Background/Aims: Late-onset Alzheimer's disease (LOAD) comprises sporadic LOAD and familial LOAD. We wanted to determine whether total plasma homocysteine (Hcy), cardiovascular risk factors and volumetric analyses of cerebral magnetic resonance imaging (MRI) were differently associated with mild cognitive impairment (MCI) in subjects from families with aggregation of LOAD (probable familial LOAD) and MCI in subjects from families without LOAD (probable sporadic LOAD). Methods: A total of 103 subjects with MCI without known stroke or other apparent causative diseases were included as cases together with 58 controls. The cases were stratified into 3 groups according to the number of biological relatives with probable LOAD on one side of the family. Cerebral MRI was obtained from all. The case groups were compared to the control group in sex-specific analyses of covariance. Results: Hcy was significantly elevated in all cases compared to controls, except for women with probable familial LOAD. These women also had significantly smaller hippocampal volume and significantly larger lateral ventricles, unlike the women in the other case groups. Conclusions: Our findings suggest that research on Hcy, cardiovascular risk factors and other potential risk factors for LOAD might benefit from distinguishing between sporadic and familial LOAD.

1.
Bekris LM, Yu C-E, Bird TD, Tsuang DW: Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol 2010;23:213-227.
2.
Nussbaum R, McInnes R, Huntington FW: Thompson and Thompson Genetics in Medicine, ed 7. Philadelphia, Saunders, 2007.
3.
Burns A, O'Brien J, Ames D (eds): Dementia, ed 3. London, Hodder Arnold, 2005.
4.
Reitz C, Brayne C, Mayeux R: Epidemiology of Alzheimer disease. Nat Rev Neurol 2011;7:135-152.
5.
Wijsman EM, Pankratz ND, Choi Y, Rothstein JH, Faber KM, Cheng R, Lee JH, Bird TD, Bennett DA, Diaz-Arrastia R, Goate AM, Farlow M, Ghetti B, Sweet RA, Foroud TM, Mayeux R: Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. PLoS Genet 2011;7:1-19.
6.
Van Duijn CM, Clayton D, Chandra V, Fratiglioni L, Graves AB, Heyman A, Jorm AF, Kokmen E, Kondo K, Mortimer JA, Rocca WA, Shalat SL, Soininen H: Familial aggregation of Alzheimer's disease and related disorders: a collaborative re-analysis of case-control studies. Int J Epidemiol 1991;20:S13-S20.
7.
Mosconi L, Valentina B, Swerdlow RH, Pupi A, Duara R, de Leon M: Maternal transmission of Alzheimer's disease: prodromal metabolic phenotype and the search for genes. Hum Genomics 2010;4:170-193.
8.
Mosconi L, Rinne JO, Tsui WH, Berti V, Li Y, Wang H, Murray J, Scheinin N, Någren K, Williams S, Glodzik L, De Santi S, Vallabhajosula S, de Leon MJ: Increased fibrillar amyloid-β burden in normal individuals with a family history of late-onset Alzheimer's. Proc Nat Acad Sci 2010;107:5949-5954.
9.
Green RC, Cupples LA, Go R, Benke KS, Edeki T, Griffith PA, Williams M, Hipps Y, Graff-Radford N, Bachman D, Farrer LA, MIRAGE Study Group: Risk of dementia among white and African American relatives of patients with Alzheimer disease. JAMA 2002;287:329-336.
10.
Fillit H, Nash DT, Rundek T, Zuckerman A: Cardiovascular risk factors and dementia. Am J Geriatr Pharmacother 2008;6:100-118.
11.
Stampfer MJ: Cardiovascular disease and Alzheimer's disease: common links. J Intern Med 2006;260:211-223.
12.
Ligthart SA, van Charante EPM, Van Gool WA, Richard E: Treatment of cardiovascular risk factors to prevent cognitive decline and dementia: a systematic review. Vasc Health Risk Manag 2010:775-785.
13.
Cheng D, Noble J, Tang MX, Schupf N, Mayeux R, Luchsinger JA: Type 2 diabetes and late-onset Alzheimer's disease. Dement Geriatr Cogn Disord 2011;31:424-430.
14.
Lesser GT, Haroutunian V, Purohit DP, Schnaider Beeri M, Schmeidler J, Honkanen L, Neufeld R, Libow LS: Serum lipids are related to Alzheimer's pathology in nursing home residents. Dement Geriatr Cogn Disord 2009;27:42-49.
15.
Li L, Cao D, Desmond R, Rahman A, Lah JJ, Levey AI, Zamrini E: Cognitive performance and plasma levels of homocysteine, vitamin B12, folate and lipids in patients with Alzheimer disease. Dement Geriatr Cogn Disord 2008;26:384-390.
16.
Solomon A, Kivipelto M, Wolozin B, Zhou J, Whitmer RA: Midlife serum cholesterol and increased risk of Alzheimer's and vascular dementia three decades later. Dement Geriatr Cogn Disord 2009;28:75-80.
17.
Plassman BL, Williams JW, Burke JR, Holsinger T, Benjamin S: Systematic review: factors associated with risk for and possible prevention of cognitive decline in later life. Ann Intern Med 2010;153:182-193.
18.
Ronnemaa E, Zethelius B, Lannfelt L, Kilander L: Vascular risk factors and dementia: 40-year follow-up of a population-based cohort. Dement Geriatr Cogn Disord 2011;31:460-466.
19.
Reitz C, Tang MX, Manly J, Schupf N, Mayeux R, Luchsinger JA: Plasma lipid levels in the elderly are not associated with the risk of mild cognitive impairment. Dement Geriatr Cogn Disord 2008;25:232-237.
20.
Nilsson K, Gustafson L, Hultberg B: Relation between plasma homocysteine and Alzheimer's disease. Dement Geriatr Cogn Disord 2002;14:7-12.
21.
Basso M, Yang J, Warren L, MacAvoy MG, Varma P, Bronen RA, van Dyck CH: Volumetry of amygdala and hippocampus and memory performance in Alzheimer's disease. Psychiatry Res 2006;146:251-261.
22.
Nestor SM, Rupsingh R, Borrie M, Smith M, Accomazzi V, Wells JL, Fogarty J, Bartha R: Ventricular enlargement as a possible measure of Alzheimer's disease progression validated using the Alzheimer's disease neuroimaging initiative database. Brain 2008;131:2443-2454.
23.
den Heijer T, Vermeer SE, Clarke R, Oudkerk M, Koudstaal PJ, Hofman A, Breteler MM: Homocysteine and brain atrophy on MRI of non-demented elderly. Brain 2003;126:170-175.
24.
Cahill L: Why sex matters for neuroscience. Nat Rev Neurosci 2006;7:477-484.
25.
Skup M, Zhu H, Wang Y, Giovanello KS, Lin J, Shen D, Shi F, Gao W, Lin W, Fan Y, Zhang H: Sex differences in grey matter atrophy patterns among AD and aMCI patients: results from ADNI. Neuroimage 2011;56:890-906.
26.
Jacobsen BK, Eggen AE, Mathiesen EB, Wilsgaard T, Njølstad I: Cohort profile: the Tromsø Study. Int J Epidemiol 2011:1-7.
27.
Lezak MD, Howieson DB, Loring DW: Neuropsychological Assessment, ed 4. New York, Oxford University Press, 2004.
28.
Bäckman L, Forsell Y: Episodic memory functioning in a community-based sample of old adults with major depression: utilization of cognitive support. J Abnorm Psychol 1994;103:361-370.
29.
Folstein MF, Folstein SE, McHugh PR: ‘Mini-mental state': a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-198.
30.
Arntzen KA, Schirmer H, Wilsgaard T, Mathiesen EB: Impact of cardiovascular risk factors on cognitive function: the Tromsø Study. Eur J Neurol 2011;18:737-743.
31.
Dierkes J, Luley C, Westphal S: Effect of lipid-lowering and anti-hypertensive drugs on plasma homocysteine levels. Vasc Health Risk Manag 2007;1:99-108.
32.
Refsum H, Smith AD, Ueland PM, Nexo E, Clarke R, McPartlin J, Johnston C, Engbaek F, Schneede J, McPartlin C, Scott JM: Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 2004;50:3-32.
33.
Reitan RM: Validity of the trail making test as an indicator of organic brain damage. Percept Mot Skills 1958:271-276.
34.
Jorm AF: A short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): development and cross-validation. Psychol Med 1994:145-153.
35.
Skjerve A, Nordhus IH, Engedal K, Pallesen S, Brækhus A, Nygaard HA: Seven minute screen performance in a normal elderly sample. Int J Geriatr Psychiatry 2007;22:764-769.
36.
Montgomery S, Asberg M: A new depression scale designed to be sensitive to change. Br J Psychiatry 1979:134:382-389.
37.
Linn MW, Linn BS: The Rapid Disability Rating Scale-2. J Am Geriatr Soc 1982;6:378-382.
38.
McKhann G, Drachman D, Folstein MF, Katzman R, Price D, Stadlan E: 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.
39.
Gauthier S, Reisberg B, Zaudig M, Petersen RC, Ritchie K, Broich K, Belleville S, Brodaty H, Bennett D, Chertkow H, Cummings JL, de Leon M, Feldman H, Ganguli M, Hampel H, Scheltens P, Tierney MC, Whitehouse P, Winblad B: Mild cognitive impairment. Lancet 2006;367:1262-1270.
40.
Florkowski CM, Chew-Harris JS: Methods of estimating GFR - different equations including CKD-EPI. Clin Biochem Rev 2011;32:75-79.
41.
Mangasser-Stephan K, Tag C, Reiser A, Gressner AM: Rapid genotyping of hemochromatosis gene mutations on the LightCycler with fluorescent hybridization probes. Clin Chem 1999;45:1875-1878.
42.
Brewer JB, Magda S, Airriess C, Smith ME: Fully-automated quantification of regional brain volumes for improved detection of focal atrophy in Alzheimer disease. AJNR Am J Neuroradiol 2009;30:578-580.
43.
Kovacevic S, Rafii MS, Brewer JB: High-throughput, fully automated volumetry for prediction of MMSE and CDR decline in mild cognitive impairment. Alzheimer Dis Assoc Disord 2009;23:139-145.
44.
Hooshmand B, Solomon A, Kareholt I, Leiviska J, Rusanen M, Ahtiluoto S, Winblad B, Laatikainen T, Soininen H, Kivipelto M: Homocysteine and holotranscobalamin and the risk of Alzheimer disease: a longitudinal study. Neurology 2010;75:1408-1414.
45.
Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K, Iivonen S, Mannermaa A, Tuomilehto J, Nissinen A, Soininen H: Apolipoprotein E ε4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med 2002;137:149-155.
46.
Gomez-Tortosa E, Barquero MS, Baron M, Sainz MJ, Manzano S, Payno M, Ros R, Almaraz C, Gomez-Garre P, Jimenez-Escrig A: Variability of age at onset in siblings with familial Alzheimer disease. Arch Neurol 2007;64:1743-1748.
47.
Selnes OA, Vinters HV: Vascular cognitive impairment. Nat Clin Pract Neurol 2006;2:538-547.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.