Recently a study that was published in the prestigious Proceedings of the National Academy of Sciences (PNAS) discussed how B vitamins (specifically folic acid, B6 and B12) may be able to slow the development of Alzheimer’s disease, slowing the shrinkage of brain volume (Douaud et al. 2013). This is not the first study of its kind, but is one piece of the mounting pile of evidence that suggests that one of the biggest causative factors of Alzheimer’s is elevated homocysteine levels, and that controlling homocysteine may be a viable treatment. It all started over 15 years ago, with the observation
I don’t know if men are really from Mars and women from Venus, but I think that the one thing we may all agree upon in this time and age of controversies is that women’s brains differ from men’s brains. Among those differences, we know that women are definitely more often diagnosed with an anxiety disorder or depression,[i] headaches and migraines[ii] and certain conditions such as Alzheimer’s disease (AD).[iii] In fact, two thirds of all persons with late-onset AD are women.[iv] A key determinant of sex differences in cognition and brain function is sex steroid hormones.[v] This fact, along with two decades accumulating comments from women fearing that they are “ going crazy” in my clinical practice beg the question: “Does menopause affect the brain and if so, how so?”.
The Brain and the Reproductive System
Interactions between the brain and the reproductive system are crucial for healthy aging in women. Our brains and ovaries are both part of the neuroendocrine system and they communicate with each other constantly through our hormones. Sexual hormones, such as estrogens, play important roles in maintaining normal reproductive and non-reproductive functions. Their contribution is essential in maintaining brain function and homeostasis. Estrogen deficit in the brain induces many undesirable symptoms such as sleep and mood disorders, hot flashes, fatigue, as well as learning and memory impairment.[vi]
Brain Anatomy of Menopause
The effects of estrogens decline are stronger in specific brain regions. For example, the hypothalamus oversees regulating body temperature so when estrogens don’t activate this master gland correctly, the brain cannot regulate the body’s temperature accordingly and it can result in those infamous hot flashes that some women undergo during menopause.[vii] Then there’s the brain stem, in charge of the sleep and wake cycle. When estrogens don’t activate this part of the brain correctly, we may experience trouble sleeping.[viii] Then, we have the amygdala – the emotional center of the brain – close to the hippocampus, our memory headquarters. When estrogen levels ebb in these regions, we start getting mood swings and perhaps, forget things.[ix]
The Brain and Energy Production
Estrogens are fundamental regulators of the metabolic system of the female brain and body. Within the brain, estrogens regulate glucose transport, aerobic glycolysis, and mitochondrial function to generate energy or ATP.[x] One type of estrogens called estradiol is key for energy production in the brain. At the cellular level, estrogens literally push neurons to burn up glucose to produce energy. When estrogens are at their optimal level, so is the brain energy but during menopause, decline in circulating estrogens coincides with decline in brain bioenergetics and a shift towards a metabolically compromised phenotype.[xi] In other words, when the level of estrogens drops, the neurons start slowing down and age faster. This accelerated aging phenotype eventually leads to the development of brain hypometabolism, a feature often observed in menopausal women and mild cognitive impairment (MCI) due to AD, also referred to as prodromal AD.[xii] Studies have shown that this process can even lead to the formation of amyloid plaques, or Alzheimer’s plaques, which are a hallmark of AD.
Dr. Lisa Mosconi, neuroscientist, and Director of the Women’s Brain Initiative at Weill Cornell Medicine in New York City and her team use positron emission tomography (PET) to show that middle-aged men usually have high brain energy levels while for women, brain energy is usually fine before menopause but gradually declines during the transition.[xiii]
Estrogens and Cognitive Function
Estrogens possess potent antioxidant properties and exert neuroprotective actions. Estrogen deficiency is associated with mitochondrial dysfunction, neuroinflammation, synaptic decline, cognitive impairment, and increased risk of age-related disorders.[xiv] Several studies have documented the profound effects and multiple mechanisms of action of estrogen on memory, mood, mental state, and neurodevelopmental and neurodegenerative processes, supporting the views that they are neurotrophic, neuroprotective, and psychoprotective.[xv] Indeed, women demonstrate a decrease in verbal memory during the menopausal transition, a change that has been linked to alterations in hippocampal function associated with loss of estradiol.[xvi]
Supporting Our Hormones, Naturally
The foods we eat, how much exercise we get, how much sleep we get (or don’t get), how much stress we have in our lives, those are all factors affecting our hormones — for better and for worse. For example, studies have shown that women on the Mediterranean diet not only have fewer hot flashes but also much lower risk of cognitive decline, of depression, of heart disease, of stroke and of cancer.[xvii] Among other beneficial factors, this diet is quite rich in foods that contain estrogens from plants (phytoestrogens) that act like mild estrogens in our bodies. Various plants have indeed been used for centuries to alleviate menstrual and menopause symptoms, such as ginger, hops, milk thistle, red clover, sage, soy, black cohosh, and vitex, to name a few.[xviii]
Menopause is a universal event experienced by all women who live to midlife and beyond. Given that women living today will on average spend one-third of their life in the postmenopausal stage,[xix] it is critical to consider menopause in brain function and AD. It is even more critical to start implementing diet and lifestyle modifications to optimise our hormonal balance and overall health BEFORE the onset of the cognitive decline process to protect our brain from accelerated aging and its deleterious consequences.
[i] Parker G, Brotchie H. Gender differences in depression. Int Rev Psychiatry. 2010;22(5):429-36. doi: 10.3109/09540261.2010.492391. PMID: 21047157.
[ii] Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF; AMPP Advisory Group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007 Jan 30;68(5):343-9. doi: 10.1212/01.wnl.0000252808.97649.21. PMID: 17261680.
[iii] Nebel RA, Aggarwal NT, Barnes LL, et al. Understanding the impact of sex and gender in Alzheimer’s disease: A call to action. Alzheimers Dement. 2018;14(9):1171-1183. doi:10.1016/j.jalz.2018.04.008
[iv] Mosconi L, Rahman A, Diaz I, Wu X, Scheyer O, Hristov HW, Vallabhajosula S, Isaacson RS, de Leon MJ, Brinton RD. Increased Alzheimer’s risk during the menopause transition: A 3-year longitudinal brain imaging study. PLoS One. 2018 Dec 12;13(12):e0207885. doi: 10.1371/journal.pone.0207885. PMID: 30540774; PMCID: PMC6291073.
[v] Nebel RA, Aggarwal NT, Barnes LL, et al. Understanding the impact of sex and gender in Alzheimer’s disease: A call to action. Alzheimers Dement. 2018;14(9):1171-1183. doi:10.1016/j.jalz.2018.04.008
[vi] Echeverria V, Echeverria F, Barreto GE, Echeverría J, Mendoza C. Estrogenic Plants: to Prevent Neurodegeneration and Memory Loss and Other Symptoms in Women After Menopause. Front Pharmacol. 2021 May 20;12:644103. doi: 10.3389/fphar.2021.644103. PMID: 34093183; PMCID: PMC8172769.
[vii] Freedman RR. Menopausal hot flashes: mechanisms, endocrinology, treatment. J Steroid Biochem Mol Biol. 2014;142:115-120. doi:10.1016/j.jsbmb.2013.08.010
[viii] Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW. Control of sleep and wakefulness. Physiol Rev. 2012;92(3):1087-1187. doi:10.1152/physrev.00032.2011
[ix] Mosconi, L. How menopause affects the brain. TEDWomen 2019. https://www.ted.com/talks/lisa_mosconi_how_menopause_affects_the_brain/transcript?language=en#t-413417
[x] Rettberg JR, Yao J, Brinton RD. Estrogen: a master regulator of bioenergetic systems in the brain and body. Front Neuroendocrinol. 2014;35(1):8-30. doi:10.1016/j.yfrne.2013.08.001
[xi] Rettberg JR, Yao J, Brinton RD. Estrogen: a master regulator of bioenergetic systems in the brain and body. Front Neuroendocrinol. 2014;35(1):8-30. doi:10.1016/j.yfrne.2013.08.001
[xii] Zárate S, Stevnsner T, Gredilla R. Role of Estrogen and Other Sex Hormones in Brain Aging. Neuroprotection and DNA Repair. Front Aging Neurosci. 2017;9:430. Published 2017 Dec 22. doi:10.3389/fnagi.2017.00430
[xiii] Mosconi, L. How menopause affects the brain. TEDWomen 2019. https://www.ted.com/talks/lisa_mosconi_how_menopause_affects_the_brain/transcript?language=en#t-413417
[xiv] Zárate S, Stevnsner T, Gredilla R. Role of Estrogen and Other Sex Hormones in Brain Aging. Neuroprotection and DNA Repair. Front Aging Neurosci. 2017;9:430. Published 2017 Dec 22. doi:10.3389/fnagi.2017.00430
[xv] Gillies GE, McArthur S. Estrogen actions in the brain and the basis for differential action in men and women: a case for sex-specific medicines. Pharmacol Rev. 2010;62(2):155-198. doi:10.1124/pr.109.002071
[xvi] Rentz DM, Weiss BK, Jacobs EG, Cherkerzian S, Klibanski A, Remington A, Aizley H, Goldstein JM. Sex differences in episodic memory in early midlife: impact of reproductive aging. Menopause. 2017 Apr;24(4):400-408. doi: 10.1097/GME.0000000000000771. PMID: 27824681; PMCID: PMC5365356.
[xvii] Mediterranean Diet May Protect Against Alzheimer’s Disease. Weill Cornell Medicine Newsroom. https://news.weill.cornell.edu/news/2018/05/mediterranean-diet-may-protect-against-alzheimer%E2%80%99s-disease
[xviii] Echeverria V, Echeverria F, Barreto GE, Echeverría J, Mendoza C. Estrogenic Plants: to Prevent Neurodegeneration and Memory Loss and Other Symptoms in Women After Menopause. Front Pharmacol. 2021 May 20;12:644103. doi: 10.3389/fphar.2021.644103. PMID: 34093183; PMCID: PMC8172769.
[xix] Nebel RA, Aggarwal NT, Barnes LL, et al. Understanding the impact of sex and gender in Alzheimer’s disease: A call to action. Alzheimers Dement. 2018;14(9):1171-1183. doi:10.1016/j.jalz.2018.04.008