More than just risk for Alzheimer's disease: APOE ε4's impact on the aging brain.

The apolipoprotein Îµ4 (APOE ε4) allele is most commonly associated with increased risk for late-onset Alzheimer's disease (AD). However, recent longitudinal studies suggest that these risks are overestimated; most ε4 carriers will not develop dementia in their lifetime. In this article, we review new evidence regarding the impact of APOE ε4 on cognition among healthy older adults. We discuss emerging work from animal models suggesting that ε4 impacts brain structure and function in multiple ways that may lead to age-related cognitive impairment, independent from AD pathology. We discuss the importance of taking an individualized approach in future studies by incorporating biomarkers and neuroimaging methods that may better disentangle the phenotypic influences of APOE ε4 on the aging brain from prodromal AD pathology.

The impact of context on pattern separation for objects among younger and older apolipoprotein ϵ4 carriers and noncarriers.

OBJECTIVE: On continuous recognition tasks, changing the context objects are embedded in impairs memory. Older adults are worse on pattern separation tasks requiring identification of similar objects compared to younger adults. However, how contexts impact pattern separation in aging is unclear. The apolipoprotein (APOE) ϵ4 allele may exacerbate possible age-related changes due to early, elevated neuropathology. The goal of this study is to determine how context and APOE status affect pattern separation among younger and older adults. METHOD: Older and younger ϵ4 carriers and noncarriers were given a continuous object recognition task. Participants indicated if objects on a Repeated White background, Repeated Scene, or a Novel Scene were old, similar, or new. The proportions of correct responses and the types of errors made were calculated. RESULTS: Novel scenes lowered recognition scores compared to all other contexts for everyone. Younger adults outperformed older adults on identifying similar objects. Older adults misidentified similar objects as old more than new, and the repeated scene exacerbated this error. APOE status interacted with scene and age such that in repeated scenes, younger carriers produced less false alarms, and this trend switched for older adults where carriers made more false alarms. CONCLUSIONS: Context impacted recognition memory in the same way for both age groups. Older adults underutilized details and over relied on holistic information during pattern separation compared to younger adults. The triple interaction in false alarms may indicate an even greater reliance on holistic information among older adults with increased risk for Alzheimer's disease.

Evaluating the Cognitive Impacts of Drospirenone, a Spironolactone-Derived Progestin, Independently and in Combination With Ethinyl Estradiol in Ovariectomized Adult Rats.

Oral contraceptives and hormone therapies require a progestogen component to prevent ovulation, curtail uterine hyperplasia, and reduce gynecological cancer risk. Diverse classes of synthetic progestogens, called progestins, are used as natural progesterone alternatives due to progesterone's low oral bioavailability. Progesterone and several synthetic analogs can negatively impact cognition and reverse some neuroprotective estrogen effects. Here, we investigate drospirenone, a spironolactone-derived progestin, which has unique pharmacological properties compared to other clinically-available progestins and natural progesterone, for its impact on spatial memory, anxiety-like behavior, and brain regions crucial to these cognitive tasks. Experiment 1 assessed three drospirenone doses in young adult, ovariectomized rats, and found that a moderate drospirenone dose benefited spatial memory. Experiment 2 investigated this moderate drospirenone dose with and without concomitant ethinyl estradiol (EE) treatment, the most common synthetic estrogen in oral contraceptives. Results demonstrate that the addition of EE to drospirenone administration reversed the beneficial working memory effects of drospirenone. The hippocampus, entorhinal cortex, and perirhinal cortex were then probed for proteins known to elicit estrogen- and progestin- mediated effects on learning and memory, including glutamate decarboxylase (GAD)65, GAD67, and insulin-like growth factor receptor protein expression, using western blot. EE increased GAD expression in the perirhinal cortex. Taken together, results underscore the necessity to consider the distinct cognitive and neural impacts of clinically-available synthetic estrogen and progesterone analogs, and why they produce unique cognitive profiles when administered together compared to those observed when each hormone is administered separately.

Hysterectomy Uniquely Impacts Spatial Memory in a Rat Model: A Role for the Nonpregnant Uterus in Cognitive Processes.

Approximately one-third of women experience hysterectomy, or the surgical removal of the uterus, by 60 years of age, with most surgeries occurring prior to the onset of natural menopause. The ovaries are retained in about half of these surgeries, whereas for the other half hysterectomy occurs concurrently with oophorectomy. The dogma is that the nonpregnant uterus is dormant. There have been no preclinical assessments of surgical variations in menopause, including hysterectomy, with and without ovarian conservation, on potential endocrine and cognitive changes. We present a novel rat model of hysterectomy alongside sham, ovariectomy (Ovx), and Ovx-hysterectomy groups to assess effects of surgical menopause variations. Rats without ovaries learned the working memory domain of a complex cognitive task faster than did those with ovaries. Moreover, uterus removal alone had a unique detrimental impact on the ability to handle a high-demand working memory load. The addition of Ovx, that is, Ovx-hysterectomy, prevented this hysterectomy-induced memory deficit. Performance did not differ amongst groups in reference memory-only tasks, suggesting that the working memory domain is particularly sensitive to variations in surgical menopause. Following uterus removal, ovarian histology and estrous cycle monitoring demonstrated that ovaries continued to function, and serum assays indicated altered ovarian hormone and gonadotropin profiles by 2 months after surgery. These results underscore the critical need to further study the contribution of the uterus to the female phenotype, including effects of hysterectomy with and without ovarian conservation, on the trajectory of brain and endocrine aging to decipher the impact of common variations in gynecological surgery in women. Moreover, findings demonstrate that the nonpregnant uterus is not dormant, and indicate that there is an ovarian-uterus-brain system that becomes interrupted when the reproductive tract has been disrupted, leading to alterations in brain functioning.