Identifying postmenopausal women at risk for cognitive decline within a healthy cohort using a panel of clinical metabolic indicators: potential for detecting an at-Alzheimer's risk metabolic phenotype

Rettberg, Jamaica R.; Dang, Ha; Hodis, Howard N.; Henderson, Victor W.; John, Jan A. St.; Mack, Wendy J.; Brinton, Roberta Dı́az

doi:10.1016/j.neurobiolaging.2016.01.011

Cited by 39 publications

(39 citation statements)

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“…It is unclear whether metabolic function in E4FAD mice contributed to, resulted from, or was unrelated to their significantly poorer behavioral performance and higher pathology burden under basal conditions. In healthy postmenopausal women, relatively poorer metabolic profile is associated with significantly worse cognitive function (49), a relationship that may be exacerbated by APOE4 genotype (50). Importantly, we found that upon challenge with an obesogenic diet, E3FAD mice showed greater glucose intolerance than E4FAD mice.…”

Section: Discussionmentioning

confidence: 63%

APOEgenotype affects metabolic and Alzheimer‐related outcomes induced by Western diet in female EFAD mice

Christensen

Pike

2018

FASEB j.

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Development of Alzheimer's disease (AD) is regulated by interactive effects of genetic and environmental risk factors. The most significant genetic risk factor for AD is the ε4 allele of apolipoprotein E (APOE4), which has been shown to exert greater AD risk in women. An important modifiable AD risk factor is obesity and its associated metabolic dysfunctions. Whether APOE genotype might interact with obesity in females to regulate AD pathogenesis is unclear. To investigate this issue, we studied the effects of Western diet (WD) on female EFAD mice, a transgenic mouse model of AD that includes human APOE alleles ε3 (E3FAD) and ε4 (E4FAD). EFAD mice were fed either control (10% fat, 7% sugar) or WD (45% fat, 17% sugar), and both metabolic and neuropathologic outcomes were determined. Although E4FAD mice generally exhibited poorer metabolic status at baseline, E3FAD mice showed greater diet‐induced metabolic impairments. Similarly, E4FAD mice exhibited higher levels of AD‐related pathology overall, but only E3FAD showed significant increases on select measures of β‐amyloid pathology after exposure to WD. These data demonstrate a gene–environment interaction between APOE and obesogenic diets in females. Understanding how AD‐promoting effects of obesity are modulated by genetic factors will foster the identification of at‐risk populations and development of preventive interventions.—Christensen, A., Pike, C. J. APOE genotype affects metabolic and Alzheimer‐related outcomes induced by Western diet in female EFAD mice. FASEB J. 33, 4054–4066 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 63%

APOEgenotype affects metabolic and Alzheimer‐related outcomes induced by Western diet in female EFAD mice

Christensen

Pike

2018

FASEB j.

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“…Preclinical studies indicate that during perimenopause, when brain estrogen plummets, the systems required for estrogen activation of cerebral glucose metabolism rates (CMRglc) and suppression of the ketogenic pathways disassemble (18). Following the decline in CMRglc is induction of an adaptive starvation reaction to increase fatty acid metabolism for the generation and utilization of ketone bodies by mitochondria as an alternative fuel (5, 18–21). Hypometabolism, reduced mitochondrial function and subsequent oxidative damage are known to promote accumulation of Aß pathology and neuronal dysfunction (22), therefore increasing risk of developing AD later in life.…”

Section: The Role Of Estrogen In the Brainmentioning

confidence: 99%

Female Sex and Alzheimer’s Risk: The Menopause Connection

et al. 2018

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Along with advanced age and apolipoprotein E (APOE)-4 genotype, female sex is a major risk factor for developing late-onset Alzheimer’s disease (AD). Considering that AD pathology begins decades prior to clinical symptoms, the higher risk in women cannot simply be accounted for by their greater longevity as compared to men. Recent investigation into sex-specific pathophysiological mechanisms behind AD risk has implicated the menopause transition (MT), a midlife neuroendocrine transition state unique to females. Commonly characterized as ending in reproductive senescence, many symptoms of MT are neurological, including disruption of estrogen-regulated systems such as thermoregulation, sleep, and circadian rhythms, as well as depression and impairment in multiple cognitive domains. Preclinical studies have shown that, during MT, the estrogen network uncouples from the brain bioenergetic system. The resulting hypometabolic state could serve as the substrate for neurological dysfunction. Indeed, translational brain imaging studies demonstrate that 40-60 year-old perimenopausal and postmenopausal women exhibit an AD-endophenotype characterized by decreased metabolic activity and increased brain amyloid-beta deposition as compared to premenopausal women and to age-matched men. This review discusses the MT as a window of opportunity for therapeutic interventions to compensate for brain bioenergetic crisis and combat the subsequent increased risk for AD in women.

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“…The presence, variability, intensity and duration of neurological symptoms provide potential advance warning signs of impending risk of later health risks, particularly neurodegenerative diseases. Multiple conditions that emerge during aging, such as metabolic dysregulation, cholesterol dyshomeostasis, insomnia, depression, subjective memory complaints and cognitive decline are associated with increased risk of neurodegenerative diseases later in life such as Alzheimer’s(17, 31). Alzheimer’s, like multiple neurodegenerative diseases, is characterized by a long prodromal period, 20 years, during which the disease progresses to clinically diagnosed dysfunction.…”

Section: Introductionmentioning

confidence: 99%

“…Alzheimer’s, like multiple neurodegenerative diseases, is characterized by a long prodromal period, 20 years, during which the disease progresses to clinically diagnosed dysfunction. Identifying persons that are at risk for AD while still in a modifiable transition states is critical for reversing or delaying development of Alzheimer’s (31). …”

Section: Introductionmentioning

confidence: 99%

Age, APOE and sex: Triad of risk of Alzheimer’s disease

Riedel

Thompson

Brinton

2016

The Journal of Steroid Biochemistry and Molecular Biology

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Age, apolipoprotein E ɛ4 (APOE) and chromosomal sex are well-established risk factors for late-onset Alzheimer’s disease (LOAD; AD). Over 60% of persons with AD harbor at least one APOE-ɛ4 allele. The sex-based prevalence of AD is well documented with over 60% of persons with AD being female. Evidence indicates that the APOE-ɛ4 risk for AD is greater in women than men, which is particularly evident in heterozygous women carrying one APOE-ɛ4 allele. Paradoxically, men homozygous for APOE-ɛ4 are reported to be at greater risk for mild cognitive impairment and AD. Herein, we discuss the complex interplay between the three greatest risk factors for Alzheimer’s disease, age, APOE-ɛ4 genotype and female sex. We propose that the convergence of these three risk factors, and specifically the bioenergetic aging perimenopause to menopause transition unique to the female, creates a risk profile for AD unique to the female. Further, we discuss the unique risk of the APOE4 positive male which appears to emerge early in the aging process. Evidence for impact of the triad of AD risk factors is most evident in the temporal trajectory of AD progression and burden of pathology in relation to APOE genotype, age and sex. Collectively, the data indicate complex interactions between age, APOE genotype and gender that belies a one size fits all approach and argues for a precision medicine approach that integrates across the three main risk factors for Alzheimer’s disease.

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Identifying postmenopausal women at risk for cognitive decline within a healthy cohort using a panel of clinical metabolic indicators: potential for detecting an at-Alzheimer's risk metabolic phenotype

Cited by 39 publications

References 40 publications

APOEgenotype affects metabolic and Alzheimer‐related outcomes induced by Western diet in female EFAD mice

APOEgenotype affects metabolic and Alzheimer‐related outcomes induced by Western diet in female EFAD mice

Female Sex and Alzheimer’s Risk: The Menopause Connection

Age, APOE and sex: Triad of risk of Alzheimer’s disease

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