alzheimer disease are antigenically related. Proc Natl Acad Sci U S A. 1985;82:8729–32.
18. Scheuner D, Eckman C, Jensen M, et al. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med. 1996;2:864–70.
19. Sherrington R, Rogaev EI, Liang Y, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995;375:754–60.
20. Levy-Lahad E, Wasco W, Poorkaj P, et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science. 1995;269:973–7.
21. Potter R, Patterson BW, Elbert DL, et al. Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers. Sci Transl Med. 2013;5:189ra177. The authors verified increased rates of Aβ42 production in AD due to PSEN1 mutations using a novel in vivo human assay (see also [33]).
22. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002;297:353–6.
23. Palop JJ, Mucke L. Epilepsy and cognitive impairments in Alzheimer disease. Arch Neurol. 2009;66:435–40.
24. Joshi A, Ringman JM, Lee AS, Juarez KO, Mendez MF. Comparison of clinical characteristics between familial and non-familial early onset Alzheimer's disease. J Neurol. 2012;259:2182–8. The authors quantified clinical differences between familial AD due to known autosomal dominant mutations and sporadic AD of young onset, and verified a higher prevalence of atypical features (spastic paraparesis, headaches, myoclonus) in autosomal dominant familial AD, but found that an amnestic cognitive presentation was commoner in this form of AD than in young-onset sporadic AD.
25. Rudzinski LA, Fletcher RM, Dickson DW, et al. Early onset familial Alzheimer disease with spastic paraparesis, dysarthria, and seizures and N135S mutation in PSEN1. Alzheimer Dis Assoc Disord. 2008;22:299–307.
26. Gomez-Isla T, Growdon WB, McNamara MJ, et al. 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(9):1709–19.
27. 42(43). Ann Neurol. 1996;40:149–56.
28. Shinohara M, Fujioka S, Murray ME, et al. Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer's disease. Brain. 2014;137:1533–49. The investigators carefully quantified Aβ and synaptic markers in the brains of persons with familial AD and compared these with those in the brains of persons with LOAD. They found a strong correlation between synaptic markers and Aβ42 accumulation in LOAD, but stronger associations with other measures of amyloid metabolism as well as more tau immunoreactivity in familial AD, supporting different pathological mechanisms in these forms of AD.
29. Nelson PT, Schmitt FA, Lin Y, et al. Hippocampal sclerosis in advanced age: clinical and pathological features. Brain. 2011;134:1506–18.
30. Davidson YS, Raby S, Foulds PG, et al. TDP-43 pathological changes in early onset familial and sporadic Alzheimer's disease, late onset Alzheimer's disease and Down's syndrome: association with age, hippocampal sclerosis and clinical phenotype. Acta Neuropathol. 2011;122:703–13.
31. Pera M, Alcolea D, Sanchez-Valle R, et al. Distinct patterns of APP processing in the CNS in autosomal-dominant and sporadic Alzheimer disease. Acta Neuropathol. 2013;125:201–13. In this neuropathology study, the investigators found that ADAD was characterized by an increase in APP (β-CTF levels, whereas the pattern in sporadic AD was mainly characterized by an increase in β-secretase levels and activity. These results suggest that the physiopathological events underlying the long-term Aβ production/clearance imbalance in sporadic AD and ADAD are distinct and should be considered in the design of intervention trials in AD.
32. Cataldo A, Rebeck GW, Ghetri B, et al. Endocytic disturbances distinguish among subtypes of Alzheimer's disease and related disorders. Ann Neurol. 2001;50:661–5.
33. Mawuenyega KG, Sigurdson W, Ovod V, et al. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science. 2010;330:1774. Using a novel in vivo technique in humans, the investigators verified that clearance of Aβ42 was decreased in late-onset AD, an effect not seen in ADAD (see [21]).
34. Coulson EJ, Paliga K, Beyreuther K, Masters CL. What the evolution of the amyloid protein precursor supergene family tells us about its function. Neurochem Int. 2000;36:175–84.
35. Hebert SS, Serneels L, Tolia A, et al. Regulated intramembrane proteolysis of amyloid precursor protein and regulation of expression of putative target genes. EMBO Rep. 2006;7:739–45.
36. Nalivaeva NN, Turner AJ. The amyloid precursor protein: a biochemical enigma in brain development, function and disease. FEBS Lett. 2013;587:2046–54.
37. Citron M, Oltersdorf T, Haass C, et al. Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production. Nature. 1992;360:672–74.
38. Borchelt DR, Thinakaran G, Eckman CB, et al. Familial Alzheimer's disease-linked presenilin 1 variants elevate Aβ1–42/1–40 ratio in vitro and in vivo. Neuron. 1996;17:1005–13.
39. Murakami K, Irie K, Morimoto A, et al. Synthesis, aggregation, neurotoxicity, and secondary structure of various Aβ 1–42 mutants of familial Alzheimer's disease at positions 21–23. Biochem Biophys Res Commun. 2002;294:5–10.
40. Gessel MM, Bernstein S, Kemper M, Teplow DB, Bowers MT. Familial Alzheimer's disease mutations differentially alter amyloid β-protein oligomerization. ACS Chem Neurosci. 2012;3:909–18.
41. Rovelet-Lecrux A, Hannequin D, Raux G, et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2006;38:24–6.
42. Scahill RI, Ridgway GR, Bartlett JW, et al. Genetic influences on atrophy patterns in familial Alzheimer's disease: a comparison of APP and PSEN1 mutations. J Alzheimers Dis. 2013;35:199–212.
43. Suarez-Calvet M, Belbin O, Pera M, et al. Autosomal-dominant Alzheimer's disease mutations at the same codon of amyloid precursor protein differentially alter Aβ production. J Neurochem. 2014;128:330–9.
44. Hendriks L, van Duijn CM, Cras P, et al. Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. Nat Genet. 1992;1:218–21.
45. Van Broeckhoven C, Haan J, Bakker E, et al. Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch). Science. 1990;248:1120–2.
46. Kumar-Singh S. Cerebral amyloid angiopathy: pathogenetic mechanisms and link to dense amyloid plaques. Genes Brain Behav. 2008;7 Suppl 1:67–82.
47. Sperling R, Salloway S, Brooks DJ, et al. Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 2012;11:241–9.
48. Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med. 2014;370:322–33. In this important clinical trial, a higher prevalence of treatment-related intracerebral edema and hemorrhage was found in carriers of the APOE ε4 allele, validating the importance of genetically characterizing subjects in the context of treatment studies.
49. Olichney JM, Hansen LA, Galasko D, et al. The apolipoprotein E epsilon 4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimer's disease and Lewy body variant. Neurology. 1996;47:190–6.
50. Klunk WE, Price JC, Mathis CA, et al. Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci. 2007;27:6174–84.
51. Villemagne VL, Ataka S, Mizuno T, et al. High striatal amyloid β-peptide deposition across different autosomal Alzheimer disease mutation types. Arch Neurol. 2009;66:1537–44.
52. Scholl M, Wall A, Thordardottir S, et al. Low PiB PET retention in presence of pathologic CSF biomarkers in Arctic APP mutation carriers. Neurology. 2012;79:229–36.
53. Ringman JM, Teplow DB, Villemagne VL. The exception makes the rule: not all Aβ plaques are created equal. Neurology. 2012;79:206–7.
54. Basun H, Bogdanovic N, Ingelsson M, et al. Clinical and neuropathological features of the arctic APP gene mutation causing early-onset Alzheimer disease. Arch Neurol. 2008;65:499–505.
55. Mann DM, Esiri MM. The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down's syndrome. J Neurol Sci. 1989;89:169–79.
56. Rumble B, Retallack R, Hilbich C, et al. Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease. N Engl J Med. 1989;320:1446–52.
57. Wilcock DM, Griffin WS. Down's syndrome, neuroinflammation, and Alzheimer neuropathogenesis. J Neuroinflammation. 2013;10:84.
58. Zana M, Janka Z, Kalman J. Oxidative stress: a bridge between Down's syndrome and Alzheimer's disease. Neurobiol Aging. 2007;28:648–76.
59. Keating DJ, Chen C, Pritchard MA. Alzheimer's disease and endocytic dysfunction: clues from the Down syndrome-related proteins, DSCR1 and ITSN1. Ageing Res Rev. 2006;5:388–401.
60. Decourt B, Mobley W, Reiman E, Shah RJ, Sabbagh MN. Recent perspectives on APP, secretases, endosomal pathways and how they influence Alzheimer's related pathological changes in Down syndrome. J Alzheimers Dis Parkinsonism. 2013;(Suppl 7):002.
61. Prasher VP, Farrer MJ, Kessling AM, et al. Molecular mapping of Alzheimer-type dementia in Down's syndrome. Ann Neurol. 1998;43:380–3.
62. Ringman JM, Rao PN, Lu PH, Cederbaum S. Mosaicism for trisomy 21 in a patient with young-onset dementia: a case report and brief literature review. Arch Neurol. 2008;65:412–5.
63. Levy-Lahad E, Wijsman EM, Nemens E, et al. A familial Alzheimer's disease locus on chromosome 1. Science. 1995;269:970–3.
64. Miklossy J, Taddei K, Suva D, et al. Two novel presenilin-1 mutations (Y256S and Q222H) are associated with early-onset Alzheimer's disease. Neurobiol Aging. 2003;24:655–62.
65. Takao M, Ghetti B, Murrell JR, et al. Ectopic white matter neurons, a developmental abnormality that may be caused by the PSEN1 S169L mutation in a case of familial AD with myoclonus and seizures. J Neuropathol Exp Neurol. 2001;60:1137–52.
66. Lemere CA, Lopera F, Kosik KS, et al. The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology. Nat Med. 1996;2:1146–50.
67. Sanchez-Valle R, Llado A, Ezquerra M, Rey MJ, Rami L, Molinuevo JL. A novel mutation in the PSEN1 gene (L286P) associated with familial early-onset dementia of Alzheimer type and lobar haematomas. Eur J Neurol. 2007;14:1409–12.
68. Akbari Y, Hitt BD, Murphy MP, et al. Presenilin regulates capacitative calcium entry dependently and independently of γ-secretase activity. Biochem Biophys Res Commun. 2004;322:1145–52.
69. Selkoe D, Kopan R. Notch and presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci. 2003;26:565–97.
70. Pigino G, Morfini G, Pelsman A, Mattson MP, Brady ST, Busciglio J. Alzheimer's presenilin 1 mutations impair kinesin-based axonal transport. J Neurosci. 2003;23:4499–508.
71. Roher AE, Maarouf CL, Malek-Ahmadi M, et al. Subjects harboring presenilin familial Alzheimer's disease mutations exhibit diverse white matter biochemistry alterations. Am J Neurodegener Dis. 2013;2:187–207.
72. Portelius E, Andreasson U, Ringman JM, et al. Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease. Mol Neurodegener. 2010;5:2.
73. Ringman JM, Elashoff D, Geschwind DH, et al. Plasma signaling proteins in persons at genetic risk for Alzheimer disease: influence of APOE genotype. Arch Neurol. 2012;69:757–64.
74. Olichney JM, Hansen LA, Lee JH, Hofstetter CR, Katzman R, Thal LJ. Relationship between severe amyloid angiopathy, apolipoprotein E genotype, and vascular lesions in Alzheimer's disease. Ann N Y Acad Sci. 2000;903:138–43.
75. Ringman JM, Sachs MC, Zhou Y, Monsell SE, Saver JL, Vinters HV. Clinical predictors of severe cerebral amyloid angiopathy and influence of APOE genotype in persons with pathologically verified Alzheimer disease. JAMA Neurol. 2014;71:878–83.
76. Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer's disease. Neuron. 2009;63:287–303.
77. van der Flier WM, Schoonenboom SN, Pijnenburg YA, Fox NC, Scheltens P. The effect of APOE genotype on clinical phenotype in Alzheimer disease. Neurology. 2006;67:526–7.
78. Kerchner GA, Berdnik D, Shen JC, et al. APOE ε4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory. Neurology. 2014;82:691–7.
79. Lehmann M, Ghosh PM, Madison C, et al. Greater medial temporal hypometabolism and lower cortical amyloid burden in ApoE4-positive AD patients. J Neurol Neurosurg Psychiatry. 2014;85:266–73.
80. Bennett DA, Wilson RS, Schneider JA, et al. Apolipoprotein E ε4 allele, AD pathology, and the clinical expression of Alzheimer's disease. Neurology. 2003;60:246–52.
81. Bennett DA, Schneider JA, Wilson RS, Bienias JL, Berry-Kravis E, Arnold SE. Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people. J Neurol Neurosurg Psychiatry. 2005;76:1194–9.
82. Rowe CC, Ellis KA, Rimajova M, et al. Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol Aging. 2010;31:1275–83.
83. Ossenkoppele R, van der Flier WM, Zwan MD, et al. Differential effect of APOE genotype on amyloid load and glucose metabolism in AD dementia. Neurology. 2013;80:359–65.
84. 18 F-Fluorodeoxyglucose positron emission tomography, aging, and apolipoprotein E genotype in cognitively normal persons. Neurobiol Aging. 2014;35:2096–106.
85. Reiman EM, Chen K, Alexander GE, et al. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc Natl Acad Sci U S A. 2004;101:284–9.
86. Dean 3rd DC, Jerskey BA, Chen K, et al. Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study. JAMA Neurol. 2014;71:11–22.
87. Swaminathan S, Risacher SL, Yoder KK, et al. Association of plasma and cortical amyloid beta is modulated by APOE ε4 status. Alzheimers Dement. 2014;10:e9–18.
88. 1–42 levels and an attenuator of cognitive decline in Alzheimer's disease. Hum Mol Genet. 2014. doi:10.1093/hmg/ddu372.
89. Czirr E, Leuchtenberger S, Dorner-Ciossek C, et al. Insensitivity to Aβ42-lowering nonsteroidal anti-inflammatory drugs and γ-secretase inhibitors is common among aggressive presenilin-1 mutations. J Biol Chem. 2007;282:24504–13.
90. Cramer PE, Cirrito JR, Wesson DW, et al. ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science. 2012;335:1503–6.
91. Mills SM, Mallmann J, Santacruz AM, et al. Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial. Rev Neurol (Paris). 2013;169:737–43.
92. Reiman EM, Langbaum JB, Fleisher AS, et al. Alzheimer's Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. J Alzheimers Dis. 2011;26 Suppl 3:321–9.
93. Ness S, Rafii M, Aisen P, Krams M, Silverman W, Manji H. Down's syndrome and Alzheimer's disease: towards secondary prevention. Nat Rev Drug Discov. 2012;11:655–6.