Abstract
It is now 10 years since the first report of mutations in the presenilin genes that were deterministic for familial autosomal dominant Alzheimer's disease. The most common of these mutations occurs in the presenilin–1 gene (PSEN1) located on chromosome 14. In the ensuing decade, more than 100 PSEN1 mutations have been described. The emphasis of these reports has largely been on the novelty of the mutations and their potential pathogenic consequences rather than detailed clinical, neuropsychological, neuroimaging and neuropathological accounts of patients with the mutation. This article reviews the clinical phenotypes of reported PSEN1 mutations, emphasizing their heterogeneity, and suggesting that other factors, both genetic and epigenetic,must contribute to disease phenotype.
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Aldudo J, Bullido MJ, Arbizu T, Oliva R, Valdivieso F (1998) Identification of a novel mutation (Leu282Arg) of the human presenilin 1 gene in Alzheimer's disease. Neurosci Lett 240:174–176
Aldudo J, Bullido MJ, Frank A, Valdivieso F (1998) Missense mutation E318G of the presenilin –1 gene appears to be a nonpathogenic polymorphism. Ann Neurol 44:985–986
Aldudo J, Bullido MJ, Valdivieso F (1999) DGGE method for the mutational analysis of the coding and proximal promoter regions of the Alzheimer's disease presenilin –1 gene: two novel mutations. Hum Mutat 14:433–439
Amtul Z, Lewis PA, Piper S, et al. (2002) A presenilin 1 mutation associated with familial frontotemporal dementia inhibits gamma –secretase cleavage of APP and Notch. Neurobiol Dis 9:269–273
Aoki M, Abe K, Oda N, et al. (1997) A presenilin –1 mutation in a Japanese family with Alzheimer's disease and distinctive abnormalities on cranial MRI. Neurology 48:1118–1120
Arango D, Cruts M, Torres O, et al. (2001) Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia. Am J Hum Genet 103:148–153
Arboleda H, Duarte N, Lozano J, et al. (2004) Dementia syndrome with predominant fronto –temporal dysfunction in a Colombian family with E280A presenilin –1 mutation. Neurobiol Aging 25(S2):S517 (abstract P4–146)
Ardila A, Lopera F, Rosselli M, et al. (2000) Neuropsychological profile of a large kindred with familial Alzheimer's disease caused by the E280A single presenilin –1 mutation. Arch Clin Neuropsychol 15:515–528
Assini A, Terreni L, Borghi R, et al. (2003) Pure spastic paraparesis associated with a novel presenilin 1 R278K mutation. Neurology 60:150–151
Ataki S, Tomiyama T, Takuma H, et al. (2004) A novel presenilin –1 mutation (Leu85Pro) in early –onset Alzheimer disease with spastic paraparesis. Arch Neurol 61:1773–1776
Athan ES, Williamson J, Ciappa A, et al. (2001) A founder mutation in presenilin 1 causing early –onset Alzheimer disease in unrelated Caribbean Hispanic families. JAMA 286:2257–2263
Axelman K, Basun H, Lannfelt L (1998) Wide range of disease onset in a family with Alzheimer disease and a His163Tyr mutation in the presenilin –1 gene. Arch Neurol 55:698–702
Bertoli Avella AM, Marchero Teruel B, Llibre Rodriguez JJ, et al. (2002) A novel presenilin 1 mutation (L174M) in a large Cuban family with early onset Alzheimer's disease. Neurogenetics 4:97–104
Besancon R, Lorenzi A, Cruts M, et al. (1998) Missense mutation in exon 11 (Codon 378) of the presenilin –1 gene in a French family with early –onset Alzheimer's disease and transmission study by mismatch enhanced allele specific amplification. Hum Mutat 11:481
Boteva K, Vitek M, Mitsuda H, et al. (1996) Mutation analysis of presenilin 1 gene in Alzheimer's disease. Lancet 347:130–131
Braak H, Braak E (1991) Neuropathological stageing of Alzheimer –related changes. Acta Neuropathol (Berl) 82:239–259
Brooks WS, Kwok JBJ, Kril JJ, et al. (2003) Alzheimer's disease with spastic paraparesis and “cotton wool” plaques: two pedigrees with PS –1 exon 9 deletions. Brain 126:783–791
Burns A, Levy R (1992) Clinical diversity in late onset Alzheimer's disease. Oxford: OUP
Campion D, Brice A, Dumanchin C, et al. (1996) A novel presenilin 1 mutation resulting in familial Alzheimer's disease with an onset age of 29 years. Neuroreport 7:1582–1584
Campion D, Brice A, Hannequin D, et al. (1995) A large pedigree with early –onset Alzheimer's disease: clinical, neuropathologic, and genetic characterization. Neurology 45:80–85
Campion D, Dumanchin C, Hannequin D, et al. (1999) Early –onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet 65:664–670
Campion D, Flaman J –M, Brice A, et al. (1995) Mutations of the presenilin 1 gene in families with early –onset Alzheimer's disease. Hum Mol Genet 4:2373–2377
Chapman J, Asherov A, Wang N, Treves TA, Korczyn AD, Goldfarb LG (1995) Familial Alzheimer's disease associated with S182 codon 286 mutation. Lancet 346:1040
Chen J –Y, Stern Y, Sano M, et al. (1991) Cumulative risk of developing extrapyramidal signs, psychosis or myoclonus in the course of Alzheimer's disease. Arch Neurol 48:1141–1143
Citron M (2001) The presenilins. In: Dawbarn D, Allen SJ (eds) Neurobiology of Alzheimer disease (2nd edition). Oxford: OUP, pp 227–240
Clarke RF, Hutton M, Fuldner RA, et al. (1995) The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet 11:219–222
Cochran EJ, Murrell JR, Fox J, Ringman J, Ghetti B (2001) A novel mutation in the presenilin –1 (PS1) gene (A431E) associated with early –onset Alzheimer disease. J Neuropathol Exp Neurol 60:544 (abstract 163)
Colacicco AM, Panza F, Basile AM, et al. (2002) F175S change and a novel polymorphism in presenilin –1 gene in lateonset familial Alzheimer's disease. Eur Neurol 47:209–213
Coleman P, Kurlan R, Crook R, Werner J, Hardy J (2004) A new presenilin Alzheimer's disease case confirms the helical alignment of pathogenic mutations in transmembrane domain 5. Neurosci Lett 364:139–140
Crook R, Ellis R, Shanks M, et al. (1997) Early –onset Alzheimer's disease with a presenilin –1 mutation at the site corresponding to the Volga German presenilin – 2 mutation. Ann Neurol 42:124–128
Crook R, Verkkoniemi A, Perez –Tur J, et al. (1998) A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med 4:452–455
Cruts M, Backhovens H, Wang SY, et al. (1995) Molecular genetic analysis of familial early onset Alzheimer's disease linked to chromosome 14q24. 3. Hum Mol Genet 4:2363–2371
Cruts M, van Broeckhoven C (1998) Presenilin mutations in Alzheimer's disease. Hum Mutat 11:183–190
Cruts M, van Duijn CM, Backhovens H, et al. (1998) Estimation of the genetic contribution of presenilin –1 and –2 mutations in a population –based study of presenile Alzheimer disease. Hum Mol Genet 7:43–51
De Jonghe C, Cras P, Vanderstichele H, et al. (1999) Evidence that Aβ 42 plasma levels in presenilin –1 mutation carriers do not allow for prediction of their clinical phenotype. Neurobiol Dis 6:280–287
De Jonghe C, Cruts M, Rogaeva EA, et al. (1999) Aberrant splicing of the presenilin –1 intron 4 mutation causes presenile Alzheimer's disease by increased Aβ 42 secretion. Hum Mol Genet 8:1529–1540
Dermaut B, Kumar –Singh S, De Jonghe C, et al. (2001) Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation. Brain 124:2383–2392
Dermaut B, Kumar –Singh S, Engelborghs S, et al. (2004) A novel presenilin 1 mutation associated with Pick's disease but not β –amyloid plaques. Ann Neurol 55:617–625
Dermaut B, Roks G, Theuns J, et al. (2001) Variable expression of presenilin 1 is not a major determinant of risk for late –onset Alzheimer's disease. J Neurol 248:935–939
De Strooper B, Saftig P, Gaessaerts K, et al. (1998) Deficiency of presenilin –1 inhibits the normal cleavage of amyloid precursor protein. Nature 391:387–390
Devi G, Fotiou A, Jyrinji D, et al. (2000) Novel presenilin 1 mutations associated with early onset of dementia in a family with both early –onset and lateonset Alzheimer disease. Arch Neurol 57:1454–1457
Doran M, du Plessis DG, Enevoldson TP, Fletcher NA, Ghadiali E, Larner AJ (2003) Pathological heterogeneity of clinically diagnosed corticobasal degeneration. J Neurol Sci 216:127–134
Doran M, Larner AJ (2004) Prominent behavioural and psychiatric symptoms in early –onset Alzheimer's disease in a sib pair with the presenilin –1 gene R269G mutation. Eur Arch Psychiatry Clin Neurosci 254:187–189
Dowjat WK, Kuchna I, Wisniewski T, Wegiel J (2004) A novel highly pathogenic Alzheimer presenilin –1 mutation in codon 117 (Pro117Ser): comparison of clinical, neuropathological and cell culture phenotypes of Pro117Leu and Pro117Ser mutations. J Alzheimers Dis 6:31–43
Dumanchin C, Brice A, Campion D, et al. for the French Alzheimer's Disease Study Group (1998) De novo presenilin 1 mutations are rare in clinically sporadic, early onset Alzheimer's disease cases. J Med Genet 35:672–673
Ezquerra M, Carnero C, Blesa R, Gelpi JL, Ballesta F, Oliva R (1999) A presenilin 1 mutation (Ser169Pro) associated with early –onset AD and myoclonic seizures. Neurology 52:566–570
Ezquerra M, Carnero C, Blesa R, Oliva R (2000) A novel presenilin 1 mutation (Leu166Arg) associated with early –onset Alzheimer disease. Arch Neurol 57:485–488
Farlow MR, Murrell JR, Unverzagt FW, et al. (2001) Familial Alzheimer's disease with spastic paraparesis associated with a mutation at codon 261 of the presenilin 1 gene. In: Iqbal K, Sisodia SS, Winblad B (eds) Alzheimer's disease: advances in etiology, pathogenesis and therapeutics. Chichester: John Wiley, pp 53–60
Finckh U, Muller –Thomsen T, Mann U, et al. (2000) High prevalence of pathogenic mutations in patients with earlyonset dementia detected by sequence analyses of four different genes. Am J Hum Genet 66:110–117
Forsell C, Froelich S, Axelman K, et al. (1997) A novel pathogenic mutation (Leu262Phe) found in the presenilin 1 gene in early –onset Alzheimer's disease. Neurosci Lett 234:3–6
Fox NC, Kennedy AM, Harvey RJ, et al. (1997) Clinicopathological features of familial Alzheimer's disease associated with the M139V mutation in the presenilin 1 gene. Pedigree but not mutation specific age at onset provides evidence for a further genetic factor. Brain 120:491–501
Frommelt P, Schnabel R, Kuhne W, Nee LE, Polinsky RJ (1991) Familial Alzheimer disease: a large, multigenerational German kindred. Alzheimer Dis Assoc Disord 5:36–43
Furuya H, Yasuda M, Terasawa K, et al. (2003) A novel mutation (L250V) in the presenilin 1 gene in a Japanese familial Alzheimer's disease with myoclonus and generalized convulsion. J Neurol Sci 209:75–77
Godbolt AK, Beck JA, Collinge J, et al. (2004) A presenilin 1 R278I mutation presenting with language impairment. Neurology 63:1702–1704
Godbolt AK, Cipolotti L, Watt H, Fox NC, Janssen JC, Rossor MN (2004) The natural history of Alzheimer disease: a longitudinal presymptomatic and symptomatic study of a familial cohort. Arch Neurol 61:1743–1748
Goldman JS, Reed B, Gearhart R, Kramer JH, Miller BL (2002) Very early –onset familial Alzheimer's disease: a novel presenilin 1 mutation. Int J Geriatr Psychiatry 17:649–651
Gomez –Isla T, Growdon WB, McNamara MJ, et al. (1999) 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 phenotypemodifying factors. Brain 122:1709–1719
Gomez –Isla T, Wasco W, Pettingell WP, et al. (1997) A novel presenilin –1 mutation: increased β –amyloid and neurofibrillary changes. Ann Neurol 41:809–813
Gustafson L, Brun A, Englund E, et al. (1998) A 50 –year perspective of a family with chromosome –14 –linked Alzheimer's disease. Hum Genet 102:253–257
Haass C, Steiner H (2002) Alzheimer disease gamma –secretase: a complex story of GxGD –type presenilin proteases. Trends Cell Biol 12:556–562
Halliday GM, Song –Yun JC, Lepar G, et al. (2005) Pick bodies in a family with presenilin –1 Alzheimer's disease. Ann Neurol 57:139–143
Haltia M, Viitanen M, Sulkava R, et al. (1994) Chromosome 14 –encoded Alzheimer's disease: genetic and clinicopathological description. Ann Neurol 36:362–367
Hanisch F, Kolmel H (2004) Genotypephenotype analysis in early –onset Alzheimer's disease due to presenilin –1 mutations at codon 139. Eur J Med Res 9:361–364
Harvey RJ, Ellison D, Hardy J, et al. (1998) Chromosome 14 familial Alzheimer's disease: the clinical and neuropathological characteristics of a family with a leucine serine (L250S) substitution at codon 250 of the presenilin 1 gene. J Neurol Neurosurg Psychiatry 64:44–49
Hattori S, Sakuma K, Wakutani Y, et al. (2004) A novel presenilin 1 mutation (Y154N) in a patient with early onset Alzheimer's disease with spastic paraparesis. Neurosci Lett 368:319–322
Heckmann JM, Low W –C, de Villiers C, et al. (2004) Novel presenilin 1 mutation with profound neurofibrillary pathology in an indigenous Southern African family with early –onset Alzheimer's disease. Brain 127:133–142
Higuchi S, Yoshino A, Matsui T, et al. (2000) A novel PS1 mutation (W165G) in a Japanese family with early –onset Alzheimer's disease. Alzheimer's Reports 3:227–231
Hiltunen M, Helisalmi S, Mannermaa A, et al. (2000) Identification of a novel 4. 6kb genomic deletion in presenilin –1 gene which results in exclusion of exon 9 in a Finnish early onset Alzheimer's disease family: an Alu core sequencestimulated recombination? Eur J Hum Genet 8:259–266
Houlden H, Baker M, McGowan E, et al. (1998) Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS –1 mutations that lead to exceptionally high amyloid –β concentrations. Ann Neurol 48:806–808
Houlden H, Crook R, Dolan RJ, McLaughlin J, Revesz T, Hardy J (2001) A novel presenilin mutation (M233V) causing very early onset Alzheimer's disease with Lewy bodies. Neurosci Lett 313:93–95
Hull M, Fiebich BL, Dykierek P, et al. (1998) Early –onset Alzheimer's disease due to mutations of the presenilin –1 gene on chromosome 14: a 7 –year follow – up of a patient with a mutation at codon 139. Eur Arch Psychiatry Clin Neurosci 248:123–129
Hutton M, Busfield F, Wragg M, et al. (1996) Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease. Neuroreport 7:801–805
Ikeda M, Sharma V, Sumi M, et al. (1996) The clinical phenotype of two missense mutations in the presenilin 1 gene in Japanese patients. Ann Neurol 40:912–917
Ishii K, Ii K, Hasegawa T, Shoji S, Doi A, Mori H (1997) Increased Aβ 42(43) – plaque deposition in early –onset familial Alzheimer's disease brains with the deletion of exon 9 and the missense point mutation (H163R) in the PS –1 gene. Neurosci Lett 228:17–20
Ishikawa A, Piao YS, Miyashita A, et al. (2005) A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer's disease. Ann Neurol 57:429–434
Jacquemont M –L, Campion D, Hahn V, et al. (2002) Spastic paraparesis and atypical dementia caused by PSEN1 mutation (P264L), responsible for Alzheimer's disease. J Med Genet 39:e2
Jacquier M, Arango D, Torres O, et al. (2000) Presenilin mutations in a Colombian familial and sporadic AD sample. Neurobiol Aging 21(1S):S176 (abstract 798)
Janssen JC, Beck JA, Campbell TA, et al. (2003) Early onset familial Alzheimer's disease. Mutation frequency in 31 families. Neurology 60:235–239
Janssen JC, Hall M, Fox NC, et al. (2000) Alzheimer's disease due to an intronic presenilin –1 (PSEN1 intron 4) mutation: a clinicopathological study. Brain 123:894–907
Janssen JC, Lantos PL, Fox NC, et al. (2001) Autopsy –confirmed familial early –onset Alzheimer's disease caused by the L153V presenilin 1 mutation. Arch Neurol 58:953–958
Jia J, Xu E, Shao Y, Jia J, Sun Y, Li D (2005) One novel presenilin –1 gene mutation in a Chinese pedigree of familial Alzheimer's disease. J Alzheimers Dis 7:119–124
Jimenez –Escrig A, Rabano A, Guerrero C, et al. (2004) New V272A presenilin 1 mutation with very early onset subcortical dementia and parkinsonism. Eur J Neurol 11:663–669
Jorgensen P, Bus C, Pallisgaard N, Bryder M, Jorgensen AL (1996) Familial Alzheimer's disease co –segregates with a Met146Ile substitution in presenilin – 1. Clin Genet 50:281–286
Kamimura K, Tanahashi H, Yamanaka H, Takahashi T, Asada T, Tabira T (1998) Familial Alzheimer's disease genes in Japanese. J Neurol Sci 160:76–81
Kamino K, Sato S, Sakaki Y, et al. (1996) Three different mutations of presenilin 1 gene in early –onset Alzheimer's disease families. Neurosci Lett 208:195–198
Kennedy AM, Rossor MN, Hodges JR (2001) Familial and sporadic Alzheimer's disease. In: Hodges JR (ed) Early –onset dementia. A multidisciplinary approach. Oxford: OUP, pp 263–283
Kimberly WT, Lavoie MJ, Ostaszewski BL, et al. (2003) Gamma –secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph –1, and Pen –2. Proc Natl Acad Sci USA 100:6382–6387
Kowalska A, Forsell C, Florczak J, et al. (1999) A Polish pedigree with Alzheimer's disease determined by a novel mutation in exon 12 of the presenilin – 1 gene: clinical and molecular characterization. Folia Neuropathol 37:57–61
Kowalska A, Wender M, Florczak J, et al. (2003) Molecular genetics of Alzheimer's disease: presenilin 1 gene analysis in a cohort of patients from the Poznan region. J Appl Genet 44:231–234
Kwok JB, Halliday GM, Brooks WS, et al. (2003) Presenilin –1 mutation L271V results in altered exon 8 splicing and Alzheimer's disease with noncored plaques and no neuritic dystrophy. J Biol Chem 278:6748–6754
Kwok JBJ, Taddei K, Hallupp M, et al. (1997) Two novel (M233T and R278T) presenilin –1 mutations in early –onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin –1 mutations with a novel phenotype. Neuroreport 8:1537–1542
La Bella V, Liquori M, Cittadella R, et al. (2004) A novel mutation (Thr116Ile) in the presenilin 1 gene in a patient with early –onset Alzheimer's disease. Eur J Neurol 11:521–524
Lampe TH, Bird TD, Nochlin D, et al. (1994) Phenotype of chromosome 14 – linked familial Alzheimer's disease in a large kindred. Ann Neurol 36:368–378
Larner AJ (1997) The cerebellum in Alzheimer's disease: a review. Dement Geriatr Cogn Disord 8:203–209
Larner AJ (2002) Alzheimer's disease: targets for drug development. Mini Rev Med Chem 2:1–9
Larner AJ (2004) Genotype –phenotype correlations in early –onset Alzheimer disease with presenilin 1 gene mutations. Arch Neurol 61:801
Larner AJ (2004) Secretases as therapeutic targets in Alzheimer's disease: patents 2000–2004. Expert Opin Ther Patents 14:1403–1420
Larner AJ, du Plessis DG (2003) Early –onset Alzheimer's disease with presenilin –1 M139V mutation: clinical, neuropsychological and neuropathological study. Eur J Neurol 10:319–323
Le TV, Crook R, Hardy J, Dickson DW (2001) Cotton wool plaques in nonfamilial late –onset Alzheimer disease. J Neuropathol Exp Neurol 60:1051–1061
Lemere CA, Lopera F, Kosik KS, et al. (1996) The E280A presenilin 1 Alzheimer mutation produces increased Aβ 42 deposition and severe cerebellar pathology. Nat Med 2:1146–1150
Lendon CL, Martinez A, Behrens IM, et al. (1997) E280A PS –1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles. Hum Mutat 10:186–195
Lippa CF, Fujiwara H, Mann DMA, et al. (1998) Lewy bodies contain altered α –synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes. Am J Pathol 153:1365–1370
Lippa CF, Swearer JM, Kane KL, et al. (2000) Familial Alzheimer's disease: site of mutation influences clinical phenotype. Ann Neurol 48:376–379
Lleo A, Blesa R, Queralt R, et al. (2002) Frequency of mutations in the presenilin and amyloid precursor protein genes in early –onset Alzheimer disease in Spain. Arch Neurol 59:1759–1763
Lopera F, Ardilla A, Martinez A, et al. (1997) Clinical features of early –onset Alzheimer disease in a large kindred with an E280A presenilin –1 mutation. JAMA 277:793–799
McKeith IG, Galasko D, Kosaka K, et al. (1996) Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 47:1113–1124
McKhann G, Drachman D, Folstein M, et al. (1984) Clinical diagnosis of Alzheimer's disease. Report of the NINCDS –ADRDA work group under the auspices of the Department of Health and Human Service Task forces on Alzheimer's disease. Neurology 34:939–944
Mann DMA, Iwatsubo T, Cairns NJ, et al. (1996) Amyloid β protein (Aβ) deposition in chromosome 14 –linked Alzheimer's disease: predominance of Aβ 42(43). Ann Neurol 40:149–156
Mann DMA, Pickering Brown SM, Takeuchi A, Iwatsubo T and the members of the Familial Alzheimer's Disease Pathology Study Group (2001) Amyloid angiopathy and variability in amyloid β deposition is determined by mutation position in presenilin – 1 –linked Alzheimer's disease. Am J Pathol 158:2165–2175
Mann DMA, Takeuchi A, Sato S, et al. (2001) Cases of Alzheimer's disease due to a deletion of exon 9 of the presenilin – 1 gene show an unusual but characteristic β –amyloid pathology known as “cotton wool” plaques. Neuropathol Appl Neurobiol 27:189–196
Marrosu MG, Floris GL, Costa G, et al. (2005) PS1 P284S mutation associated with dementia, pyramidal system involvement and multiple sclerosis – like MRI abnormalities. J Neurol 252(Suppl 2):II44–II45 (abstract O153)
Martin JJ, Gheuens J, Bruyland M, et al. (1991) Early –onset Alzheimer's disease in 2 large Belgian families. Neurology 41:62–68
Matsushita Y, Arai H, Okamura N, et al. (2002) Clinical and biomarker investigation of a patient with a novel presenilin –1 mutation (A431V) in the mild cognitive impairment stage of Alzheimer's disease. Biol Psychiatry 52:907–910
Mattila KM, Forsell C, Pirttila T, et al. (1998) The Glu318Gly mutation of the presenilin –1 gene does not necessarily cause Alzheimer's disease. Ann Neurol 44:965–967
Mehrabian S, Traykov LD, Jordanova AK, et al. (2005) L250V/PSEN1 mutation in a large early onset Alzheimer's disease Bulgarian pedigree with atypical phenotype. Eur J Neurol 12(Suppl 2):17 (abstract SC120)
Mehrabian S, Traykov L, Rademakers R, et al. (2004) A novel PSEN1 mutation in an EOAD family with spastic paraparesis and extrapyramidal signs. Eur J Neurol 11(Suppl 2):16 (abstract SC123)
Mehta ND, Refolo LM, Eckman C, et al. (1998) Increased Aβ 42(43) from cell lines expressing presenilin 1 mutations. Ann Neurol 43:256–258
Mendez MF, Ghajarania M, Perryman KM (2002) Posterior cortical atrophy: clinical characteristics and differences compared to Alzheimer's disease. Dement Geriatr Cogn Disord 14:33–40
Miklossy J, Taddei K, Suva D, et al. (2003) Two novel presenilin –1 mutations (Y256S and Q222H) are associated with early –onset Alzheimer's disease. Neurobiol Aging 24:655–662
Miravalle L, Murrell JR, Takao M, et al. (2002) Genetic mutations associated with presenile dementia. Neurobiol Aging 23(1S):S322 (abstract 1197)
Mirra SS, Heyman A, McKeel D, et al. (1991) The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 41:479–486
Moehlmann T, Winkler E, Xia X, et al. (2002) Presenilin –1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ 42 production. Proc Natl Acad Sci USA 99:8025–8030
Morelli L, Prat MI, Levy E, Mangone CA, Castano EM (1998) Presenilin 1 Met146Leu variant due to an A→T transversion in an early –onset familial Alzheimer's disease pedigree from Argentina. Clin Genet 53:469–473
Moretti P, Lieberman AP, Wilde EA, et al. (2004) Novel insertional presenilin 1 mutation causing Alzheimer disease with spastic paraparesis. Neurology 62:1865–1868
Mullan M, Houlden H, Crawford F, Kennedy A, Roques P, Rossor M (1993) Age of onset in familial early onset Alzheimer's disease correlates with genetic aetiology. Am J Med Genet 48:129–130
O'Riordan S, McMonagle P, Janssen JC, et al. (2002) Presenilin –1 mutation (E280G), spastic paraparesis, and cranial MRI white –matter abnormalities. Neurology 59:1108–1110
Palmer MS, Beck JA, Campbell TA, et al. (1999) Pathogenic presenilin 1 mutations (P436S and I143F) in early –onset Alzheimer's disease in the UK. Hum Mutat 13:256
Perez –Tur J, Croxton R, Wright K, et al. (1996) A further presenilin 1 mutation in the exon 8 cluster in familial Alzheimer's disease. Neurodegeneration 5:207–212
Perez –Tur J, Froelich S, Prihar G, et al. (1995) A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin –1 gene. Neuroreport 7:297–301
Poduslo SE, Herring K, Neal M (1996) A presenilin 1 mutation in an early onset Alzheimer's family: no association with presenilin 2. Neuroreport 7:2018–2020
Poorkaj P, Sharma V, Anderson L, et al. (1998) Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin –1 gene. Hum Mutat 11:216–221
Portet F, Dauvilliers Y, Campion D, et al. (2003) Very early onset AD with a de novo mutation in the presenilin – 1 gene (Met233Leu). Neurology 61:1136–1137
Prihar G, Verkkoniemi A, Perez –Tur J, et al. (1999) Alzheimer's disease PS –1 exon 9 deletion defined. Nat Med 5:1090
Queralt R, Ezquerra M, Castellvi M, Lleo A, Blesa R, Oliva R (2001) Detection of the presenilin 1 gene mutation (M139T) in early –onset familial Alzheimer disease in Spain. Neurosci Lett 299:239–241
Queralt R, Ezquerra M, Lleo A, et al. (2002) A novel mutation (V89L) in the presenilin –1 gene in a family with early onset Alzheimer's disease and marked behavioural disturbances. J Neurol Neurosurg Psychiatry 72:266–269
Raman A, Lin X, Suri M, Hewitt C, Constantinescu C, Phillips M (2005) A novel presenilin 1 mutation associated with early onset Alzheimer's disease and spastic paraparesis. J Neurol 252(Suppl 2):II38 (abstract O128)
Ramirez –Duenas MG, Rogaeva EA, Leal CA, et al. (1998) A novel Leu171Pro mutation in presenilin –1 gene in a Mexican family with early onset Alzheimer disease. Ann Genet 41:149–153
Raux G, Gantier R, Martin C, et al. (2000) A novel presenilin 1 missense mutation (L153V) segregating with early –onset autosomal dominant Alzheimer's disease. Hum Mutat 16:95
Raux G, Gantier R, Thomas –Anterion C, et al. (2000) Dementia with prominent frontotemporal features associated with the L113P presenilin 1 mutation. Neurology 55:1577–1578
Revesz T, McLaughlin JL, Rossor MN, Lantos PL (1997) Pathology of familial Alzheimer's disease with Lewy bodies. J Neural Transm 104(Suppl 51):121–135
Reznik –Wolf H, Treves TA, Davidson M, et al. (1996) A novel mutation of presenilin 1 in familial Alzheimer's disease in Israel detected by denaturing gradient gel electrophoresis. Hum Genet 98:700–702
Rippon GA, Crook R, Baker M, et al. (2003) Presenilin 1 mutation in an African American family presenting with atypical Alzheimer dementia. Arch Neurol 60:884–888
Rogaev EI, Sherrington R, Rogaeva EA, et al. (1995) Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to Alzheimer's disease type 3. Nature 376:775–778
Rogaev EI, Sherrington R, Wu C, et al. (1997) Analysis of the 5' sequence, genomic structure, and alternative splicing of the presenilin –1 gene (PSEN1) associated with early onset Alzheimer disease. Genomics 40:415–424
Rogaeva EA, Bergeron C, Sato C, et al. (2003) PS1 Alzheimer's disease family with spastic paraplegia: the search for a gene modifier. Neurology 61:1005–1007
Rogaeva EA, Fafel KG, Song YQ, et al. (2001) Screening for PS1 mutations in a referral –based series of AD cases. 21 novel mutations. Neurology 57:621–625
Romero I, Jorgensen P, Bolwig G, et al. (1999) A presenilin –1 Thr116Asn substitution in a family with early –onset Alzheimer's disease. Neuroreport 10:2255–2260
Rossor MN, Fox NC, Beck J, Campbell TC, Collinge J (1996) Incomplete penetrance of familial Alzheimer's disease in a pedigree with a novel presenilin – 1 gene mutation. Lancet 347:1560
Sandbrink R, Zhang D, Schaeffer S, et al. (1996) Missense mutations of the PS –1/S182 gene in German earlyonset Alzheimer's disease patients. Ann Neurol 40:265–266
Sato S, Kamino K, Miki T, et al. (1998) Splicing mutation of presenilin –1 gene for early –onset familial Alzheimer's disease. Hum Mutat Suppl 1:S91–S94
Scheuner D, Eckman C, Jensen M, et al. (1996) Secreted amyloid β –protein similar to that in the amyloid 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 2:864–870
Selkoe D, Kopan R (2003) Notch and presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci 26:565–597
Sherrington R, Rogaev EI, Liang Y, et al. (1995) Cloning of a gene bearing missense mutations in early –onset familial Alzheimer's disease. Nature 375:754–760
Singleton AB, Hall R, Ballard CG, et al. (2000) Pathology of early –onset Alzheimer's disease cases bearing the Thr113–114ins presenilin –1 mutation. Brain 123:2467–2474
Smith MJ, Gardner RJ, Knight MA, et al. (1999) Early –onset Alzheimer's disease caused by a novel mutation at codon 219 of the presenilin –1 gene. Neuroreport 10:503–507
Smith MJ, Kwok JB, McLean CA, et al. (2001) Variable phenotype of Alzhemier's disease with spastic paraparesis. Ann Neurol 49:125–129
Sodeyama N, Iwata T, Ishikawa K, et al. (2001) Very early onset Alzheimer's disease with spastic paraparesis associated with a novel presenilin 1 mutation (Phe237Ile). J Neurol Neurosurg Psychiatry 71:556–557
Sorbi S, Nacmias B, Forleo P, et al. (1995) Missense mutation of S182 gene in Italian families with early –onset Alzheimer's disease. Lancet 346:439–440
Sorbi S, Tedde A, Nacmias B, et al. (2002) Novel presenilin 1 and presenilin 2 mutations in early –onset Alzheimer's disease families. Neurobiol Aging 23(1S):S312–S313 (abstract 1164)
Steiner H, Revesz T, Neumann M, et al. (2001) A pathogenic presenilin –1 deletion causes abberrant [sic] Aβ 42 production in the absence of congophilic amyloid plaques. J Biol Chem 276:7233–7239
Steiner H, Romig H, Grim MG, et al. (1999) The biological and pathological function of the presenilin –1 Δexon 9 mutation is independent of its defect to undergo proteolytic processing. J Biol Chem 274:7615–7618
Styczynska M, Zekanowski C, Peplonska B, et al. (2004) Early onset Alzheimer's disease associated with a novel P117R presenilin 1 mutation and initial features of frontotemporal dementia. Eur J Neurol 11(Suppl 2):190 (abstract P2023)
Sugiyama N, Suzuki K, Matsumara T, et al. (1999) A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene in a Japanese family with presenile familial Alzheimer's disease. Hum Mutat 14:90
Suva D, Favre I, Kraftsik R, Esteban M, Lobrinus A, Miklossy J (1999) Primary motor cortex involvement in Alzheimer's disease. J Neuropathol Exp Neurol 58:1125–1134
Tabira T, Chui DH, Nakayama H, Kuroda S, Shibuya M (2002) Alzheimer's disease with spastic paresis and cotton wool type plaques. J Neurosci Res 70:367–372
Taddei K, Kwok JBJ, Kril JJ, et al. (1998) Two novel presenilin –1 mutations (Ser169Leu and Pro436Gln) associated with very early onset Alzheimer's disease. Neuroreport 9:3335–3339
Takao M, Ghetti B, Hayakawa I, et al. (2002) A novel mutation (G217D) in the Presenilin 1 gene (PSEN1) in a Japanese family: presenile dementia and parkinsonism are associated with cotton wool plaques in the cortex and striatum. Acta Neuropathol (Berl) 104:155–170
Takao M, Ghetti B, Murrell JR, et al. (2001) 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 60:1137–1152
Takao M, Piccardo P, Murrell J, et al. (2002) Neuropathological heterogeneity associated with presenilin 1 gene mutations. Neurobiol Aging 23 (1S):S417 (abstract 1533)
Tanahashi H, Kawakatsu S, Kaneko M, Yamanaka H, Takahashi K, Tabira T (1996) Sequence analysis of presenilin – 1 gene mutation in Japanese Alzheimer's disease patients. Neurosci Lett 218:139–141
Tanahashi H, Mitsunaga Y, Takahashi K, Tasaki H, Watanabe S, Tabira T (1995) Missense mutation of S182 gene in Japanese familial Alzheimer's disease. Lancet 346:440
Tang –Wai D, Lewis P, Boeve B, et al. (2002) Familial frontotemporal dementia associated with a novel presenilin – 1 mutation. Dement Geriatr Cogn Disord 14:13–21
Tedde A, Forleo P, Nacmias B, et al. (2000) A presenilin –1 mutation (Leu392Pro) in a familial AD kindred with psychiatric symptoms at onset. Neurology 55:1590–1591
Tedde A, Nacmias B, Ciantelli M, et al. (2003) Identification of new presenilin gene mutations in early –onset Alzheimer disease. Arch Neurol 60:1541–1544
Terreni L, Valeria C, Calella AM, et al. (2000) A novel missense mutation (L219F) in exon 8 of the presenilin 1 gene in an Italian family with presenile familial Alzheimer's disease. Neurobiol Aging 21(1S):S176–S177 (abstract 800)
Tysoe C, Whittaker J, Xuereb JH, et al. (1998) A presenilin –1 truncating mutation is present in two cases with autopsy – confirmed early –onset Alzheimer disease. Am J Hum Genet 62:70–76
Van Broeckhoven C, Backhoven H, Cruts M, et al. (1994) ApoE genotype does not modulate age of onset in families with chromosome 14 encoded Alzheimer's disease. Neurosci Lett 169:179–180
Velez –Pardo C, Arellano JI, Cardona – Gomez P, et al. (2004) CA1 hippocampal neuronal loss in familial Alzheimer's disease presenilin –1 E280A mutation is related to epilepsy. Epilepsia 45:751–756
Verkkoniemi A, Kalimo H, Paetau A, et al. (2001). Variant Alzheimer disease with spastic paraparesis: neuropathological phenotype. J Neuropathol Exp Neurol 60:483–492
Verkkoniemi A, Ylikoski R, Rinne JO, et al. (2004) Neuropsychological functions in variant Alzheimer's disease with spastic paraparesis. J Neurol Sci 218:29–37
Wakutani Y, Adachi Y, Wada –Isoe K, Yamagata K, Urakami K, Nakashima K (2004) Genetic analysis of familial Alzheimer's disease in a Japanese population. In: Takeda M, Tanaka T, Cacabelos R (eds) Molecular neurobiology of Alzheimer disease and related disorders. Basel: Karger, pp 157–163
Warrington EK, Agnew SK, Kennedy AM, Rossor MN (2001) Neuropsychological profiles of familial Alzheimer's disease associated with mutations in the presenilin 1 and amyloid precursor protein genes. J Neurol 248:45–50
Wasco W, Pettingell WP, Jondro PD, et al. (1995) Familial Alzheimer's chromosome 14 mutations. Nat Med 1:848
Wisniewski T, Dowjat WK, Buxbaum JD, et al. (1998) A novel Polish presenilin – 1 mutation (P117L) is associated with familial Alzheimer's disease and leads to death as early as the age of 28 years. Neuroreport 9:217–221
Wragg M, Hutton M, Talbot C and the Alzheimer's Disease Collaborative Group (1996) Genetic association between intronic polymorphism in presenilin –1 gene and late –onset Alzheimer's disease. Lancet 347:509–512
Yasuda M, Maeda K, Hashimoto M, et al. (1999) A pedigree with a novel presenilin 1 mutation at a residue that is not conserved in presenilin 2. Arch Neurol 56:65–69
Yasuda M, Maeda K, Ikejiri Y, Kawamata T, Kuroda S, Tanaka C (1997) A novel missense mutation in the presenilin – 1 gene in a familial Alzheimer's disease pedigree with abundant amyloid angiopathy. Neurosci Lett 232:29–32
Yasuda M, Maeda K, Kawamata T, et al. (2000) Novel presenilin –1 mutation with widespread cortical amyloid deposition but limited cerebral amyloid angiopathy. J Neurol Neurosurg Psychiatry 68:220–223
Zekanowski C, Styczynska M, Peplonska B, et al. (2003) Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early –onset Alzheimer's disease in Poland. Exp Neurol 184:991–996
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Larner, A.J., Doran, M. Clinical phenotypic heterogeneity of Alzheimer's disease associated with mutations of the presenilin–1 gene. J Neurol 253, 139–158 (2006). https://doi.org/10.1007/s00415-005-0019-5
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DOI: https://doi.org/10.1007/s00415-005-0019-5