Paternal age is a risk factor for Alzheimer disease in the absence of a major gene

Bertram, Lars; Busch, Raymonde; Spiegl, M.; Lautenschlager, Nicola T.; Müller, Ulrich; Kurz, Alexander

doi:10.1007/s100480050041

Cited by 59 publications

(28 citation statements)

References 27 publications

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“…New mutations may also explain associations between advanced paternal age and some adultonset disorders, including sporadic Alzheimer's disease (26) and cancers of the prostate (27) and the nervous system (28). It has been similarly hypothesized that de novo point mutations play a role in the etiology of schizophrenia (29).…”

Section: Potential Explanationsmentioning

confidence: 99%

Paternal Age and Risk of Schizophrenia in Adult Offspring

Brown

Schaefer²,

Wyatt³

et al. 2002

AJP

165

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Objective-The study examined the relation between paternal age at the time of birth and risk of schizophrenia in the adult offspring.Method-Data from the birth cohort of the Prenatal Determinants of Schizophrenia study were used in this study. Virtually all members of this birth cohort had prospective information about paternal age at the time of the offspring's birth. Subjects with schizophrenia and other schizophrenia spectrum disorders (N=71) among members of this birth cohort were previously ascertained. In separate analyses, paternal age was modeled as a continuous variable and as a categorical variable, and its relation with the risk of adult schizophrenia and other schizophrenia spectrum disorders and with the risk of schizophrenia separately were examined.Results-There was a marginally significant, monotonic association between advancing paternal age and risk of adult schizophrenia and schizophrenia spectrum disorders. The association held after the analysis controlled for the effects of maternal age and other potential con-founders. Similar results were observed when only subjects with schizophrenia were included in the analysis.Conclusions-Advanced paternal age at the time of birth of the offspring may be a risk factor for adult schizophrenia.We sought to investigate whether older paternal age at the time of birth is associated with schizophrenia and other schizophrenia spectrum disorders among the offspring. Several lines of evidence support a relation between older paternal age and schizophrenia spectrum disorders. First, most previous studies that examined this relationship have demonstrated positive associations (1-5), although these studies have been criticized for methodologic limitations. Most recently, Malaspina et al. (1), in a large Israeli birth cohort, demonstrated a robust and "dose-related" effect of paternal age on risk of schizophrenia and related disorders, a finding that was unaltered after adjusting for maternal age.A second reason for examining paternal age in relation to schizophrenia is that older age of the father at the time of birth has been associated with several congenital disorders (6-10). The etiology of these associations is believed to involve new, autosomal dominant mutations in the male germ cell line. If a disruption of fetal development plays a role in the pathogenesis of schizophrenia, then new mutations secondary to advanced paternal age may operate to increase the risk of this disorder by adversely affecting brain development. In the present investigation, we used data from the birth cohort of the Prenatal Determinants of Schizophrenia study (11) to address the relation of paternal age to schizophrenia. We hypothesized that the risk of schizophrenia would increase with advancing paternal age.The Prenatal Determinants of Schizophrenia study had several design advantages that permitted us to address significant limitations of previous studies. First, most prior studies relied on exposure data from a variety of sources, some of questionable reliability. In co...

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Section: Potential Explanationsmentioning

confidence: 99%

Paternal Age and Risk of Schizophrenia in Adult Offspring

Brown

Schaefer²,

Wyatt³

et al. 2002

AJP

165

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“…While the decline in a woman's fertility with age is well studied and the consequences are well documented, it is only recently that issues relating to paternal age have started to be recognized (2). Epidemiologic studies on the effect of paternal age on offspring development have linked increased age with a number of genetic diseases, such as dwarfism, schizophrenia, Alzheimer's disease, cardiac defects, and cancers (3)(4)(5)(6)(7). Furthermore, both clinical studies and animal models show that the quality of spermatozoa and ejaculate change with advancing age, leading to decreased motility, abnormal morphology, decreased semen volume, and altered pregnancy outcome (8 -12).…”

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confidence: 99%

Changes in spermatozoal chromatin packaging and susceptibility to oxidative challenge during aging

Zubkova

Wade

Robaire

2005

Fertility and Sterility

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Objective: Our goal was to test the hypothesis that spermatozoal chromatin packaging changes with age and that aging affects the susceptibility of spermatozoal DNA to oxidative damage. Design: Laboratory study. Setting: Academic facility. Patient(s): Young (4 months) and old (21 months) Brown Norway rats. Intervention(s): Spermatozoa were collected from the cauda epididymidis and were incubated in saline or H 2 O 2 . Main Outcome Measurement(s): Thiols levels, chromatin condensation, DNA susceptibility to acid-induced DNA denaturation, and DNA damage were evaluated using monobromobimane, chromomycin A3 (CMA3), acridine orange, and polymerase chain reaction, respectively. Result(s): Spermatozoa from old rats had 25% fewer disulfides but similar levels of free thiols as compared with young. The CMA3 staining was decreased by 13% with age. Levels of chromatin denaturation and DNA damage were similar in control groups. After exposure to oxidant, free thiols became oxidized by about 20% irrespective of age, but CMA3 staining changed little. The acridine orange assay, however, showed a trend for greater chromatin denaturation in spermatozoa from old rats after oxidant treatment. Furthermore, the DNA from spermatozoa of old rats was significantly more susceptible to developing DNA breaks and modification after oxidative challenge.

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“…Growing evidence indicates that paternal aging is also a risk factor for congenital malformations and genetic disorders (Newcombe and Tavendale, 1965;Savitz et al, 1991;Crow, 2000;Zhu et al, 2008), which may be linked to accumulation of mutations in germ cells of aging parents, perhaps resulting from normal wear and tear as well as exposure to harmful environments over time (Savitz et al, 1991;Yauk et al, 2007;Malik et al, 2008). Moreover, child bearing at a later age is associated with adverse birth outcomes, such as preeclampsia, pre-term birth, stillbirth, low birthweight and child mortality; and predisposition of the offspring to serious health problems such as autism, epilepsy, schizophrenia and Alzheimer's disease (Fretts et al, 1995;Bertram et al, 1998;Abel et al, 2002;Harlap et al, 2002;Byrne et al, 2003;Astolfi et al, 2004Astolfi et al, , 2006Vestergaard et al, 2005;Durkin et al, 2008;Zhu et al, 2008). Advanced maternal age at childbirth has been linked to menstrual disorders and subfecundity in daughters owing to endocrinological irregularities (Smits et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Parental age at childbirth and age of menarche in the offspring

Shrestha¹,

Nøhr

Bech

et al. 2010

Human Reproduction

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background: Early age of menarche (AOM) is associated with serious health problems including breast cancer and heart disease.Rising parental age at childbirth is associated with some adverse health outcomes in the offspring, but whether early menarche is one of them is not known. methods:We studied a Danish cohort of singleton females (n ¼ 3168) born in [1984][1985][1986][1987]. Prenatal data were collected from mothers around 36th week of pregnancy (self-administered questionnaire), although the menarcheal age was collected from daughters aged 17 -21 years in 2005 (Web-based questionnaire). We assessed each parental age association in separate linear regression models adjusted for covariates (socioeconomic status, parity, maternal pre-pregnancy BMI, marital status, maternal smoking and daughter's self-reported BMI), then included both ages in a third model. conclusions: We found no significant association between parental age and AOM, but the small sample of advance aged parents (over 30 years) limits the information we have. Future studies with a larger sample or a sample with over-representation of older parents will be of value.

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Paternal age is a risk factor for Alzheimer disease in the absence of a major gene

Cited by 59 publications

References 27 publications

Paternal Age and Risk of Schizophrenia in Adult Offspring

Paternal Age and Risk of Schizophrenia in Adult Offspring

Changes in spermatozoal chromatin packaging and susceptibility to oxidative challenge during aging

Parental age at childbirth and age of menarche in the offspring

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