Women, Perimenopause, and Alzheimer’s Disease: A Call to Action

When your hormones go down in your forties, your risk of dementia and Alzheimer’s disease go up. Alzheimer’s disease (AD) is the most common cause of dementia, accounting for half of the cases. AD is a progressive brain/body disorder characterized by gradual memory loss, nerve cell loss, dysfunction of connections between nerve cells (synapses), and subsequent impairment in cognitive and behavioral functions. Physically, AD is characterized by two types of pathological lesions: plaques of accumulated amyloid beta peptide outside the cells and abnormal forms of tau protein—collections of neurofibrillary tangles—inside the cells. The plaques result from abnormal protein folding and aggregation, like misfolded bedsheets.

Women make up two-thirds of Alzheimer’s cases, and it’s not just because we live longer than men. Getting old and being female are the two most common risk factors for Alzheimer’s disease. You can think of this as a chronological and a hormonal trigger for the big “A,” yet we don’t completely understand why the gender difference occurs.[1] There is a desperate need to address knowledge gaps in understanding sex and gender differences in the development of cognitive decline.

The Alzheimer’s Gene: APOE4

The best-known gene for AD is Apolipoprotein E (APOE4, sometimes APO-e4). You inherit a copy of the APOE gene—E2, E3, or E4—from each parent. So you can end up with one or two copies of the APOE4 or “Alzheimer’s gene.” APOE gene instructs cells to make a protein called apolipoprotein A, which combines with fat in the body to make a package that carries cholesterol back to the liver for disposal through feces. People with the bad variant of this gene, APOE4, don’t recycle cholesterol, leading to higher levels of low-density lipoprotein (LDL, or bad cholesterol) in the blood.

Women with APOE4 have a threefold greater risk of developing Alzheimer’s disease. About 20 to 25 percent of the population has one or two copies of the APOE4 gene. However, only about 20 percent of patients with Alzheimer’s disease carry the gene.[2]

What We Know:

• Women have a significantly higher risk of developing Alzheimer’s disease compared with men, even when you control for increased lifespan.[3]
• Not only that, but women with AD have a faster decline.[4] One study showed in post-hoc analysis that women who are positive for APOE4 and amyloid beta decline faster compared with men.[5]
• Overall, the risk of dementia is 18 percent higher in women, and the risk of Alzheimer’s disease is increased by 56 percent.[6]
• One factor that is unique to women is that we suddenly experience rapid changes in estrogen, progesterone, and testosterone starting in perimenopause, the two to ten years before your final menstrual period. This hormonal transition appears to be a sex-specific and major risk factor for developing AD.
• Women in perimenopause, which typically occurs in your forties, develop low energy in the brain, also known as “hypometabolism.” This seems to be a precursor to cognitive decline that occurs decades later.[7]
• Sleep disorders are more common in women and may modulate risk of dementia and effect of sex hormones.[8]
• Other nutritional factors, such as folate intake, may modify a woman’s risk of dementia.[9]
• On the other hand, cumulative estrogen exposure and hormone therapy do not decrease the risk of dementia later in life.[10]

How the Perimenopausal Transition and Menopause May Trigger Cognitive Decline

As we try to uncover the specific reasons that women’s brains are more vulnerable to cognitive decline and Alzheimer’s disease, several mechanisms have been proposed.

• Low brain energy. In perimenopause, there is a dramatic decline in the brain’s energy levels as you transition from premenopause (cycling regularly and fertile) to menopause (no more periods). In short, brain’s use of glucose as fuel begins to falter, leading to a decline in mitochondrial function and difficulty using glucose. If you’ve ever been told in your forties by a well-meaning doctor that the symptoms you have are all in your head, here’s the proof![11]
• When you follow men and women with mild cognitive decline to suss out what factors put them at risk of developing AD, the factors are different. For women, it’s whether they have the “Alzheimer’s gene” (APOE4) and depression at baseline.[12] For men, it’s the presence of severe periventricular white matter hyperintensities, and poorer global cognitive function at baseline. So, depression in women and genetic testing become extremely important.
• Premenopausal women have mitochondria that are protected from amyloid beta toxicity and generate less reactive oxygen species, and release fewer apoptogenic signals compared with men.[13] Estrogen seems to be what protects the mitochondria, and as estrogen withdraws in perimenopause, women may be more vulnerable to amyloid-beta toxicity and oxidative stress.
• Microbiome alterations are a root cause of Alzheimer’s disease,[14] and females may have a different microbiome compared with males, or at least different bidirectional influences.[15] For example, in women, the estrobolome, the subset of the DNA of the gut flora that modulates estrogen levels, may affect a woman’s risk of breast cancer.[16] Could microbiome alterations be related to a woman’s risk of AD?
• Changes occur even in the young females who undergo removal of the ovaries, at least in rats.[17] When you remove the ovaries in young female rates, an imbalance develops between the “on” (excitatory) and “off” (inhibitory) brain chemicals. Tau protein and calcium signaling go haywire. These are some of the specific brain changes that we are just starting to understand and appear to be related to a woman’s greater vulnerability to not only dementia and AD, but depression too.

Tick Tock

My brain is getting older and yours is too. I like to think it’s getting better, because I know that the math of a healthy brain involves a better balance between inputs (like eating a big salad, regular HIIT exercise, and meditating) and outputs (such as prioritizing sleep, preventing leaky gut, and even keeping mitochondria in top shape). Still, part of the challenge for me is that I know brain problems are twice as common in women, particularly dementia and Alzheimer’s disease, but also anxiety and depression.

Most people consider old age as a progressive decline toward drooling and living in a nursing home, which is one of our greatest fears. By 2050, the number of people age sixty-five and older with the big “A” is expected to have tripled, according to conservative estimates.[18] Sadly, after age sixty-five, an individual’s risk of developing Alzheimer’s doubles every five years. After you hit age eighty-five, the risk reaches nearly 50 percent.[19]

What Can Be Done

The latest version of the Alzheimer’s Facts and Figures gets one fact completely wrong: “It’s the only cause of death in the top 10 in America that cannot be prevented, cured, or slowed.”[20]  Since first described a century ago, Alzheimer’s disease has been without effective treatment. Until now.

Dr. Dale Bredesen, M.D., a neurologist, UCLA professor, and investigator at the Buck Institute for Research on Aging, has pioneered a program that reverses memory loss in nearly all of his patients within three to six months.[21] Yes, reverses. Larger clinical trials need to be done, but this is a rare bright spot in the treatment of Alzheimer’s that you need to know about now before it’s too late.

Yet the cure is probably not a single drug with one target. Instead, the best solution appears to be a functional medicine approach that addresses multiple root causes. Imagine having a roof with thirty-six holes in it, and a drug that patches only one hole. Dr. Bredesen says that if you seal one hole, you still have a leaky roof with thirty-five other holes. So taking a drug for treatment isn’t helpful. But if you address multiple holes, you may get an additive or even synergistic effect, even if each hole is only modestly affected. You might reduce the leakiness by 90 percent. You haven’t fixed everything, but you’re much better off. This is the premise of functional medicine, and it especially applies to women.

Whether you’re male or female, reversing or preventing cognitive decline demands a change in diet, exercise, stress, sleep, brain stimulation, and supplements. Patients with Alzheimer’s often have poor hygiene, high perceived stress, inflammation, insulin resistance, vitamin D abnormalities and hormonal imbalances, and toxic exposures. As a woman, it becomes especially important to solve the hormonal problems, stress-related fatigue, and insulin block so that you can modify your genetic or epigenetic risk of Alzheimer’s. The key is to intervene before the window closes—ideally within ten years of the very first symptoms (walking into a room and not remembering why, losing your keys, forgetting a word that’s on the tip of your tongue), when there’s still time to reverse the imbalanced signals. Or, even better, way before any symptoms start.

Call to Action

You now understand our urgent need to understand sex differences in the development of cognitive decline and Alzheimer’s disease. Here are ideas for what you can do, and I look forward to hearing from you in the comments section below for your additional ideas.

1. Eat anti-inflammatory food that keeps your blood sugar stable.
2. Test for the APOE gene. Talk to a functional medicine doctor about what to do with the results, and read book, Younger, pages 32, 302-33, and 312-313. My later book Brain Body Diet is another good resource. While the main point of that book isn’t to prevent or reverse Alzheimer’s, the strategies I share are aimed at reversing insulin block, which will also help you prevent some cases of Alzheimer’s disease, including early manifestations like forgetfulness and mood changes.
3. Get good sleep. Seven to 8.5 hours every night.
4. Fast 12 to 18 hours overnight to reduce your risk of AD.
5. Exercise 30 to 60 minutes, four to six times per week.
6. Keep inflammation low, such as a serum hsCRP < 1.0, and homocysteine < 7.

[1] Mosconi, L., et al. “Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging.” Neurology 89, no. 13 (2017): 1382-1390.

[2] Mayeux, R., et al. “Epidemiology of Alzheimer disease.” Cold Spring Harbor Perspectives in 
Medicine 2, no. 8 (2012): a006239.

[3] Callahan, M. J., et al. “Augmented senile plaque load in aged female β-amyloid precursor protein-transgenic mice.” The American Journal of Pathology 158, no. 3 (2001): 1173-1177; Musicco, M. “Gender differences in the occurrence of Alzheimer’s disease.” Functional Neurology 24, no. 2 (2009): 89-92; Dye, R. V., et al. “Hormone replacement therapy and risk for neurodegenerative diseases.” International Journal of Alzheimer’s Disease 2012 (2012); Mielke, M. M., et al. “Clinical epidemiology of Alzheimer’s disease: Assessing sex and gender differences.” Clinical Epidemiology 6 (2014): 37-48; Kim, S., et al. “Gender differences in risk factors for transition from mild cognitive impairment to Alzheimer’s disease: A CREDOS study.” Comprehensive Psychiatry 62 (2015): 114-122.

[4] Henderson, V. W., et al. “Cognitive deficits of men and women with Alzheimer’s disease.” Neurology 44, no. 1 (1994): 90-90; Read, S., et al. “Sex differences after all those years? Heritability of cognitive abilities in old age.” The Journals of Gerontology Series B: Psychological Sciences and Social Sciences 61, no. 3 (2006): P137-P143; Proust-Lima, C., et al. “Gender and education impact on brain aging: A general cognitive factor approach.” Psychology and Aging 23, no. 3 (2008): 608.

[5] Buckley, R. F., et al. “Sex, amyloid, and APOE ε4 and risk of cognitive decline in preclinical Alzheimer’s disease: Findings from three well-characterized cohorts.” Alzheimer’s & Dementia (2018).

[6] Gao, S., et al. “The relationships between age, sex, and the incidence of dementia and Alzheimer disease: A meta-analysis.” Archives of General Psychiatry 55, no. 9 (1998): 809-815.

[7] Mosconi, L., et al. “Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging.” Neurology 89, no. 13 (2017): 1382-1390.

[8] Lacreuse, A., et al. “Neurocognitive effects of estrogens across the adult lifespan in nonhuman primates: State of knowledge and new perspectives.” Hormones and Behavior 74 (2015): 157-166; Gervais, N. J., et al. “Ovarian hormones, sleep and cognition across the adult female lifespan: An integrated perspective.” Frontiers in Neuroendocrinology (2017)

[9] Agnew-Blais, J. C., et al. “Folate, vitamin B-6, and vitamin B-12 intake and mild cognitive impairment and probable dementia in the Women’s Health Initiative Memory Study.” Journal of the Academy of Nutrition and Dietetics 115, no. 2 (2015): 231-241.

[10] Maki, P. M., et al. “Hormone therapy, dementia, and cognition: The Women’s Health Initiative 10 years on.” Climacteric 15, no. 3 (2012): 256-262; Rocca, W. A., et al. “Oophorectomy, estrogen, and dementia: a 2014 update.” Molecular and Cellular Endocrinology 389, no. 1-2 (2014): 7-12; Gartlehner, G., et al. “Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: An evidence review for the US preventive services task force.” (2017); Prince, M. J., et al. “Reproductive period, endogenous estrogen exposure and dementia incidence among women in Latin America and China; A 10/66 population-based cohort study.” PLoS One 13, no. 2 (2018): e0192889.

[11] Mosconi, L., et al. “Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery.” PLoS One 12, no. 10 (2017): e0185926.

[12] Kim, S., et al. “Gender differences in risk factors for transition from mild cognitive impairment to Alzheimer’s disease: A CREDOS study.” Comprehensive Psychiatry 62 (2015): 114-122.

[13] Viña, J., et al. “Why women have more Alzheimer’s disease than men: Gender and mitochondrial toxicity of amyloid-β peptide.” Journal of Alzheimer’s Disease20, no. s2 (2010): S527-S533.

[14] Naseer, M. I., et al. “Role of gut microbiota in obesity, type 2 diabetes and Alzheimer’s disease.” CNS & Neurological Disorders-Drug Targets 13, no. 2 (2014): 305-311; Hu, X., et al. “Alzheimer’s disease and gut microbiota.” Science China Life Sciences 59, no. 10 (2016): 1006-1023; Kohler, C. A., et al. “The gut-brain axis, including the microbiome, leaky gut and bacterial translocation: Mechanisms and pathophysiological role in Alzheimer’s disease.” Current Pharmaceutical Design 22, no. 40 (2016): 6152-6166; Pistollato, F., et al. “Role of gut microbiota and nutrients in amyloid formation and pathogenesis of Alzheimer disease.” Nutrition Reviews 74, no. 10 (2016): 624-634; Alkasir, R., et al. “Human gut microbiota: The links with dementia development.” Protein & Cell 8, no. 2 (2017): 90-102; Jiang, C., et al. “The gut microbiota and Alzheimer’s disease.” Journal of Alzheimer’s Disease 58, no. 1 (2017): 1-15; Solas, M., et al. “Inflammation and gut-brain axis link obesity to cognitive dysfunction: Plausible pharmacological interventions.” Current Opinion in Pharmacology 37 (2017): 87-92; Zhao, Y., et al. “Secretory products of the human GI tract microbiome and their potential impact on Alzheimer’s disease (AD): Detection of lipopolysaccharide (LPS) in AD hippocampus.” Frontiers in Cellular and Infection Microbiology 7 (2017): 318; Lin, L., et al. “Neuroinflammation, gut microbiome, and Alzheimer’s disease.” Molecular Neurobiology (2018): 1-8; Sochocka, M., et al. “The gut microbiome alterations and inflammation-driven pathogenesis of Alzheimer’s disease- A critical review.” Molecular Neurobiology (2018).

[15] Clarke, G., et al. “The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.” Molecular Psychiatry 18, no. 6 (2013): 666; Flak, M. B., et al. “Welcome to the Microgenderome.” Science 339, no. 6123 (2013): 1044-1045; Markle, J. G., et al. “Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity.” Science 339, no. 6123 (2013): 1084-1088; Yurkovetskiy, L., et al. “Gender bias in autoimmunity is influenced by microbiota.” Immunity 39, no. 2 (2013): 400-412; Israelian, N., et al. “Sex effects at the ramparts: Nutrient-and microbe-mediated regulation of the immune-metabolic interface.” Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes and Obesity (2017): 113-140; Most, J., et al. “Gut microbiota composition strongly correlates to peripheral insulin sensitivity in obese men but not in women.” Beneficial Microbes 8, no. 4 (2017): 557-562; Rizzetto, L., et al. “Connecting the immune system, systemic chronic inflammation and the gut microbiome: The role of sex.” Journal of Autoimmunity (2018).

[16] Plottel, C. S., et al. “Microbiome and malignancy.” Cell Host & Microbe 10, no. 4 (2011): 324-335; Kwa, M., et al. “The intestinal microbiome and estrogen receptor–positive female breast cancer.” JNCI: Journal of the National Cancer Institute 108, no. 8 (2016); Baker, J. M., et al. “Estrogen–gut microbiome axis: Physiological and clinical implications.” Maturitas 103 (2017): 45-53.

[17] Fang, Y. Y., et al. “Evidence of altered depression and dementia-related proteins in the brains of young rats after ovariectomy.” Journal of Neurochemistry (2018).

[18] Alzheimer’s Association. “2015 Alzheimer’s disease facts and figures.” Alzheimer’s and Dementia: Journal of the Alzheimer’s Association 11, no. 3 (2015): 332.

[19] “What we know today about Alzheimer’s Disease,” Alzheimer’s Association, accessed June 27, 2018. https://www.alz.org/alzheimers-dementia/treatments

[20] Alzheimer’s Association. “2015 Alzheimer’s disease facts and figures.” Alzheimer’s and Dementia: Journal of the Alzheimer’s Association 11, no. 3 (2015): 332.

[21] Bredesen, D. E. “Reversal of cognitive decline: a novel therapeutic program.” Aging 6, no. 9 (2014): 707; Bredesen, D. E., et al. “Reversal of cognitive decline in Alzheimer’s disease.” Aging 8, no. 6 (2016): 1250; Bredesen, D. E. “Metabolic profiling distinguishes three subtypes of Alzheimer’s disease.” Aging 7, no. 8 (2015): 595; Bredesen, D. E. “Inhalational Alzheimer’s disease: an unrecognized—and treatable—epidemic.” Aging 8, no. 2 (2016): 304.