By: Clifford Morris, Ph.D.
Chief Chemist and Research Scientist
The largest failure of the biomedical research enterprise over the past 50 years has been its inability to adequately address Alzheimer’s disease. There are currently four FDA-approved medications for the relief of Alzheimer’s symptoms; three of which are acetylcholine esterase inhibitors, and the other is memantine. However, there exists no pharmaceutical intervention that arrests or reverses the disease. Moreover, a meta-analysis recently revealed that patients diagnosed with Alzheimer’s receiving acetylcholine esterase inhibitors showed an increase in cognitive decline compared to placebo.1 Since 2003, every disease-modifying agent has failed in Phase II or III trials.2 Alzheimer’s is the sixth leading cause of death in the United States, afflicting more than 5.8 million Americans.3 Between 2000 and 2017, heart disease mortality dropped nearly 9%, while Alzheimer’s mortality increased 145% (all ages).3 Taken together, this data reveals a grim outlook for the future of progression towards traditional disease-modifying therapies. For these reasons, Alzheimer’s risk reduction and prevention efforts have gained traction. Current Alzheimer’s prevention protocols seek to reduce the area under the curve of a function of Alzheimer’s risk factors. We can think of Alzheimer’s risk as being a function of certain variables, some of which are modifiable while others are non-modifiable. Modifiable risk factors include insulin resistance, obesity, inflammation, and smoking, whereas non-modifiable risk factors are age, sex, and family history. The figure below is meant to depict the difference between an at-risk individual who has taken measures to reduce his/her risk for Alzheimer’s versus one who has not.
The Interplay Between Hormones and Alzheimer’s Disease
One of the most notable non-modifiable disease risk factors is sex: women are two times more likely to die of Alzheimer’s than are men.3–5 Estrogen depletion in postmenopausal women is thought to be associated with this risk.4,5 In 2002, The Cache County Study revealed that women who have used hormone replacement therapy (HRT) for 10 years or more are no more likely to develop Alzheimer’s then are men. However, there was no suggestion of risk reduction if used for less than 10 years.6 These findings highlight the importance of identifying at-risk individuals and starting treatment early. More recently, some studies have suggested that long term use of hormone replacement therapy may actually increase Alzheimer’s risk in women.7 Thus, the story here is complicated, and there is still much to uncover. However, the majority consensus is that hormone replacement therapy may reduce Alzheimer’s risk for certain individuals.6,8,9 Estrogen has been found to play many roles in the human body, most notably in females. It has a unique property of being synthesized directly in the brain; this leads to many of its neuroprotective and neurodegenerative effects. It also plays a role in growth, differentiation, and sexual development.10 Most recently, Estrogen has been implicated with hormone replacement therapy in an attempt to treat Alzheimer’s.10–13 Although HRT can involve many hormones, the ones that most seem to be implicated in impacting Alzheimer’s disease are estrogen and progesterone. The reason for estrogen and progesterone having such a large implication in Alzheimer’s is their perceived sex bias. It has been suggested, although not all studies agree, that women are more likely to develop Alzheimer’s, and it is likely that Alzheimer’s dementia-inducing and deteriorating effects also occur more rapidly in women. There are numerous reasons for this, but perhaps one of the more pronounced ones is the gene APOE-4. APOE-4 is known to be a huge risk marker for Alzheimer’s and plays a role in the development of amyloid plaque deposition. However, it has been shown that being positive for APOE-4 plays a much larger role in cognitive decline in women than it does in men. This could be due to the extra amounts of estrogen in women, and that is why HRT has been viewed as a possible way to help treat Alzheimer’s. The two most common forms of HRT used for Alzheimer’s are estrogen-only therapy and estrogen in combination with progesterone. Studies have found that younger women (aged 50-63 years) who had undergone hormone therapy were significantly less likely to develop Alzheimer’s, while HRT showed no such effect for older women.10,12 However, in the Women’s Health Initiative trial, women who were on active treatment with estrogen plus progesterone had nearly a twice as likely chance of getting Alzheimer’s with serious dementia, while the women on only estrogen were nearly half as likely to get Alzheimer’s with full-fledged dementia. Data like this has led to a hypothesis known as the critical window hypothesis, where HRT (especially estrogen and progesterone) are only effective for a short amount of time in post-menopausal women. This seems to indicate that the critical window for estrogen therapy would be starting younger and using for a longer amount of time. This window, however, does differ from the window associated with HRT that combines estrogen and progesterone. Women using combination HRT for under a year revealed an elevated risk, but women using combination HRT for between 1-3 years had a lower risk. This not only backs up the critical window hypothesis but also seems to suggest that it changes depending on which hormones are used. That being said, women are not the only ones effected by Alzheimer’s; men also are, but generally at a lower rate. If estrogen decline was found to be a large factor in the development of Alzheimer’s, then that may help explain why men are not affected as much. Serum estrogen rates have actually been found to be higher in elderly males than in post-menopausal women. This is because men constantly make testosterone and then convert that testosterone (albeit at a low rate of 0.2%) to estrogen, providing them with what may be increased protection. Further, another reason that men might be more well protected is the drop-off found in women’s estrogen levels post menopause is not nearly as severe for elderly men despite reduced testosterone production. While it has been shown that estrogen effects Alzheimer’s, it is unknown in exactly what way it does. While HRT may be a promising field that can help with Alzheimer’s, finding out what the critical window is for each person and which set of hormones to use remains a challenge. In the future, a more appropriate form of treatment may be personalized HRT based on the patients’ medical history combined with genetic testing to see if they have an increased risk for Alzheimer’s disease. Physicians Lab offers comprehensive urinary hormone testing to help assess hormone levels and biomarkers that may be critical in developing a therapeutic solution for Alzheimer’s disease prevention.
Dietary Approaches for Alzheimer’s Disease
As our appreciation for the complexity of Alzheimer’s pathology has evolved, we have begun to view the disease through several different lenses (e.g., the amyloid hypothesis, mitochondrial disfunction, and cerebral hypoperfusion). An emerging viewpoint is Alzheimer’s as an inflammatory disease.14 Studies have shown that Alzheimer’s patients present with elevated serum levels of inflammatory markers, such as COX, TNF-α, and IL-6.15–18 These inflammatory markers have shown the ability to disrupt amyloid clearance and combat signaling pathways responsible for cell survival.16,17 Because of the relationship between Alzheimer’s and inflammation, anti-inflammatory drugs show promise in reducing Alzheimer’s risk. Long term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of Alzheimer’s disease.15 Studies suggest that unselective COX inhibitors are more potent than selective inhibitors in terms of risk reduction.19 Further, dietary and lifestyle changes associated with reduced inflammation show promise in Alzheimer’s risk reduction. Specific dietary changes may involve avoiding high-carbohydrate, high-calorie meals that are associated with elevated serum levels of IL-6.15
In regards to lifestyle changes, Matthew Walker has devoted a large part of his career to understanding the relationship between sleep disruption and Alzheimer’s. His findings overlap well with the inflammatory hypothesis and suggest that high quality sleep may be critical in preventing the onset of Alzheimer’s disease.20 Despite many positive discoveries to help with the treatment of Alzheimer’s, a cure still remains unknown. This has led individuals to study other areas outside of traditional pharmacology, such as diet and nutritional supplementation. Although a majority of trend diets come and go, there is evidence to support a few diets that may help reduce the incidence of the Alzheimer’s disease: the Mediterranean diet, DASH (Dietary Approaches to Stop Hypertension), and MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay). Studies have shown that the DASH diet and Mediterranean diet were both effective in reducing Alzheimer’s risk.21 The DASH and the Mediterranean diet were originally designed to help with cardiovascular health, while the MIND diet is actually focused on reducing Alzheimer’s risk. Data shows that the MIND diet has close to a 50% chance of being an effective preventative action in regard to Alzheimer’s disease. These studies make sense as these diets are high in foods known as AGE (advanced glycation end products).2,21 Low AGE foods are considered to be good and include fish, fruit, legumes, and certain carbohydrates. These are foods that are rich in Omega-3’s, DHA’s (docosahexaenoic acid), and EPA’s (eicosapentaenoic acid), as well as B and D vitamins. Low AGE foods tend to be prevalent in the MIND diet, furthering the belief that MIND diet can help prevent Alzheimer’s. Diet is not the only non-traditional means used to combat Alzheimer’s either; natural supplements have also been in the mix as well. There are a lot of supplements that have been tested, but only a few were found to have clinical relevance. Huperzine A, Ginkgo biloba, Coral calcium, Coenzyme Q10, and Caprylic acid were all found to be ineffective by the Alzheimer’s Association. Despite these being touted by celebrities, they have failed to display real evidence in working in phase three trials. However, not all hope is lost as far as alternative therapies go, but larger scale studies will be needed to provide conclusive evidence in Alzheimer’s prevention.
The Unknown Factors
Another neuropathological feature of Alzheimer’s is oxidative stress. Postmortem examination of the Alzheimer’s brain reveals increased lipid peroxidation, protein and DNA oxidation, and evidence of impaired mitochondrial function.15,22 Alzheimer’s risk reduction with respect to reactive oxygen species (ROS) generation is primarily concerned with mediating homocysteine levels. Epidemiological studies have associated homocysteine, a known ROS stimulator, with the onset of Alzheimer’s disease.23 B vitamins are required to metabolize homocysteine to either methionine or cysteine. In 2007, a double-blind, placebo-controlled trial showed that extended use of vitamin B9 is associated with significantly slower cognitive decline versus placebo.24 It is important to note that a significant fraction of Hispanics and Caucasians may suffer from an MTHFR polymorphism that is linked to hyperhomocysteinemia.25 Such at-risk individuals are important to identify and treat appropriately as early as possible. There are a multitude of unknown and co-dependent factors resulting in the presentation of Alzheimer’s disease. The nebulous mechanisms in which these all act in concert are a testament to the complexity of the disease, and it will take significantly more time and resources until we fully understand these discreet processes.
We have reviewed some of the most trafficked avenues of Alzheimer’s risk reduction and sought to understand Alzheimer’s as a multifaceted malady. Alzheimer’s risk is a function of many variables, some modifiable and others non-modifiable. Clinical action towards addressing each variable is unique. Some risks may be alleviated with pharmaceutical intervention, while others may require lifestyle and dietary changes.
(1) Kennedy, R. E.; Cutter, G. R.; Fowler, M. E.; Schneider, L. S. Association of Concomitant Use of Cholinesterase Inhibitors or Memantine With Cognitive Decline in Alzheimer Clinical Trials. JAMA Netw. Open 2018, 1 (7), e184080.
(2) Galvin, J. E. Prevention of Alzheimer’s Disease: Lessons Learned and Applied. J. Am. Geriatr. Soc. 2017, 65 (10), 2128–2133.
(3) Alzheimer’s Association. 2019 Alzheimer’s Disease Facts and Figures. Alzheimer’s Dement. 2019, 15 (3), 321–387.
(4) Launer, L. J.; Andersen, K.; Dewey, M. E.; Letenneur, L.; Ott, A.; Amaducci, L. A.; Brayne, C.; Copeland, J. R. M.; Dartigues, J.-F.; Kragh-Sorensen, P.; et al. Rates and Risk Factors for Dementia and Alzheimer’s Disease: Results from EURODEM Pooled Analyses. Neurology 1999, 52 (1), 78–84.
(5) Medeiros, A. D. M.; Silva, R. H. Sex Differences in Alzheimer’s Disease: Where Do We Stand? J. Alzheimer’s Dis. 2019, 67 (1), 35–60.
(6) Zandi, P. P.; Carlson, M. C.; Plassman, B. L.; Welsh-bohmer, K. A.; Mayer, L. S.; Steffens, D. C.; Breitner, J. C. S. Hormone Replacement Therapy and Incidence of Alzheimer Disease in Older Women. Health Care (Don. Mills). 2002, 288 (17), 2123–2129.
(7) Savolainen-Peltonen, H.; Rahkola-Soisalo, P.; Hoti, F.; Vattulainen, P.; Gissler, M.; Ylikorkala, O.; Mikkola, T. S. Use of Postmenopausal Hormone Therapy and Risk of Alzheimer’s Disease in Finland: Nationwide Case-Control Study. BMJ 2019, 364, 1–8.
(8) Imtiaz, B.; Taipale, H.; Tanskanen, A.; Tiihonen, M.; Kivipelto, M.; Heikkinen, A. M.; Tiihonen, J.; Soininen, H.; Hartikainen, S.; Tolppanen, A. M. Risk of Alzheimer’s Disease among Users of Postmenopausal Hormone Therapy: A Nationwide Case-Control Study. Maturitas 2017, 98, 7–13.
(9) Seshadri, S.; Zornberg, G. L.; Derby, L. E.; Myers, M. W.; Jick, H.; Drachman, D. A. Postmenopausal Estrogen Replacement Therapy and the Risk of Alzheimer Disease. Arch. Neurol. 2001, 58 (3), 435–440.
(10) Henderson, V. W. Alzheimer’s Disease: Review of Hormone Therapy Trials and Implications for Treatment and Prevention after Menopause. Journal of Steroid Biochemistry and Molecular Biology. 2014.
(11) Scheyer, O.; Rahman, A.; Hristov, H.; Berkowitz, C.; Isaacson, R. S.; Diaz Brinton, R.; Mosconi, L. Female Sex and Alzheimer’s Risk: The Menopause Connection. J. Prev. Alzheimer’s Dis. 2018.
(12) Maki, P. M.; Henderson, V. W. Hormone Therapy, Dementia, and Cognition: The Women’s Health Initiative 10 Years On. Climacteric. 2012.
(13) Janicki, S. C.; Schupf, N. Hormonal Influences on Cognition and Risk for Alzheimer’s Disease. Current Neurology and Neuroscience Reports. 2010.
(14) Bolós, M.; Perea, J. R.; Avila, J. Alzheimer’s Disease as an Inflammatory Disease. Biomol. Concepts 2017, 8 (1), 37–43.
(15) Schelke, M. W.; Attia, P.; Palenchar, D. J.; Kaplan, B.; Mureb, M.; Ganzer, C. A.; Scheyer, O.; Rahman, A.; Kachko, R.; Krikorian, R.; et al. Mechanisms of Risk Reduction in the Clinical Practice of Alzheimer’s Disease Prevention. Front. Aging Neurosci. 2018, 10 (APR), 1–14.
(16) Álvarez, A.; Cacabelos, R.; Sanpedro, C.; García-Fantini, M.; Aleixandre, M. Serum TNF-Alpha Levels Are Increased and Correlate Negatively with Free IGF-I in Alzheimer Disease. Neurobiol. Aging 2007, 28 (4), 533–536.
(17) Hüll, M.; Strauss, S.; Berger, M.; Volk, B.; Bauer, J. The Participation of Interleukin-6, a Stress-Inducible Cytokine, in the Pathogenesis of Alzheimer’s Disease. Behav. Brain Res. 1996, 78 (1), 37–41.
(18) Heneka, M. T.; O’Banion, M. K.; Terwel, D.; Kummer, M. P. Neuroinflammatory Processes in Alzheimer’s Disease. J. Neural Transm. 2010, 117 (8), 919–947.
(19) Gasparini, L.; Ongini, E.; Wenk, G. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in Alzheimer’s Disease: Old and New Mechanisms of Action. J. Neurochem. 2004, 91 (3), 521–536.
(20) Mander, B. A.; Winer, J. R.; Jagust, W. J.; Walker, M. P. Sleep: A Novel Mechanistic Pathway, Biomarker, and Treatment Target in the Pathology of Alzheimer’s Disease? Trends Neurosci. 2016, 39 (8), 552–566.
(21) Hu, N.; Yu, J.-T.; Tan, L.; Wang, Y.-L.; Sun, L.; Tan, L. Nutrition and the Risk of Alzheimer’s Disease. Biomed Res. Int. 2013.
(22) Markesbery, W. R. Oxidative stress hypothesis in alzheimer’s disease. Free Radic. Biol. Med. 1997, 23 (1), 134–147.
(23) Morris, M. S. Homocysteine and Alzheimer’s Disease. Lancet Neurol. 2003, 2 (7), 425–428.
(24) Durga, J.; van Boxtel, M. P.; Schouten, E. G.; Kok, F. J.; Jolles, J.; Katan, M. B.; Verhoef, P. Effect of 3-Year Folic Acid Supplementation on Cognitive Function in Older Adults in the FACIT Trial: A Randomised, Double Blind, Controlled Trial. Lancet 2007, 369 (9557), 208–216.
(25) Dean, L. Methylenetetrahydrofolate Reductase Deficiency. Med. Genet. Summ. 2012, No. Md, 1–5.