Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland
Dr. Jensen reports he is a consultant for and receives grant/research support from Bayer, Merck, ContraMed, and FHI360; receives grant/research support from Abbvie, HRA Pharma, Medicines 360, and CONRAD; and is a consultant for the Population Council.
SYNOPSIS: In an observational multimodality brain imaging study, investigators found sex and age differences correlated with endophenotypes of late-onset Alzheimer’s disease.
SOURCE: Mosconi L, Berti V, Quinn C, et al. Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging. Neurology 2017;89:1382-1390.
Epidemiologic studies show that Alzheimer’s disease (AD) occurs more frequently in women and suggest that hormonal therapy (HT) may protect women from developing the disorder.1 Mosconi and colleagues performed a cross-sectional, observational, multimodality brain imaging study to investigate the emergence of brain imaging patterns during the transition to menopause that might reflect AD risk. They evaluated a cohort of clinically and cognitively normal women and age-matched men between the ages of 40 to 60 years and measured “endophenotypes” (heritable, reliable, and quantifiable biological traits more closely related to the root cause of the disease than the broad clinical phenotype) considered reflective of late-onset AD risk.
To justify the neuroimaging used, the authors cited literature that links declining levels of estrogen during perimenopause to altered glucose metabolism that in turn induces a hypometabolic state accompanied by increased fatty acid catabolism. This leads to β-amyloid (a hallmark of AD pathology) deposition and the decline in synaptic plasticity associated with the development of AD later in life.2 To test whether age- and sex hormone-related effects influence the risk of AD development, they evaluated subjects using multimodality brain imaging measuring three putative biomarkers associated with AD development: 1) β-amyloid deposition (C11–Pittsburgh compound B [PiB]) PET scan); 2) glucose hypometabolism (F18-fluoro-2-deoxyglucose [FDG]) PET scan; and 3) brain atrophy (MRI). These have been proposed as surrogate measures of AD risk.3
The authors selected subjects for this study from a larger pool of clinically and cognitively normal adults participating in brain imaging studies for AD.4 After exclusion, they selected 42 women and used clinical judgment and symptoms to group them as: asymptomatic perimenopausal women (control, n = 15); symptomatic perimenopausal women (PERI, n = 13); and postmenopausal women (POST, n = 14). They also selected a cohort of 18 age- and education-matched men. All of the subjects previously had received volumetric MRI, PiB, and FDG-PET scans using the same standardized procedures. All subjects underwent genotyping for APOE4, a genetic marker for brain atrophy.
With the exception of age (older in the POST group), the female groups were comparable on clinical and neuropsychological measures and APOE4 distribution. Compared to asymptomatic perimenopausal control women (and to men) and controlling for age, the PERI and POST groups exhibited significantly increased indicators of AD endophenotype, including hypometabolism, increased β-amyloid deposition, and reduced gray and white matter volumes in AD-vulnerable regions. These AD biomarker abnormalities were greatest in POST, intermediate in PERI, and lowest in control women (P < 0.001). β-amyloid deposition was significantly greater in APOE4-positive POST women compared to the other groups.
Based on these multimodality brain imaging results demonstrating sex differences in the development of the AD endophenotype, the authors concluded that the preclinical AD phase begins early in the female aging process during the endocrine transition of perimenopause. They suggested that therapeutic intervention with estrogen during the perimenopause might reduce the risk of AD development.
A catchy image on my electronic edition of The New York Times, The Menopause-Alzheimer’s Connection,5 drew my attention to this manuscript. In the Times article, the lead author, a neuroscientist named Dr. Lisa Mosconi, presents a lay summary of her recent publication. The article begins with the impressive image, a PET scan, of an AD sufferer’s brain in full color showing serial sections highlighted with electric red, green, blue, and magenta. You don’t need to be a neuroradiologist to be impressed by this image. It looks important and not the way you would like to see your brain. Dr. Mosconi leads off the article dramatically stating, “In the next three minutes, three people will develop Alzheimer’s disease. Two of them will be women.” A clear call for action.
She goes on to explain that the estrogen deficiency that develops with the transition to menopause explains this gender difference in AD risk. She summarizes the research results from her group as evidence proving this association. The concluding recommendation is to initiate hormonal therapy (HT) early to prevent cognitive decline. This recommendation also falls in line with the literature supporting the “timing” hypothesis to maximize benefits of HT for cardiovascular disease.6
While I want to believe in this mechanism, I need to point out that this paper greatly overstates the significance of the data. We need to be intellectually honest about the science, and not cherry-pick results consistent with our beliefs. Major limitations of the multimodality brain imaging study include classification and ascertainment bias. They authors used history to classify women into healthy control, perimenopausal, and menopausal groups. There is no mention of hormonal therapy or whether this was exclusionary. They also do not report hormonal contraception use. Since the assessment of the multimodality brain imaging is somewhat subjective, it would be important to know whether the authors used a blinded independent reader. Unfortunately, the authors fail to mention this important detail. While the data support an age-associated adverse change in AD imaging findings in women, they do not provide convincing evidence that this is due to hypoestrogenism. Although they state that no age-related changes were observed in the smaller cohort of age-matched men, they do not present sufficient data to determine if this is true. They present no ad hoc hypothesized effect size, and no justification for the sample size selected. Furthermore, the use of imaging as a surrogate for Alzheimer risk has not been validated.
What do we know about cognition and hormonal therapy? In the subset of women aged 65 years or older in the Women’s Health Initiative (WHI) study, HT did not improve cognitive function when compared with placebo, and more women in the HT group experienced cognitive decline.7 Just as with cardiovascular disease, one explanation for the negative effects observed in WHI and the positive benefits seen in observational studies may be a critical window for initiation of treatment.
The randomized ELITE-Cog study was designed to evaluate this “aging” or “timing” hypothesis with respect to cognitive outcomes.8 The primary hypothesis of this study was that postmenopausal estrogen initiated soon after menopause (< 6 years) would affect verbal memory differently than initiation at a later time (≥ 10 years). Subjects were randomized to receive oral 17β-estradiol (1 mg daily) or matching placebo. Women with a uterus received cyclic micronized progesterone as a 4% vaginal gel or matched placebo gel for 10 days each month. The investigators assessed cognitive skills at baseline, 2.5 years, and five years using a comprehensive neuropsychological battery that emphasized standardized tests sensitive to age-related changes. Results of the cognitive tests showed no overall significant or clinically important difference in verbal memory in women who received estradiol compared to placebo, and no difference with respect to early or late initiation of hormonal therapy. A similar lack of effect was seen for executive function and global cognition. The authors concluded that estradiol therapy neither benefits nor harms cognitive ability regardless of time of initiation of HT after menopause.
The results of ELITE-Cog were consistent with KEEPS-Cog.9 The KEEPS-Cog study randomized recently postmenopausal women to receive transdermal estradiol or oral conjugated equine estrogens (with cyclic micronized progesterone in women with a uterus). Participants averaged 53 years of age and were 1.4 years past their last menstrual period. As with ELITE-Cog, no treatment-related benefit of HT was seen with respect to cognitive function.
While the KEEPS-Cog, ELITE-Cog, and WHI results do not support the use of estrogen therapy to prevent cognitive decline in postmenopausal women, all of these studies have limitations. Some brain researchers (like Mosconi) believe that susceptibility for irreversible cognitive effects may manifest in the perimenopausal transition.10 It also could be that the estrogen doses studied have been too low. The median estradiol level on treatment in the ELITE-Cog study was around 40 pg/mL. KEEPS-Cog used a very low dose of conjugated equine estrogens. These may be insufficient to produce cardiovascular or brain benefits.
While the results of Mosconi et al do not definitively support a role of HT in the prevention of Alzheimer's disease, these brain imaging techniques need further evaluation. I would like to see a true prospective multimodality brain imaging study similar to ELITE-Cog randomizing women early and late in the menopausal transition to HT or placebo. This powerful tool could help provide real evidence in support of a cognitive benefit of HT. Right now, all we have is pretty pictures.
- Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: The Cache County Study. JAMA 2002;288:2123-2129.
- Yao J, Brinton RD. Estrogen regulation of mitochondrial bioenergetics: Implications for prevention of Alzheimer’s disease. Adv Pharmacol 2012;64:327-371.
- Jack CR Jr, Knopman DS, Jagust WJ, et al. Tracking pathophysiological processes in Alzheimer’s disease: An updated hypothetical model of dynamic biomarkers. Lancet Neurol 2013;12:207-216.
- Mosconi L, Brys M, Switalski R, et al. Maternal family history of Alzheimer’s disease predisposes to reduced brain glucose metabolism. Proc Natl Acad Sci U S A 2007;104:19067-19072.
- Mosconi L. The Menopause-Alzheimer’s Connection. The New York Times. Available at: https://www.nytimes.com/2018/04/18/opinion/menopause-alzheimers-connection.html. Accessed April 25, 2018.
- Harman SM, Brinton EA, Cedars M, et al. KEEPS: The Kronos Early Estrogen Prevention Study. Climacteric 2005;8:3-12.
- Rapp SR, Legault C, Henderson VW, et al. Subtypes of mild cognitive impairment in older postmenopausal women: The Women’s Health Initiative Memory Study. Alzheimer Dis Assoc Disord 2010;24:248-255.
- Henderson VW, St John JA, Hodis HN, et al. Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis. Neurology 2016;87:699-708.
- Gleason CE, Dowling NM, Wharton W, et al. Effects of hormone therapy on cognition and mood in recently postmenopausal women: Findings from the randomized, controlled KEEPS-Cognitive and Affective Study. PLoS Med 2015;12:e1001833.
- Brinton RD, Yao J, Yin F, et al. Perimenopause as a neurological transition state. Nat Rev Endocrinol 2015;11:393-405.