Maternal age affects brain metabolism in adult children of mothers affected by Alzheimer's disease

Abstract

Cognitively normal (NL) individuals with a maternal history of late-onset Alzheimer's disease (MH) show reduced brain glucose metabolism on FDG-PET as compared to those with a paternal history (PH) and those with negative family history (NH) of Alzheimer's disease (AD). This FDG-PET study investigates whether metabolic deficits in NL MH are associated with advancing maternal age at birth. Ninety-six NL individuals with FDG-PET were examined, including 36 MH, 24 PH, and 36 NH. Regional-to-whole brain gray matter standardized FDG uptake value ratios were examined for associations with parental age across groups using automated regions-of-interest and statistical parametric mapping. Groups were comparable for clinical and neuropsychological measures. Brain metabolism in AD-vulnerable regions was lower in MH compared to NH and PH, and negatively correlated with maternal age at birth only in MH. There were no associations between paternal age and metabolism in any group. Evidence for a maternally inherited, maternal age-related mechanism provides further insight on risk factors and genetic transmission in late-onset AD.

Introduction

After advanced age, having a first-degree family history of late onset Alzheimer's disease (LOAD) is a major risk factor for developing the disease among cognitively normal (NL) individuals. While the rare early-onset forms of AD have autosomal dominant genetic inheritance, the genetics of LOAD remain elusive. Evidence for genetic transmission in LOAD comes from the familial aggregation of many cases. Risk is 4 to 10 times increased when a parent is affected (Farrer et al., 1989, Green et al., 2002).

Among adult children of parents with LOAD, those with a maternal history (MH, i.e., only the mother is affected) present with progressive reductions of brain glucose metabolism on 2-[^18PF] fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) compared to those with a paternal history (PH, i.e., only the father is affected) and to those with negative family history (NH, i.e., neither parent is affected) (Mosconi et al., 2007, Mosconi et al., 2009). Moreover, NL MH showed increased fibrillar amyloid-beta (Aβ) depositions on N-methyl-[¹¹C] 2-(4′-methylaminophenyl)-6-hydroxybenzothiazole (PiB)-PET, a major hallmark of Alzheimer's disease pathology, compared to PH and NH (Mosconi et al., 2010b). These data indicate that as yet unidentified, maternally transmitted factors influence brain pathophysiology in the offspring of LOAD-mothers, leading to altered glucose and Aβ metabolism years before symptoms might arise (Mosconi et al., 2010a).

Among several possible mechanisms involved in maternal transmission of LOAD (Mosconi et al., 2010a), advanced maternal age at birth has been investigated as a possible risk factor. In humans, as in other mammals, female fertility and oocyte quality diminish with age (Navot et al., 1991). Advanced maternal age at birth has been associated with a variety of conditions, ranging from increased risk for stillbirths and congenital malformations to dyslexia, as well as with some neurological disorders (Heffner, 2004). There is a well-established increase in aneuploidy with increasing maternal age (Heffner, 2004), a typical example of which is Down's syndrome (DS). DS is caused by trisomy of chromosome 21 which is most frequently due to chromosomal non-disjunction during maternal meiosis with advanced maternal age (Yoon et al., 1996). In the 1980s, clinical and pathological similarities were recognized between DS and AD (Masters et al., 1985), as both diseases are associated with increased accumulation of brain Aβ followed by dementia (Masters et al., 1985). In DS, this is due to the fact that chromosome 21 contains the amyloid precursor protein (APP) gene, and as such individuals carrying 3 copies of the chromosome show increased brain Aβ accumulation over time (Masters et al., 1985). According to a popular theoretical model in AD, the “amyloid cascade hypothesis”, Aβ dysmetabolism is a primary event in the pathogenesis of AD (Hardy and Selkoe, 2002). Despite genetic differences between AD and DS, the clinico-pathologic similarities have led investigators to examine late maternal age as a risk factor for AD, especially for the late-onset forms of AD which are likely due to a complex interaction of genetic and non-genetic factors (Hardy and Selkoe, 2002).

Some epidemiological studies in AD patients provided evidence for an association between maternal age and risk for AD (Amaducci et al., 1986, Cohen et al., 1982, Urakami et al., 1989, Whalley et al., 1982), while others did not (Bertram et al., 1998, Farrer et al., 1991, Hofman et al., 1990). A re-analysis of existing data sets showed that, across all studies, late maternal age at birth increases risk of developing AD, particularly for late-onset AD patients (Rocca et al., 1991). However, these studies did not take into account the patient's family history and did not examine parental age at birth as a risk factor for NL individuals. Moreover, there are no studies that examined the relationship between parental age and biological markers of AD.

This FDG-PET study examined the associations between maternal and paternal age at birth and brain glucose metabolism in NL individuals as a function of the subject's family history of LOAD.