Oxidative stress and amyloid-beta pathology in normal individuals with a maternal history of Alzheimer's.
BACKGROUND
Epidemiology and imaging studies showed that cognitively normal (NL) individuals with a maternal history (MH) of late-onset Alzheimer's disease (LOAD) might be at increased risk for Alzheimer's disease (AD) compared with NL with a paternal history (PH) and NL with a negative family history of LOAD (NH). With a panel of cerebrospinal fluid (CSF) markers, this study examined whether NL MH showed evidence for AD pathology compared with PH and NH.


METHODS
Fifty-nine 40-80-year-old NL subjects were examined, including 23 MH and 14 PH whose parents had a clinician-certified diagnosis of LOAD and 22 NH. All subjects completed clinical neuropsychological examinations and a lumbar puncture to measure CSF levels of amyloid-beta (Aβ(40), Aβ(42), Aβ(42/40)), total and hyperphosphorylated tau (T-Tau and P-Tau(231); markers of axonal degeneration and neurofibrillary tangles, respectively), and F₂-isoprostanes (IsoP) (a marker of oxidative stress).


RESULTS
Groups were comparable for demographic and neuropsychological measures. The MH subjects showed higher IsoP and reduced Aβ(42/40) CSF levels compared with NH and with PH (p values ≤ .05), whereas no differences were found between NH and PH. No group differences were found for P-Tau(231) and T-Tau. The IsoP and Aβ(42/40) levels were correlated only within the MH group (R² = .32, p = .005) and discriminated MH from the other subjects with 70% accuracy (relative risk = 3.7%, 95% confidence interval = 1.6-9.7, p < .001). Results remained significant controlling for age, gender, education, and apolipoprotein E genotype.


CONCLUSIONS
Adult children of LOAD-affected mothers express a pathobiological phenotype characterized by Aβ-associated oxidative stress consistent with AD, which might reflect increased risk for developing the disease.
Mosconi
Lisa
L
Center for Brain Health, Department of Psychiatry, New York University School of Medicine, New York, New York 10016, USA. lisa.mosconi@nyumc.org
Glodzik
Lidia
L
Mistur
Rachel
R
McHugh
Pauline
P
Rich
Kenneth E
KE
Javier
Elizabeth
E
Williams
Schantel
S
Pirraglia
Elizabeth
E
De Santi
Susan
S
Mehta
Pankaj D
PD
Zinkowski
Raymond
R
Blennow
Kaj
K
Pratico
Domenico
D
de Leon
Mony J
MJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D028441:F2-Isoprostanes / Q000134:cerebrospinal fluid; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009035:Mothers; D018384:Oxidative Stress; D016875:tau Proteins / Q000134:cerebrospinal fluid
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D028441:F2-Isoprostanes; D016875:tau Proteins
Lancet Neurol. 2006 Mar;5(3):228-34
16488378
Ann Neurol. 2000 Nov;48(5):809-12
11079549
J Nucl Med. 2006 Nov;47(11):1778-86
17079810
Ann Neurol. 1989 May;25(5):485-93
2774490
Arch Neurol. 2002 Aug;59(8):1267-72
12164722
AJNR Am J Neuroradiol. 1986 Jul-Aug;7(4):567-70
3088934
J Neurol Neurosurg Psychiatry. 2007 May;78(5):461-4
17098843
Arch Gen Psychiatry. 2005 May;62(5):565-73
15867110
Neurology. 1997 Oct;49(4):918-25
9339668
Arch Neurol. 2007 Mar;64(3):343-9
17210801
Science. 1990 Oct 12;250(4978):279-82
2218531
Mitochondrion. 2006 Dec;6(6):323-30
17123871
Arch Neurol. 2007 Dec;64(12):1743-8
18071037
J Neurochem. 1994 Dec;63(6):2179-84
7964738
Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19067-72
18003925
Dement Geriatr Cogn Disord. 2007;23(5):316-20
17374949
J Neurochem. 2004 Jun;89(6):1417-26
15189344
Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10966-71
11526211
Am J Physiol. 1996 Nov;271(5 Pt 1):C1424-37
8944624
Nat Rev Neurol. 2010 Mar;6(3):131-44
20157306
Ann Neurol. 2010 Jan;67(1):122-31
20186853
Neurobiol Aging. 2009 May;30(5):682-90
17889968
Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10726-31
15247418
J Neurosci. 2001 May 1;21(9):3017-23
11312286
Science. 2002 Jul 19;297(5580):353-6
12130773
J Neurosci. 2001 Jul 1;21(13):4923-30
11425920
Neurology. 2009 Dec 15;73(24):2071-8
20007524
Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13381-6
10557329
Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12
17245412
Lancet. 1974 Jul 27;2(7874):207-10
4135618
Am J Pathol. 2001 Jan;158(1):293-7
11141503
JAMA. 2009 Jul 22;302(4):385-93
19622817
Neuropsychology. 2008 Jul;22(4):469-84
18590359
Biol Psychiatry. 2000 Feb 1;47(3):183-99
10682216
J Neurosci. 2007 Jun 6;27(23):6174-84
17553989
Biol Psychiatry. 2008 Mar 15;63(6):609-18
17720148
Exp Neurol. 2000 Mar;162(1):37-50
10716887
Neurobiol Aging. 2004 Mar;25(3):273-81
15123331
Neurology. 1994 Jun;44(6):1086-90
8208406
Neurology. 2009 Feb 10;72(6):513-20
19005175
Hum Genomics. 2010 Feb;4(3):170-93
20368139
Neurology. 2008 Jul 8;71(2):85-92
18509095
Neurosci Lett. 2000 Jun 30;287(3):187-90
10863026
Neurobiol Aging. 2002 May-Jun;23(3):371-6
11959398
Neurobiol Aging. 2008 May;29(5):676-92
17222480
Cell. 1994 Jun 17;77(6):817-27
8004671
Nature. 2006 Oct 19;443(7113):787-95
17051205
Am J Med Genet. 1999 Aug 20;88(4):378-82
10402505
Nature. 2009 Feb 19;457(7232):981-9
19225519
Neurology. 2006 Aug 8;67(3):446-52
16894106
Lancet. 2006 Jul 29;368(9533):387-403
16876668
Am J Psychiatry. 1982 Sep;139(9):1136-9
7114305
Arch Neurol. 2000 Jan;57(1):100-5
10634455
Neurology. 1984 Jul;34(7):939-44
6610841
Neurology. 1996 Jul;47(1):254-6
8710088
Lancet Neurol. 2010 Jan;9(1):119-28
20083042
Arch Neurol. 2002 Nov;59(11):1737-46
12433261
Neurobiol Aging. 2004 Jan;25(1):105-10
14675736
Ann Neurol. 2000 Aug;48(2):148-55
10939564
Trends Neurosci. 1989 Mar;12(3):94-101
2469224
Lancet Neurol. 2008 Aug;7(8):668-70
18635012
Arch Neurol. 1994 Sep;51(9):901-6
8080390
Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5949-54
20231448
JAMA. 2002 Jan 16;287(3):329-36
11790212