General Information:

Id: 7,322
Diseases: Alzheimer disease - [OMIM]
Mammalia
review
Reference: Mielke MM et al.(2014) Clinical epidemiology of Alzheimers disease: assessing sex and gender differences Clin Epidemiol 6: 37-48 [PMID: 24470773]

Interaction Information:

Comment The prevalence of AD is significantly higher in women compared to men. Recent estimates suggest that almost two-thirds of the individuals diagnosed with AD are women. A reason for the higher prevalence among women may be that they live longer, on average, than men. From European and Asian populations have also observed a higher incidence in women after the age of 80–85 years. In contrast to these studies, the Cache County Study, did report a higher incidence of AD in men than women until age 78, after which women had a higher incidence than men.
Formal Description
Interaction-ID: 71909

phenotype

sex, female

increases_activity of

a higher prevalence of AD in women is suggested.
Comment Some studies suggest a higher prevalence of mild cognitive impairment (MCI) in men, while others suggest either a higher prevalence in women or no sex difference. In general, women have a higher incidence of MCI at older ages. Men consistently have a higher incidence of the non-amnestic type of MCI.
Formal Description
Interaction-ID: 71916

phenotype

sex, male

increases_activity of

phenotype

mild cognitive impairment

a higher prevalence of MCI in men is suggested.
Comment The risk of dementia is higher in persons with MCI compared to cognitively normal individuals.
Formal Description
Interaction-ID: 71917

phenotype

mild cognitive impairment

increases_activity of

disease

Dementia

Comment Incidence studies examining sex differences in AD are equivocal. The majority of studies conducted in the US have not observed sex differences in the rates of developing AD.
Formal Description
Interaction-ID: 71919

phenotype

sex

NOT affects_activity of

The majority of studies conducted in the US have not observed sex differences concerning developing AD.
Comment Men consistently have a higher incidence of the non-amnestic type of MCI. While amnestic MCI is considered prodromal for AD, non-amnestic MCI is considered prodromal for non-AD dementias, such as vascular dementia.
Formal Description
Interaction-ID: 71923

phenotype

mild cognitive impairment, non-amnestic

increases_activity of

disease

Dementia, non-AD

a higher prevalence of non-amnestic MCI is found in men.
Comment Non-amnestic MCI is considered prodromal for non-AD dementias, such as vascular dementia.
Formal Description
Interaction-ID: 71924

phenotype

mild cognitive impairment, amnestic

increases_activity of

Comment Men consistently have a higher incidence of the non-amnestic type of MCI. While amnestic MCI is considered prodromal for AD, non-amnestic MCI is considered prodromal for non-AD dementias, such as vascular dementia.
Formal Description
Interaction-ID: 71935

phenotype

mild cognitive impairment, non-amnestic

increases_activity of

disease

Vascular dementia

Comment Men consistently have a higher incidence of the non-amnestic type of MCI. While amnestic MCI is considered prodromal for AD, non-amnestic MCI is considered prodromal for non-AD dementias, such as vascular dementia.
Formal Description
Interaction-ID: 71936

phenotype

sex, male

increases_activity of

phenotype

mild cognitive impairment, non-amnestic

Comment The most striking difference between the brain anatomy of men and women is the larger head size and cerebral brain volume in men (about 10%).
Formal Description
Interaction-ID: 71937

phenotype

sex, male

increases_activity of

phenotype

increased head size

Comment The most striking difference between the brain anatomy of men and women is the larger head size and cerebral brain volume in men (about 10%).
Formal Description
Interaction-ID: 71938

phenotype

sex, male

increases_activity of

phenotype

increased cerebral brain volume

Comment In patients with MCI and AD, brain volumes have been found to decline faster in women than men, supporting the evidence of faster progression of women from MCI to AD.
Formal Description
Interaction-ID: 71939

phenotype

sex, female

increases_activity of

phenotype

brain volume decline

in AD women; compared to AD men, brain volumes decline faster
Comment Women typically have a higher percentage of grey matter in several brain regions, whereas men have a higher percentage of white matter.
Formal Description
Interaction-ID: 71941

phenotype

sex, male

increases_quantity of

tissue/cell line

cerebral white matter

in men; a higher percentage of white matter is found
Comment Women typically have a higher percentage of grey matter in several brain regions, whereas men have a higher percentage of white matter.
Formal Description
Interaction-ID: 71942

phenotype

sex, female

increases_quantity of

tissue/cell line

cerebral gray matter

in women; a higher percentage of grey matter in several brain regions is found
Comment Men have more pronounced cerebral metabolic deficits compared to women at the same level of cognitive impairment, suggesting that the greater brain reserve in men may be helping them withstand more pathology than women at the same level of dementia severity.
Formal Description
Interaction-ID: 71943

phenotype

sex

affects_activity of

phenotype

cerebral metabolic deficits

Comment The E4 allele of the apolipoprotein E (APOE) gene is the strongest known genetic risk factor for late-onset AD. Compared to non-carriers, heterozygous carriers of one E4 allele are 3–4 times more likely to develop AD, whereas the risk for homozygous carriers is even higher. The APOE E4 allele is specifically associated with an earlier age of onset of AD.
Formal Description
Interaction-ID: 71967

gene/protein mutant

APOE (isoform E4)

increases_activity of

Comment The effects of the E4 genotype are more pronounced in women than in men. Three studies reported that women with one E4 allele had about a four-fold risk of AD, whereas men with one E4 allele showed little increased risk.
Formal Description
Interaction-ID: 71968

phenotype

sex, female

increases_activity of

gene/protein mutant

APOE (isoform E4)

concerning AD in women
Comment The APOE E4 allele has a greater deleterious effect on hippocampal pathology, functional connectivity changes in the default mode network, cortical thickness, and memory performance in women compared with men at different stages of AD.
Formal Description
Interaction-ID: 71969

gene/protein mutant

APOE (isoform E4)

decreases_activity of

tissue/cell line

hippocampus

depending on sex: worse in women compared with men at different stages of AD.
Comment The APOE E4 allele has a greater deleterious effect on hippocampal pathology, functional connectivity changes in the default mode network, cortical thickness, and memory performance in women compared with men at different stages of AD.
Formal Description
Interaction-ID: 71970

gene/protein mutant

APOE (isoform E4)

affects_activity of

tissue/cell line

brain

Comment The APOE E4 allele has a greater deleterious effect on hippocampal pathology, functional connectivity changes in the default mode network, cortical thickness, and memory performance in women compared with men at different stages of AD.
Formal Description
Interaction-ID: 71971

gene/protein mutant

APOE (isoform E4)

decreases_activity of

process

memory

depending on sex: worse in women compared with men at different stages of AD.
Comment A large autopsy study found that amyloid plaque and neurofibrillary tangle pathology was greatest among women who were E4 carriers.
Formal Description
Interaction-ID: 71972

gene/protein mutant

APOE (isoform E4)

increases_quantity of

especially in women who were E4 carriers.
Comment A large autopsy study found that amyloid plaque and neurofibrillary tangle pathology was greatest among women who were E4 carriers.
Formal Description
Interaction-ID: 71973

gene/protein mutant

APOE (isoform E4)

increases_quantity of

especially in women who were E4 carriers.
Comment A large study consisting of 16 research centers worldwide (including 4,711 patients and 4,537 controls) reported that the Met66 allele of Brain Derived Neurotrophic Factor (BDNF) gene, which reduces the transport of BDNF, is associated with an increased risk of AD in women (odds ratio =1.14, 95% confidence interval 1.05–1.24, P=0.002), but not in men. This finding is biologically plausible since estrogen plays an important role in the expression of BDNF. Post-menopausal women with the MET66 allele would therefore have both reduced transport and expression of BDNF, thus causing an increased risk of AD.
Formal Description
Interaction-ID: 71974

gene/protein mutant

BDNF-p.V66M

increases_activity of

in women, but not in men.
Comment SNPs found to pose a risk of AD among men, but not women, include a SNP (rs688) of the low-density lipoprotein receptor and functional apolipoprotein E receptor, the rs17571 SNP of the lysosomal protease cathepsin D, SOS2 (involved in signal transduction pathways, including insulin signaling), and PCK1 (catalyzes the first step in hepatic gluconeogenesis).
Formal Description
Interaction-ID: 71975

increases_activity of

in men, but not in women.
Comment SNPs found to pose a risk of AD among men, but not women, include a SNP (rs688) of the low-density lipoprotein receptor and functional apolipoprotein E receptor, the rs17571 SNP of the lysosomal protease cathepsin D, SOS2 (involved in signal transduction pathways, including insulin signaling), and PCK1 (catalyzes the first step in hepatic gluconeogenesis).
Formal Description
Interaction-ID: 71976

increases_activity of

in men, but not in women.
Comment SNPs found to pose a risk of AD among men, but not women, include a SNP (rs688) of the low-density lipoprotein receptor and functional apolipoprotein E receptor, the rs17571 SNP of the lysosomal protease cathepsin D, SOS2 (involved in signal transduction pathways, including insulin signaling), and PCK1 (catalyzes the first step in hepatic gluconeogenesis).
Formal Description
Interaction-ID: 71977

gene/protein mutant

SOS2-mut

increases_activity of

in men, but not in women.
Comment SNPs found to pose a risk of AD among men, but not women, include a SNP (rs688) of the low-density lipoprotein receptor and functional apolipoprotein E receptor, the rs17571 SNP of the lysosomal protease cathepsin D, SOS2 (involved in signal transduction pathways, including insulin signaling), and PCK1 (catalyzes the first step in hepatic gluconeogenesis).
Formal Description
Interaction-ID: 71978

gene/protein mutant

PCK1-mut

increases_activity of

in men, but not in women.
Comment A diabetes-related gene, the G allele of NSP65 of the peroxisome proliferators-activated receptors gamma was associated with a significantly increased odds of AD in men, but a reduced odds in women.
Formal Description
Interaction-ID: 71979

gene/protein mutant

PPARG-p.P12A

affects_activity of

significantly increased in men, but reduced in women
Comment The 219K allele of the ATP Binding Cassette Transporter 1 (ABCA1) gene had a 1.75-fold increased risk of developing AD in women, but was found to be protective in men.
Formal Description
Interaction-ID: 71980

gene/protein mutant

ABCA1-p.R219K

increases_activity of

in women, but protective in men
Comment A large study consisting of 16 research centers worldwide (including 4,711 patients and 4,537 controls) reported that the Met66 allele of Brain Derived Neurotrophic Factor (BDNF) gene, which reduces the transport of BDNF, is associated with an increased risk of AD in women (odds ratio =1.14, 95% confidence interval 1.05–1.24, P=0.002), but not in men. This finding is biologically plausible since estrogen plays an important role in the expression of BDNF. Post-menopausal women with the MET66 allele would therefore have both reduced transport and expression of BDNF, thus causing an increased risk of AD.
Formal Description
Interaction-ID: 71981

phenotype

sex, female

increases_activity of

gene/protein mutant

BDNF-p.V66M

increased risk of AD in women but not in men.
Comment SNPs found to pose a risk of AD among men, but not women, include a SNP (rs688) of the low-density lipoprotein receptor and functional apolipoprotein E receptor, the rs17571 SNP of the lysosomal protease cathepsin D, SOS2 (involved in signal transduction pathways, including insulin signaling), and PCK1 (catalyzes the first step in hepatic gluconeogenesis).
Formal Description
Interaction-ID: 71982

phenotype

sex, male

increases_activity of

increased risk of AD in men but not in women.
Comment SNPs found to pose a risk of AD among men, but not women, include a SNP (rs688) of the low-density lipoprotein receptor and functional apolipoprotein E receptor, the rs17571 SNP of the lysosomal protease cathepsin D, SOS2 (involved in signal transduction pathways, including insulin signaling), and PCK1 (catalyzes the first step in hepatic gluconeogenesis).
Formal Description
Interaction-ID: 71983

phenotype

sex, male

increases_activity of

increased risk of AD in men but not in women.
Comment SNPs found to pose a risk of AD among men, but not women, include a SNP (rs688) of the low-density lipoprotein receptor and functional apolipoprotein E receptor, the rs17571 SNP of the lysosomal protease cathepsin D, SOS2 (involved in signal transduction pathways, including insulin signaling), and PCK1 (catalyzes the first step in hepatic gluconeogenesis).
Formal Description
Interaction-ID: 71984

phenotype

sex, male

increases_activity of

gene/protein mutant

SOS2-mut

increased risk of AD in men but not in women.
Comment SNPs found to pose a risk of AD among men, but not women, include a SNP (rs688) of the low-density lipoprotein receptor and functional apolipoprotein E receptor, the rs17571 SNP of the lysosomal protease cathepsin D, SOS2 (involved in signal transduction pathways, including insulin signaling), and PCK1 (catalyzes the first step in hepatic gluconeogenesis).
Formal Description
Interaction-ID: 71985

phenotype

sex, male

increases_activity of

gene/protein mutant

PCK1-mut

increased risk of AD in men but not in women.
Comment A diabetes-related gene, the G allele of NSP65 of the peroxisome proliferators-activated receptors gamma was associated with a significantly increased odds of AD in men, but a reduced odds in women.
Formal Description
Interaction-ID: 71986

phenotype

sex

affects_activity of

gene/protein mutant

PPARG-p.P12A

significantly increased risk of AD in men, but reduced in women.
Comment The 219K allele of the ATP Binding Cassette Transporter 1 (ABCA1) gene had a 1.75-fold increased risk of developing AD in women, but was found to be protective in men.
Formal Description
Interaction-ID: 71987

phenotype

sex

affects_activity of

gene/protein mutant

ABCA1-p.R219K

increased risk of AD in women, but protective in men.
Comment sex and gender.
Formal Description
Interaction-ID: 71988

phenotype

sex

cooccurs with

phenotype

sex, female

Comment sex and gender.
Formal Description
Interaction-ID: 71989

phenotype

sex

cooccurs with

phenotype

sex, male

Comment Following menopause, women experience relatively rapid loss of the ovarian sex hormones 17 beta-estradiol and progesterone.
Formal Description
Interaction-ID: 71996

process

menopause

decreases_quantity of

drug/chemical compound

Progesterone

Drugbank entries Show/Hide entries for
Comment Following menopause, women experience relatively rapid loss of the ovarian sex hormones 17 beta-estradiol and progesterone.
Formal Description
Interaction-ID: 71997

process

menopause

decreases_quantity of

drug/chemical compound

Estradiol

Drugbank entries Show/Hide entries for
Comment Animal and cellular models have consistently shown the neuroprotective effects of estrogen which include: improving synapse formation on hippocampal dendritic spines, maintaining hippocampal function during aging; improving cerebral blood flow and glucose metabolism, increasing choline acetyltransferase activity in the basal forebrain and hippocampus (choline acetyltransferase is involved in the synthesis of acetylcholine, a neurotransmitter reduced in AD and implicated in memory function), reducing the aggregation of amyloid-beta and associated neurotoxicity, and preventing mitochondrial damage.
Formal Description
Interaction-ID: 71998

drug/chemical compound

Estrogen

increases_activity of

Comment Animal and cellular models have consistently shown the neuroprotective effects of estrogen which include: improving synapse formation on hippocampal dendritic spines, maintaining hippocampal function during aging; improving cerebral blood flow and glucose metabolism, increasing choline acetyltransferase activity in the basal forebrain and hippocampus (choline acetyltransferase is involved in the synthesis of acetylcholine, a neurotransmitter reduced in AD and implicated in memory function), reducing the aggregation of amyloid-beta and associated neurotoxicity, and preventing mitochondrial damage.
Formal Description
Interaction-ID: 72002

drug/chemical compound

Estrogen

decreases_activity of

estrogen has neuroprotective effects
Comment The Mayo Clinic Cohort Study of Oophorectomy and Aging showed an almost doubled risk of dementia in women who underwent bilateral oophorectomy before menopause.
Formal Description
Interaction-ID: 72003

environment

oophorectomy

increases_activity of

disease

Dementia

in women with bilateral oophorectomy before menopause.
Comment Women who initiated hormone replacement therapy (HRT) after the bilateral oophorectomy, and continued utilizing HRT at least until the age of natural menopause (approximately 51 years), did not experience an increased risk of AD.
Formal Description
Interaction-ID: 72004

environment

hormone replacement therapy

decreases_activity of

environment

oophorectomy

when HRT is utilised at least until the age of natural menopause (approximately 51 years).
Comment The Women’s Health Initiative Memory Study (WHIMS), a large randomized clinical trial of HRT, reported a two-fold increased risk of dementia in women randomized to HRT after age 65 years.
Formal Description
Interaction-ID: 72006

environment

hormone replacement therapy

increases_activity of

disease

Dementia

in women randomized to HRT after age 65 years.
Comment The use of hormone replacement therapy (HRT), when initiated around the time of menopause but not years after, reduces the risk of AD. In the Cache County Study, women who initiated HRT within 5 years of menopause had a 30% lower risk of AD compared to women who reported no use of HRT. Women who began hormone therapy more than 5 years after menopause did not have a lowered risk.
Formal Description
Interaction-ID: 72008

environment

hormone replacement therapy

decreases_activity of

when initiated around the time of menopause but not years after.
Comment Women who began hormone replacement therapy (HRT) more than 5 years after menopause did not have a lowered risk of AD. In fact, those who started hormone use when they were 65 years or older had almost a two-fold increased risk of AD.
Formal Description
Interaction-ID: 72015

process

aging

affects_activity of

environment

hormone replacement therapy

Comment The age of natural menopause is approximately 51 years.
Formal Description
Interaction-ID: 72017

process

aging

increases_activity of

process

menopause

in women
Comment Hypothesis: There are two ongoing hypotheses for the lack of benefit, or even detrimental effects, when estrogen is initiated years after menopause or bilateral oophorectomy. The first, “window of opportunity,” hypothesis is based on the mechanistic findings that long-term estrogen depletion (LTED) can cause decreased levels of estrogen receptor (ER)-alpha, in the CA1 region of the hippocampus, a highly responsive region to estrogen therapy, resulting in cognitive enhancement and neuroprotection. Therefore, the initiation of estrogen after LTED, when ER-alpha receptors are already downregulated, does not result in the neuroprotective benefits of estrogen. The second, “healthy cell bias of estrogen benefit,” hypothesis suggests that estrogen only yields neuroprotective benefits when applied to healthy neurons. Neurons with damaged mitochondria, a feature of aging, will not benefit, and estrogen may even be detrimental under these conditions. It is likely that both hypotheses contribute to differential benefits of estrogen when initiated peri-menopausal compared to after LTED.
Formal Description
Interaction-ID: 72024

none selected

Drugbank entries Show/Hide entries for or
Comment Long-term estrogen depletion (LTED) can cause decreased levels of estrogen receptor (ER)-alpha, in the CA1 region of the hippocampus, a highly responsive region to estrogen therapy, resulting in cognitive enhancement and neuroprotection.
Formal Description
Interaction-ID: 72027

process

response to long-term estrogen depletion

decreases_quantity of

gene/protein

ESR1

in the CA1 region of the hippocampus
Drugbank entries Show/Hide entries for ESR1
Comment Specific factors related to gender identity that may contribute to the risk of AD include education, occupation, diet and exercise, and smoking and drinking behaviors. Gender is also strongly linked with the concept of cognitive reserve such that a higher education/occupation and greater engagement in cognitive activities provides higher reserve against disease and results in varying cognitive aging trajectories among individuals.
Formal Description
Interaction-ID: 72037

environment

education

affects_activity of

phenotype

sex

Comment Specific factors related to gender identity that may contribute to the risk of AD include education, occupation, diet and exercise, and smoking and drinking behaviors. Gender is also strongly linked with the concept of cognitive reserve such that a higher education/occupation and greater engagement in cognitive activities provides higher reserve against disease and results in varying cognitive aging trajectories among individuals.
Formal Description
Interaction-ID: 72039

environment

occupation

affects_activity of

phenotype

sex

Comment Specific factors related to gender identity that may contribute to the risk of AD include education, occupation, diet and exercise, and smoking and drinking behaviors. Gender is also strongly linked with the concept of cognitive reserve such that a higher education/occupation and greater engagement in cognitive activities provides higher reserve against disease and results in varying cognitive aging trajectories among individuals.
Formal Description
Interaction-ID: 72040

environment

diet

affects_activity of

phenotype

sex

Comment Specific factors related to gender identity that may contribute to the risk of AD include education, occupation, diet and exercise, and smoking and drinking behaviors. Gender is also strongly linked with the concept of cognitive reserve such that a higher education/occupation and greater engagement in cognitive activities provides higher reserve against disease and results in varying cognitive aging trajectories among individuals.
Formal Description
Interaction-ID: 72041

environment

exercise

affects_activity of

phenotype

sex

Comment Specific factors related to gender identity that may contribute to the risk of AD include education, occupation, diet and exercise, and smoking and drinking behaviors. Gender is also strongly linked with the concept of cognitive reserve such that a higher education/occupation and greater engagement in cognitive activities provides higher reserve against disease and results in varying cognitive aging trajectories among individuals.
Formal Description
Interaction-ID: 72042

environment

smoking

affects_activity of

phenotype

sex

Comment Specific factors related to gender identity that may contribute to the risk of AD include education, occupation, diet and exercise, and smoking and drinking behaviors. Gender is also strongly linked with the concept of cognitive reserve such that a higher education/occupation and greater engagement in cognitive activities provides higher reserve against disease and results in varying cognitive aging trajectories among individuals.
Formal Description
Interaction-ID: 72043

environment

drinking behavior

affects_activity of

phenotype

sex

Comment Specific factors related to gender identity that may contribute to the risk of AD include education, occupation, diet and exercise, and smoking and drinking behaviors. Gender is also strongly linked with the concept of cognitive reserve such that a higher education/occupation and greater engagement in cognitive activities provides higher reserve against disease and results in varying cognitive aging trajectories among individuals.
Formal Description
Interaction-ID: 72044

phenotype

sex

affects_activity of

Comment Specific factors related to gender identity that may contribute to the risk of AD include education, occupation, diet and exercise, and smoking and drinking behaviors. Gender is also strongly linked with the concept of cognitive reserve such that a higher education/occupation and greater engagement in cognitive activities provides higher reserve against disease and results in varying cognitive aging trajectories among individuals.
Formal Description
Interaction-ID: 72045

environment

cognitive activities

affects_activity of

phenotype

sex

Comment Gender is also strongly linked with the concept of cognitive reserve such that a higher education/occupation and greater engagement in cognitive activities provides higher reserve against disease and results in varying cognitive aging trajectories among individuals.
Formal Description
Interaction-ID: 72046

environment

cognitive activities

decreases_activity of

process

cognitive aging

Comment Gender is also strongly linked with the concept of cognitive reserve such that a higher education/occupation and greater engagement in cognitive activities provides higher reserve against disease and results in varying cognitive aging trajectories among individuals.
Formal Description
Interaction-ID: 72047

environment

higher education

decreases_activity of

process

cognitive aging

Comment Gender is also strongly linked with the concept of cognitive reserve such that a higher education/occupation and greater engagement in cognitive activities provides higher reserve against disease and results in varying cognitive aging trajectories among individuals.
Formal Description
Interaction-ID: 72048

environment

occupation

decreases_activity of

process

cognitive aging

Comment Gender is also strongly linked with the concept of cognitive reserve such that a higher education/occupation and greater engagement in cognitive activities provides higher reserve against disease and results in varying cognitive aging trajectories among individuals.
Formal Description
Interaction-ID: 72049

environment

cognitive activities

increases_activity of

process

cognitive reserve

Comment Gender is also strongly linked with the concept of cognitive reserve such that a higher education/occupation and greater engagement in cognitive activities provides higher reserve against disease and results in varying cognitive aging trajectories among individuals.
Formal Description
Interaction-ID: 72050

environment

higher education

increases_activity of

process

cognitive reserve

Comment Gender is also strongly linked with the concept of cognitive reserve such that a higher education/occupation and greater engagement in cognitive activities provides higher reserve against disease and results in varying cognitive aging trajectories among individuals.
Formal Description
Interaction-ID: 72051

environment

occupation

increases_activity of

process

cognitive reserve

Comment Cognitive activities have been shown to reduce the risk of dementia in the elderly.
Formal Description
Interaction-ID: 72053

environment

cognitive activities

decreases_activity of

disease

Dementia

in elderly people
Comment Low childhood mental ability and IQ is associated with lower cognitive ability in late-life, with an increased risk of dementia, and with increased mortality.
Formal Description
Interaction-ID: 72054

process

intelligence quotient

affects_activity of

process

cognitive function

Comment Low childhood mental ability and IQ is associated with lower cognitive ability in late-life, with an increased risk of dementia, and with increased mortality.
Formal Description
Interaction-ID: 72055

process

intelligence quotient

affects_activity of

disease

Dementia

Comment Low childhood mental ability and IQ is associated with lower cognitive ability in late-life, with an increased risk of dementia, and with increased mortality.
Formal Description
Interaction-ID: 72056

process

intelligence quotient

affects_activity of

process

mortality

Comment Low childhood mental ability and IQ is associated with lower cognitive ability in late-life, with an increased risk of dementia, and with increased mortality.
Formal Description
Interaction-ID: 72057

process

mental ability

affects_activity of

process

cognitive function

Comment Low childhood mental ability and IQ is associated with lower cognitive ability in late-life, with an increased risk of dementia, and with increased mortality.
Formal Description
Interaction-ID: 72058

process

mental ability

affects_activity of

disease

Dementia

Comment Low childhood mental ability and IQ is associated with lower cognitive ability in late-life, with an increased risk of dementia, and with increased mortality.
Formal Description
Interaction-ID: 72059

process

mental ability

affects_activity of

process

mortality

Comment One study of over 9,000 women collected self-reported information on physical activity when the women were in their teens, age 30, age 50, and in later-life. Physical activity at all time points was associated with a reduced risk of cognitive impairment in late-life. However, physical activity in the teenage years was associated with the greatest reduction in risk. Women who were not active as teenagers, but who were physically active at age 30 and 50, also had a reduced risk, but not as much as those who were active as teenagers. Among women who were physically active as teenagers, late-life physical activity did not appear to further reduce the risk of cognitive impairment, suggesting that early activity, when the brain is developing, may be most important.
Formal Description
Interaction-ID: 72060

environment

exercise

decreases_activity of

phenotype

cognitive impairment

Physical activity in the teenage years was associated with the greatest reduction in cognitive impairment risk.
Comment Long-term estrogen depletion (LTED) can cause decreased levels of estrogen receptor (ER)-alpha, in the CA1 region of the hippocampus, a highly responsive region to estrogen therapy, resulting in cognitive enhancement and neuroprotection.
Formal Description
Interaction-ID: 72061

gene/protein

ESR1

is localized in

tissue/cell line

hippocampus

in the CA1 region of the hippocampus
Drugbank entries Show/Hide entries for ESR1
Comment Long-term estrogen depletion (LTED) can cause decreased levels of estrogen receptor (ER)-alpha, in the CA1 region of the hippocampus, a highly responsive region to estrogen therapy, resulting in cognitive enhancement and neuroprotection.
Formal Description
Interaction-ID: 72062

drug/chemical compound

Estrogen

increases_activity of

tissue/cell line

hippocampus

in the CA1 region
Comment Long-term estrogen depletion (LTED) can cause decreased levels of estrogen receptor (ER)-alpha, in the CA1 region of the hippocampus, a highly responsive region to estrogen therapy, resulting in cognitive enhancement and neuroprotection.
Formal Description
Interaction-ID: 72063

drug/chemical compound

Estrogen

increases_quantity of

gene/protein

ESR1

in the CA1 region of the hippocampus
Drugbank entries Show/Hide entries for ESR1
Comment Acetylcholine is a neurotransmitter that is decreased in Alzheimer’s patients.
Formal Description
Interaction-ID: 72068

drug/chemical compound

Acetylcholine

increases_activity of

Drugbank entries Show/Hide entries for Acetylcholine
Comment Acetylcholine is a neurotransmitter that is decreased in Alzheimer’s patients.
Formal Description
Interaction-ID: 72070

decreases_quantity of

drug/chemical compound

Acetylcholine

Drugbank entries Show/Hide entries for
Comment Nicotinic acetylcholine receptors are especially reduced in AD. Therefore, it was hypothesized that nicotine could be used to prevent or delay the progression of AD, and that smoking may be associated with a reduced risk of AD. Although it is possible that nicotine could be beneficial for AD, cigarette smoking contains several other toxins, has carcinogenic effects, is a known risk factor for cardiovascular and pulmonary disease, and therefore may increase the risk of AD. Additionally, many smokers also drink, and the interaction between cigarette smoking and heavy alcohol use may be especially detrimental for cognition. The differential changes in smoking by gender may impact the subsequent incidence rate of AD among women and men.
Formal Description
Interaction-ID: 72071

decreases_quantity of

complex/PPI

Nicotinic acetylcholine receptor

Comment The effects of the E4 genotype are more pronounced in women than in men. Three studies reported that women with one E4 allele had about a four-fold risk of AD, whereas men with one E4 allele showed little increased risk.
Formal Description
Interaction-ID: 72092

gene/protein mutant

APOE (isoform E4)

increases_activity of

concerning AD in women.
Comment A bilateral oophorectomy prior to menopause causes an abrupt deficiency of estrogen, progesterone, testosterone, and a disruption of the hypothalamic–pituitary–ovarian axis.
Formal Description
Interaction-ID: 85050

environment

oophorectomy

decreases_quantity of

drug/chemical compound

Estrogen

if bilateral and prior to menopause
Comment A bilateral oophorectomy prior to menopause causes an abrupt deficiency of estrogen, progesterone, testosterone, and a disruption of the hypothalamic–pituitary–ovarian axis.
Formal Description
Interaction-ID: 85051

environment

oophorectomy

decreases_quantity of

drug/chemical compound

Progesterone

if bilateral and prior to menopause
Drugbank entries Show/Hide entries for
Comment A bilateral oophorectomy prior to menopause causes an abrupt deficiency of estrogen, progesterone, testosterone, and a disruption of the hypothalamic–pituitary–ovarian axis.
Formal Description
Interaction-ID: 85052

environment

oophorectomy

decreases_quantity of

drug/chemical compound

Testosterone

if bilateral and prior to menopause
Drugbank entries Show/Hide entries for
Comment A bilateral oophorectomy prior to menopause causes an abrupt deficiency of estrogen, progesterone, testosterone, and a disruption of the hypothalamic–pituitary–ovarian axis.
Formal Description
Interaction-ID: 85053

environment

oophorectomy

decreases_activity of

drug/chemical compound

HPO axis

if bilateral and prior to menopause
Comment Women who initiated hormone replacement therapy (HRT) after the bilateral oophorectomy, and continued utilizing HRT at least until the age of natural menopause (approximately 51 years), did not experience an increased risk of AD.
Formal Description
Interaction-ID: 85054

environment

hormone replacement therapy

NOT increases_activity of

before menopause, when HRT is utilised at least until the age of natural menopause (approximately 51 years) after oophorectomy
Comment Observational studies generally report reduced risks of AD in women who initiate HRT within a short period (typically ,3 years) after natural menopause and after oophorectomy performed prior to menopause.
Formal Description
Interaction-ID: 85055

environment

hormone replacement therapy

decreases_activity of

in women who initiate HRT within a short period (typically ,3 years) after natural menopause and after oophorectomy performed prior to menopause
Comment Animal and cellular models have consistently shown the neuroprotective effects of estrogen which include: improving synapse formation on hippocampal dendritic spines, maintaining hippocampal function during aging; improving cerebral blood flow and glucose metabolism, increasing choline acetyltransferase activity in the basal forebrain and hippocampus (choline acetyltransferase is involved in the synthesis of acetylcholine, a neurotransmitter reduced in AD and implicated in memory function), reducing the aggregation of amyloid-beta and associated neurotoxicity, and preventing mitochondrial damage.
Formal Description
Interaction-ID: 115232

drug/chemical compound

Estrogen

increases_activity of

process

synapse formation

on hippocampal dendritic spines; estrogen has neuroprotective effects
Comment Animal and cellular models have consistently shown the neuroprotective effects of estrogen which include: improving synapse formation on hippocampal dendritic spines, maintaining hippocampal function during aging; improving cerebral blood flow and glucose metabolism, increasing choline acetyltransferase activity in the basal forebrain and hippocampus (choline acetyltransferase is involved in the synthesis of acetylcholine, a neurotransmitter reduced in AD and implicated in memory function), reducing the aggregation of amyloid-beta and associated neurotoxicity, and preventing mitochondrial damage.
Formal Description
Interaction-ID: 115233

drug/chemical compound

Estrogen

increases_activity of

process

maintaining hippocampal function during aging

estrogen has neuroprotective effects
Comment Animal and cellular models have consistently shown the neuroprotective effects of estrogen which include: improving synapse formation on hippocampal dendritic spines, maintaining hippocampal function during aging; improving cerebral blood flow and glucose metabolism, increasing choline acetyltransferase activity in the basal forebrain and hippocampus (choline acetyltransferase is involved in the synthesis of acetylcholine, a neurotransmitter reduced in AD and implicated in memory function), reducing the aggregation of amyloid-beta and associated neurotoxicity, and preventing mitochondrial damage.
Formal Description
Interaction-ID: 115234

drug/chemical compound

Estrogen

increases_activity of

estrogen has neuroprotective effects
Comment Animal and cellular models have consistently shown the neuroprotective effects of estrogen which include: improving synapse formation on hippocampal dendritic spines, maintaining hippocampal function during aging; improving cerebral blood flow and glucose metabolism, increasing choline acetyltransferase activity in the basal forebrain and hippocampus (choline acetyltransferase is involved in the synthesis of acetylcholine, a neurotransmitter reduced in AD and implicated in memory function), reducing the aggregation of amyloid-beta and associated neurotoxicity, and preventing mitochondrial damage.
Formal Description
Interaction-ID: 115235

drug/chemical compound

Estrogen

increases_activity of

estrogen has neuroprotective effects
Comment Animal and cellular models have consistently shown the neuroprotective effects of estrogen which include: improving synapse formation on hippocampal dendritic spines, maintaining hippocampal function during aging; improving cerebral blood flow and glucose metabolism, increasing choline acetyltransferase activity in the basal forebrain and hippocampus (choline acetyltransferase is involved in the synthesis of acetylcholine, a neurotransmitter reduced in AD and implicated in memory function), reducing the aggregation of amyloid-beta and associated neurotoxicity, and preventing mitochondrial damage.
Formal Description
Interaction-ID: 115236

drug/chemical compound

Estrogen

increases_activity of

gene/protein

CHAT

in the basal forebrain and hippocampus; estrogen has neuroprotective effects
Comment Animal and cellular models have consistently shown the neuroprotective effects of estrogen which include: improving synapse formation on hippocampal dendritic spines, maintaining hippocampal function during aging; improving cerebral blood flow and glucose metabolism, increasing choline acetyltransferase activity in the basal forebrain and hippocampus (choline acetyltransferase is involved in the synthesis of acetylcholine, a neurotransmitter reduced in AD and implicated in memory function), reducing the aggregation of amyloid-beta and associated neurotoxicity, and preventing mitochondrial damage.
Formal Description
Interaction-ID: 115237

drug/chemical compound

Estrogen

decreases_quantity of

and associated neurotoxicity; estrogen has neuroprotective effects
Comment Animal and cellular models have consistently shown the neuroprotective effects of estrogen which include: improving synapse formation on hippocampal dendritic spines, maintaining hippocampal function during aging; improving cerebral blood flow and glucose metabolism, increasing choline acetyltransferase activity in the basal forebrain and hippocampus (choline acetyltransferase is involved in the synthesis of acetylcholine, a neurotransmitter reduced in AD and implicated in memory function), reducing the aggregation of amyloid-beta and associated neurotoxicity, and preventing mitochondrial damage.
Formal Description
Interaction-ID: 115238

drug/chemical compound

Estrogen

decreases_activity of

process

neuron death

via reducing amyloid-beta aggregations; estrogen has neuroprotective effects
Comment The effects of the E4 genotype are more pronounced in women than in men. Three studies reported that women with one E4 allele had about a four-fold risk of AD, whereas men with one E4 allele showed little increased risk.
Formal Description
Interaction-ID: 124712

phenotype

sex, male

decreases_activity of

gene/protein mutant

APOE (isoform E4)

in men; concerning AD, compared to women