Patterns of Aging Changes in Bodyweight May Predict Alzheimer’s Disease

Ukraintseva, Svetlana; Duan, Hongzhe; Holmes, Rachel; Bagley, Olivia; Wu, Deqing; Yashkin, Arseniy; Kulminski, Alexander; Akushevich, Igor; Whitson, Heather; Stallard, Eric; Yashin, Anatoliy; Arbeev, Konstantin

doi:10.3233/jad-220998

Cited by 4 publications

(1 citation statement)

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“…Certain metabolic phenotypes (e.g., diabetes and serum lipids) were proposed as potential mediators, however, their mediating role in the association of APOE4 with longevity was not confirmed (Noordam et al 2016). APOE4 was also linked to a lower weight and body mass index (BMI) and its changes with age (Bäckman et al 2015; Bell et al 2017; Blautzik et al 2018; Ando et al 2022; Kulminski, et al 2019; Ukraintseva et al 2023). E.g., we recently demonstrated using HRS and FHS data that APOE4 carriers had lower weight than non-carriers starting around age 65, and reached maximum of the weight at younger ages compared to non-carriers, as well as declined in weight faster than non-carriers (Ukraintseva, et al 2023).…”

Section: Introductionmentioning

confidence: 99%

How areAPOE4, changes in body weight, and longevity related? Insights from a causal mediation analysis

Holmes,

Duan,

Bagley

et al. 2024

Preprint

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The ε4 allele of theAPOEgene (APOE4)is known for its negative association with human longevity, however, the mechanism is unclear.APOE4was also linked to changes in body weight, and the latter changes were associated with survival in some studies. Here we explore the role of aging changes in weight in the connection betweenAPOE4and longevity, using a Causal Mediation Analysis (CMA) approach to uncovering mechanisms of genetic associations. Using the Health and Retirement Study (HRS) data, we tested a hypothesis, whether the association ofAPOE4with reduced survival to age 85+ is mediated by key characteristics of age-trajectories of weight, such as age at reaching peak values, and slope of the decline in weight afterwards. Mediation effects were evaluated by the Total Effect (TE), Natural Indirect Effect, and Proportion Mediated. Controlled Direct Effect and Natural Direct Effect are also reported. The CMA results suggest thatAPOE4carriers have 19%-22% (TE p=0.019-0.038) lower chances of surviving to age 85 and beyond in part because they reach peak values of weight at younger ages, and their weight declines faster afterwards, compared to non-carriers. This finding is in line with the idea that detrimental effect ofAPOE4on longevity is in part related to accelerated physical aging of ε4 carriers.

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Section: Introductionmentioning

confidence: 99%

How areAPOE4, changes in body weight, and longevity related? Insights from a causal mediation analysis

Holmes,

Duan,

Bagley

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

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Association of Age with Dual-Task Objective Cognitive Indicators and Gait Parameters in Older Adults

Wang,

Zhang,

Wang

et al. 2024

Journal of Alzheimer’s Disease

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Background: Early recognition of dementia like Alzheimer’s disease is crucial for disease diagnosis and treatment, and existing objective tools for early screening of cognitive impairment are limited. Objective: To investigate age-related behavioral indicators of dual-task cognitive performance and gait parameters and to explore potential objective markers of early cognitive decline. Methods: The community-based cognitive screening data was analyzed. Hierarchical cluster analysis and Pearson correlation analysis were performed on the 9-item subjective cognitive decline (SCD-9) scores, walking-cognitive dual-task performance, walking speed, and gait parameters of 152 participants. The significant differences of indicators that may related to cognitive decline were statistically analyzed across six age groups. A mathematical model with age as the independent variable and motor cognition composite score as the dependent variable was established to observe the trend of motor cognition dual-task performance with age. Results: Strong correlation was found between motor cognitive scores and SCD and age. Gait parameters like the mean value of ankle angle, the left-right difference rate of ankle angle and knee angle and the coefficient of variation of gait cycle showed an excellent correlation with age. Motor cognition scores showed a decreasing trend with age. The slope of motor cognition scores with age after 50 years (k = –1.06) was six times higher than that before 50 years (k = –0.18). Conclusions: Cognitive performance and gait parameters in the walking-cognitive dual-task state are promising objective markers that could characterize age-related cognitive decline.

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The novel estrogen receptor beta agonist EGX358 and APOE genotype influence memory, vasomotor, and anxiety outcomes in an Alzheimer’s mouse model

Schwabe,

Fleischer,

Kuehn

et al. 2024

Front. Aging Neurosci.

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IntroductionAlzheimer’s disease (AD) prevalence and severity are associated with increased age, female sex, and apolipoprotein E4 (APOE4) genotype. Although estrogen therapy (ET) effectively reduces symptoms of menopause including hot flashes and anxiety, and can reduce dementia risk, it is associated with increased risks of breast and uterine cancer due to estrogen receptor alpha (ERβ)-mediated increases in cancer cell proliferation. Because ERβ activation reduces this cell proliferation, selective targeting of ERβ may provide a safer method of improving memory and reducing hot flashes in menopausal women, including those with AD. APOE genotype influences the response to ET, although it is unknown whether effects of ERβ activation vary by genotype.MethodsHere, we tested the ability of long-term oral treatment with a novel highly selective ERβ agonist, EGX358, to enhance object recognition and spatial recognition memory, reduce drug-induced hot flashes, and influence anxiety-like behaviors in female mice expressing 5 familial AD mutations (5xFAD-Tg) and human APOE3 (E3FAD) or APOE3 and APOE4 (E3/4FAD). Mice were ovariectomized at 5 months of age and were then treated orally with vehicle (DMSO) or EGX358 (10 mg/kg/day) via hydrogel for 8 weeks. Spatial and object recognition memory were tested in object placement (OP) and object recognition (OR) tasks, respectively, and anxiety-like behaviors were tested in the open field (OF) and elevated plus maze (EPM). Hot flash-like symptoms (change in tail skin temperature) were measured following injection of the neurokinin receptor agonist senktide (0.5 mg/kg).ResultsEGX358 enhanced object recognition memory in E3FAD and E3/4FAD mice but did not affect spatial recognition memory. EGX358 also reduced senktide-induced tail temperature elevations in E3FAD, but not E3/4FAD, females. EGX358 did not influence anxiety-like behaviors or body weight.DiscussionThese data indicate that highly selective ERβ agonism can facilitate object recognition memory in both APOE3 homozygotes and APOE3/4 heterozygotes, but only reduce the magnitude of a drug-induced hot flash in APOE3 homozygotes, suggesting that APOE4 genotype may blunt the beneficial effects of ET on hot flashes. Collectively, these data suggest a potentially beneficial effect of selective ERβ agonism for memory and hot flashes in females with AD-like pathology, but that APOE genotype plays an important role in responsiveness.

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Patterns of Aging Changes in Bodyweight May Predict Alzheimer’s Disease

Cited by 4 publications

References 20 publications

How areAPOE4, changes in body weight, and longevity related? Insights from a causal mediation analysis

How areAPOE4, changes in body weight, and longevity related? Insights from a causal mediation analysis

Association of Age with Dual-Task Objective Cognitive Indicators and Gait Parameters in Older Adults

The novel estrogen receptor beta agonist EGX358 and APOE genotype influence memory, vasomotor, and anxiety outcomes in an Alzheimer’s mouse model

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