There are many active research projects accessing and applying shared ADNI data. Use the search above to find specific research focuses on the active ADNI investigations. This information is requested annually as a requirement for data access.
| Principal Investigator | |
| Principal Investigator's Name: | Liisa Galea |
| Institution: | University of British Columbia |
| Department: | Psychology |
| Country: | |
| Proposed Analysis: | Women are diagnosed with Alzheimer’s disease (AD) more than men [1]. Pregnancy and motherhood exert long-lasting effects on brain health and our research shows that the sensitivity of the female brain to estrogens is altered with past reproductive experience in rodents [2-3]. Menopause is associated with cognitive decline and hormone therapies (HTs) that positively affect cognition depend on estrogen type (estradiol vs estrone) [4]. The current study aims to assess the impact of reproductive experience and HT on longitudinal cognitive change in the context of normal cognitive aging versus AD. The manifestation and progression of AD is related to gonadal hormone levels in men and women, as men with lower levels of testosterone and women with lower levels of estradiol present with poorer cognition and increased incidence of AD [5]. Conversely, HT in menopausal women can reduce the risk of AD and improve cognition but meta-analyses suggest these positive findings depend on type of HT, time since menopause (critical window hypothesis), the healthy status of the women (healthy cell bias hypothesis), and perhaps APOE genotype [6-11]. Importantly, research from our lab show that reproductive experience (pregnancy and motherhood) alters estrogens’ effects on cognitive aging [2-3]. However, few studies have been done in women but collectively those studies suggest that the effects of reproductive experience, like HT, to influence cognitive aging, depends on a number of factors including amount of experience and whether the studies are done across normal aging or with dementia (reviewed in [12]). Indeed, studies that stratify analyses based on diagnosis and risk factors of AD are vital, as both the impacts of HT and reproductive experience depend on whether an individual is at genetic risk for or actively experiencing AD. Neuroinflammation is evident in AD with pro-inflammatory effects contributing to neuronal loss and anti-inflammatory effects via Aβ clearance [13]. Reproductive experience is associated with increased inflammation in women and mice [13-14] and APOE4 genotype is associated with increased pro-inflammatory cytokines [15], suggesting that neuroinflammation may mediate the differential risk of APOE genotypes for AD. Furthermore estradiol is anti-inflammatory [16] but under APOE4 polymorphisms, estradiol’s anti-inflammatory effects are reduced in mice [17]. Thus we hypothesize that neuroinflammation may be a mechanistic link between increasing reproductive experience and risk for AD. Using the ADNI database, we will examine whether reproductive history and HT type interact with APOE status and inflammation (central from cerebrospinal fluid and peripheral from blood) to influence cognitive ability in older women. We will therefore restrict our analyses to only include female participants. We will use Hierarchical Linear Modeling to determine whether parity (number of pregnancies, sex of the child) and HT interact with APOE status to influence cognitive ability (using neuropsychological tests such as ADAS, MMSE, MoCA, Everyday Cognition), volume of the hippocampus (using MRI data), and biomarkers of AD and inflammation in older cognitively healthy, mild cognitively impaired (MCI), and AD women. We hypothesize that reproductive experience and HT use will influence cognitive ability and rates of progression to dementia in postmenopausal women differently depending on APOE4 allele status. We expect that several cognitive domains and hippocampal volume will be influenced by past reproductive experience and HT, with both verbal and visual memory affected positively by previous experience of motherhood in the context of ‘normal’ aging but negatively in the context of APOE4 allele possession or a diagnosis of AD. We anticipate that age of AD onset will be lower among parous women, particularly those with an APOE4 allele. Finally, we predict that biomarkers of AD progression (CSF levels of Aβ, tau, and p-tau) and inflammation (central and peripheral) will similarly show an interaction between reproductive experience, HT use, and APOE allele status such that progression of AD pathology will be more aggressive in parous women with an APOE4 allele. It is becoming increasingly clear that tailored treatment based on genetics and possibly reproductive history need to be developed to best treat individuals. Very little work has been done to characterize the aging female brain, and there is a shocking lack of studies on the effects of pregnancy and motherhood on the aging brain. The effects of pregnancy and motherhood on AD will become increasingly important as the population continues to age, as both dementia rates and the number of nulliparous women will continue to increase in the coming years. Key References [1] Gao S et al. The Relationships Between Age, Sex, and the Incidence of Dementia and Alzheimer Disease: A Meta-analysis. Arch Gen Psychiat.1998;55:809. [2] Barha CK et al. Motherhood alters the cellular response to estrogens in the hippocampus later in life. Neurobiol Aging. 2011;32:2091. [3] Barha CK et al. Multiparity-induced enhancement of hippocampal neurogenesis and spatial memory depends on ovarian hormone status in middle age. Neurobiol Aging. 2015;36:2391. [4] Hogervorst E et al. Hormone replacement therapy to maintain cognitive function in women with dementia. Cochrane Data Syst Rev. 2009;21:CD003799. [5] Pike CJ et al. Protective actions of sex steroid hormones in Alzheimer's disease. Front Neuroendocrinol. 2009;30:239-58. [6] Hogervorst E et al. The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis. Neurosci. 2000;101:485. [7] Ryan J et al. Hormonal treatment, mild cognitive impairment and AD. Int Psychogeriat 2008;20:47. [8] Shumaker SA et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a RCT. JAMA 2003;289:2651. [9] Shumaker SA et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a RCT. JAMA 2003;289:2651. [10] Brinton RD. The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications. Trends Neurosci. 2008; 31:529. [11] Burkhardt MS et al. Oestrogen replacement therapy may improve memory functioning in the absence of APOE epsilon4. J Alzheimers Dis. 2004;6:221. [12] Roes, M.M., Galea, L.A.M., 2015. The maternal brain: short and long-term effects of reproductive experience on hippocampus structure and function in adulthood. In: Shansky, R., J.Johnson (Eds.), Sex Differences in the Central Nervous System. Elsevier. [13] Latta CH et al. Neuroinflammation in Alzheimer's disease; A source of heterogeneity and target for personalized therapy. Neurosci.2015;302:103. [14] Chollet-Hinton LS et al. Temporal trends in the inflammatory cytokine profile of human breastmilk. Breastfeed Med.2014;9:530. [15] Rodriguez GA et al. Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition. J Neuroinflam. 2014;11:111. [16] Habib P et al. Regulation of hypoxia-induced inflammatory responses and M1-M2 phenotype switch of primary rat microglia by sex steroids. J Mol Neurosci.2014;52:277 [17] Brown CM et al. The APOE4 genotype alters the response of microglia and macrophages to 17β-estradiol. Neurobiol Aging. 2008;29:1783 |
| Additional Investigators | |
| Investigator's Name: | Paula Duarte-Guterman |
| Proposed Analysis: | Women are diagnosed with Alzheimer’s disease (AD) more than men [1]. Pregnancy and motherhood exert long-lasting effects on brain health and our research shows that the sensitivity of the female brain to estrogens is altered with past reproductive experience in rodents [2-3]. Menopause is associated with cognitive decline and hormone therapies (HTs) that positively affect cognition depend on estrogen type (estradiol vs estrone) [4]. The current study aims to assess the impact of reproductive experience and HT on longitudinal cognitive change in the context of normal cognitive aging versus AD. The manifestation and progression of AD is related to gonadal hormone levels in men and women, as men with lower levels of testosterone and women with lower levels of estradiol present with poorer cognition and increased incidence of AD [5]. Conversely, HT in menopausal women can reduce the risk of AD and improve cognition but meta-analyses suggest these positive findings depend on type of HT, time since menopause (critical window hypothesis), the healthy status of the women (healthy cell bias hypothesis), and perhaps APOE genotype [6-11]. Importantly, research from our lab show that reproductive experience (pregnancy and motherhood) alters estrogens’ effects on cognitive aging [2-3]. However, few studies have been done in women but collectively those studies suggest that the effects of reproductive experience, like HT, to influence cognitive aging, depends on a number of factors including amount of experience and whether the studies are done across normal aging or with dementia (reviewed in [12]). Indeed, studies that stratify analyses based on diagnosis and risk factors of AD are vital, as both the impacts of HT and reproductive experience depend on whether an individual is at genetic risk for or actively experiencing AD. Neuroinflammation is evident in AD with pro-inflammatory effects contributing to neuronal loss and anti-inflammatory effects via Aβ clearance [13]. Reproductive experience is associated with increased inflammation in women and mice [13-14] and APOE4 genotype is associated with increased pro-inflammatory cytokines [15], suggesting that neuroinflammation may mediate the differential risk of APOE genotypes for AD. Furthermore estradiol is anti-inflammatory [16] but under APOE4 polymorphisms, estradiol’s anti-inflammatory effects are reduced in mice [17]. Thus we hypothesize that neuroinflammation may be a mechanistic link between increasing reproductive experience and risk for AD. Using the ADNI database, we will examine whether reproductive history and HT type interact with APOE status and inflammation (central from cerebrospinal fluid and peripheral from blood) to influence cognitive ability in older women. We will therefore restrict our analyses to only include female participants. We will use Hierarchical Linear Modeling to determine whether parity (number of pregnancies, sex of the child) and HT interact with APOE status to influence cognitive ability (using neuropsychological tests such as ADAS, MMSE, MoCA, Everyday Cognition), volume of the hippocampus (using MRI data), and biomarkers of AD and inflammation in older cognitively healthy, mild cognitively impaired (MCI), and AD women. We hypothesize that reproductive experience and HT use will influence cognitive ability and rates of progression to dementia in postmenopausal women differently depending on APOE4 allele status. We expect that several cognitive domains and hippocampal volume will be influenced by past reproductive experience and HT, with both verbal and visual memory affected positively by previous experience of motherhood in the context of ‘normal’ aging but negatively in the context of APOE4 allele possession or a diagnosis of AD. We anticipate that age of AD onset will be lower among parous women, particularly those with an APOE4 allele. Finally, we predict that biomarkers of AD progression (CSF levels of Aβ, tau, and p-tau) and inflammation (central and peripheral) will similarly show an interaction between reproductive experience, HT use, and APOE allele status such that progression of AD pathology will be more aggressive in parous women with an APOE4 allele. It is becoming increasingly clear that tailored treatment based on genetics and possibly reproductive history need to be developed to best treat individuals. Very little work has been done to characterize the aging female brain, and there is a shocking lack of studies on the effects of pregnancy and motherhood on the aging brain. The effects of pregnancy and motherhood on AD will become increasingly important as the population continues to age, as both dementia rates and the number of nulliparous women will continue to increase in the coming years. Key References [1] Gao S et al. The Relationships Between Age, Sex, and the Incidence of Dementia and Alzheimer Disease: A Meta-analysis. Arch Gen Psychiat.1998;55:809. [2] Barha CK et al. Motherhood alters the cellular response to estrogens in the hippocampus later in life. Neurobiol Aging. 2011;32:2091. [3] Barha CK et al. Multiparity-induced enhancement of hippocampal neurogenesis and spatial memory depends on ovarian hormone status in middle age. Neurobiol Aging. 2015;36:2391. [4] Hogervorst E et al. Hormone replacement therapy to maintain cognitive function in women with dementia. Cochrane Data Syst Rev. 2009;21:CD003799. [5] Pike CJ et al. Protective actions of sex steroid hormones in Alzheimer's disease. Front Neuroendocrinol. 2009;30:239-58. [6] Hogervorst E et al. The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis. Neurosci. 2000;101:485. [7] Ryan J et al. Hormonal treatment, mild cognitive impairment and AD. Int Psychogeriat 2008;20:47. [8] Shumaker SA et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a RCT. JAMA 2003;289:2651. [9] Shumaker SA et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a RCT. JAMA 2003;289:2651. [10] Brinton RD. The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications. Trends Neurosci. 2008; 31:529. [11] Burkhardt MS et al. Oestrogen replacement therapy may improve memory functioning in the absence of APOE epsilon4. J Alzheimers Dis. 2004;6:221. [12] Roes, M.M., Galea, L.A.M., 2015. The maternal brain: short and long-term effects of reproductive experience on hippocampus structure and function in adulthood. In: Shansky, R., J.Johnson (Eds.), Sex Differences in the Central Nervous System. Elsevier. [13] Latta CH et al. Neuroinflammation in Alzheimer's disease; A source of heterogeneity and target for personalized therapy. Neurosci.2015;302:103. [14] Chollet-Hinton LS et al. Temporal trends in the inflammatory cytokine profile of human breastmilk. Breastfeed Med.2014;9:530. [15] Rodriguez GA et al. Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition. J Neuroinflam. 2014;11:111. [16] Habib P et al. Regulation of hypoxia-induced inflammatory responses and M1-M2 phenotype switch of primary rat microglia by sex steroids. J Mol Neurosci.2014;52:277 [17] Brown CM et al. The APOE4 genotype alters the response of microglia and macrophages to 17β-estradiol. Neurobiol Aging. 2008;29:1783 |
| Investigator's Name: | Wendy Robinson |
| Proposed Analysis: | Examining sex differences with diagnosis in changes to the epigenetic clock |
