- This population-based study of 212 subjects, 45 to 55 years old, investigated the effect of brain-derived neurotrophic factor (BDNF) on memory as a function of sex and, in women, reproductive status
- In postmenopausal women, higher plasma levels of BDNF were associated with better associative and verbal memory performance; these effects were particularly strong for associative memory
- During a working memory task, lower BDNF levels in postmenopausal women were associated with higher functional MRI activity in the hippocampus and dorsolateral prefrontal cortex
- BDNF levels did not significantly affect memory performance or memory circuitry function in early middle-aged men or pre/perimenopausal women
- In theory, therapies that promote higher levels of BDNF might help attenuate the risk of memory decline in women in early midlife
Reproductive aging in women presents a critical period for neurological changes that have long-term implications for the risk of cognitive impairment and Alzheimer's disease. Previous findings in the Journal of Neuroscience, by the same team at Massachusetts General Hospital that conducted the present study, demonstrated that during the menopausal transition, decreasing estradiol levels altered memory circuitry function and performance.
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Separately, it's been shown that brain-derived neurotrophic factor (BDNF) plays a significant neuroprotective role in memory circuitry aging. BDNF impacts the development and functioning of the hippocampus, a key region in memory circuitry, that is highly sexually dimorphic and dense in estrogen receptors.
Kyoko Konishi, PhD, research fellow, Jill M. Goldstein, PhD, MPH, executive director of the Innovation Center on Sex Differences in Medicine and the Helen T. Moerschner Endowed MGH Research Institute Chair in Women’s Health, and colleagues in the Department of Psychiatry and Department of Obstetrics and Gynecology at Mass General, extend previous findings, reporting in Neurobiology of Aging that the neuroprotective effect of BDNF on memory performance varies by sex and, in women, by reproductive status.
The researchers selected 212 subjects (equally divided by sex) from the New England Family Study, a sample of more than 17,000 people who received prenatal care in Boston or Providence between 1959 and 1966. Now 45 to 55 years old, they completed a battery of neuropsychological tests that assessed episodic memory, and 180 participants performed a verbal working memory task (N-back) during functional MRI scanning.
The researchers found:
- In postmenopausal women, higher plasma levels of BDNF were associated with better associative and verbal memory performance; the link was particularly strong for associative memory
- In contrast, BDNF levels did not significantly affect memory performance in men or pre-/perimenopausal women
Working Memory Circuitry
The researchers found:
- Low plasma BDNF levels in postmenopausal women were associated with higher functional MRI activity in the hippocampus and dorsolateral prefrontal cortex
- BDNF levels did not significantly affect memory circuitry function in men or pre-/perimenopausal women
Potential Therapeutic Target
On the N-back task, activation of the dorsolateral prefrontal cortex is normally accompanied by robust deactivation of the hippocampus. In contrast, the findings of this study suggest a failure to disengage in postmenopausal women with lower levels of BDNF.
Some have hypothesized that failure to disengage is related to a failure to suppress the default mode network (DMN) during the task, which has been observed in preclinical Alzheimer's disease. However, findings may also suggest a compensatory mechanism in healthy postmenopausal healthy women involving increased hippocampal activity to maintain intact memory function.
Memory performance was related to BDNF levels only in postmenopausal and not pre/perimenopausal women. In the absence of estradiol, higher levels of BDNF (downstream from estradiol) may have a greater impact on memory function, whereas in premenopausal women, regulation of memory function by estradiol itself may reduce the impact of BDNF.
These results suggest the need for therapeutic options that promote higher levels of BDNF postmenopause, if women cannot supplement with estradiol. This could contribute to attenuating risk of memory decline in women in early midlife.
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