The preventive role of tempeh isoflavones on menopausal women's cognitive function: A multiple mechanism pathway

Abstract

Cognitive dysfunction in the elderly is not only a disease but also could be considered a preclinical condition of Alzheimer's disease (AD), one of the most common types of dementia in the elderly. Therefore, treatment such as early detection and management of risk factors that could slow and prevent the onset of dementia is necessary for the elderly. Estrogen reduces the risk of AD in postmenopausal women. It has also been shown to reduce amyloid-β (Aβ) pathology in animal models of AD and suppress Aβ secretion from neuronal tissue. Estrogen receptors are involved in cognitive processes such as learning and memory, the formation of the hippocampus, the amygdala, and the cerebral cortex. Hormone replacement therapy (HRT) could improve cognition and thus delay the development of AD. Giving HRT after 9 years has been shown to increase the risk of breast cancer two-fold and cardiovascular disease. Phytoestrogens are hormones found in plants that can be an alternative to HRT. One of the foods that contains phytoestrogens and is widely consumed in Indonesia is tempeh. Isoflavone is a dominant phytoestrogen, structurally an estrogen-like substance, and functionally similar to 17β-estradiol. In this review article, we will discuss the role of tempeh isoflavones in a mechanism pathway on cognition.

Introduction

Cognitive function is a mental process that includes perception, memory, language, problem-solving, and creativity.^1,2 Cognitive decline, including mild cognitive impairment (MCI), is generally characterized by no disruption to daily activities.^3,4 MCI with memory impairment (amnestic MCI) is at high risk of developing dementia, especially Alzheimer's disease (AD). MCI is a transitional state from normal cognition to AD. The effects of impaired cognitive function are serious, irreversible, and detrimental to health. ⁵ Cognitive decline occurs in women after the age of 50; during this period, women could be in the pre-menopausal stage or have already experienced menopause. ⁶ If cognitive decline continues into old age, there will be helplessness in doing various daily physical activities. Elderly disability is defined by the International Classification of Impairments, Disabilities, and Handicaps as a decrease or limitation of a person's ability to do normal daily activities. ⁷ The differences in the process of cognitive decline are related to the time or period of the emergence of neuropathological abnormalities in different brain parts. ⁸ The emergence of brain cell atrophy occurs when a person begins to enter the fifth decade of life. ⁹ Neurotransmitter changes, such as reduced dopamine production, occur as humans enter their seventh decade of life and continue to occur as they get older. ¹⁰

Cognitive disorders are often the result of a combination of neurotransmitter abnormalities and changes in brain structure and function. ¹⁰ These physical changes can lead to difficulties with language, decision-making, attention, and other areas of mental function, as well as personality changes. ¹¹ Several risk factors can contribute to cognitive impairment and dementia. These include genetic predispositions, diabetes mellitus, smoking, depression, high blood pressure, elevated total cholesterol, obesity, cardiovascular disease, inactivity (both physical and social), loss of estrogen (which may occur due to surgical menopause), and deficiencies in folate and vitamin B12. ¹² Additionally, behavioral factors such as smoking and alcohol consumption can worsen cognitive decline. On the other hand, certain factors may help improve or maintain cognitive function. These include adequate intake of vitamin B6, vitamin B12, folate, ¹³ isoflavones, ¹⁴ education, hormone replacement therapy (HRT), ¹⁵ and sufficient physical activity/exercise. ¹⁶ Preventing significant cognitive decline in old age can be achieved by incorporating foods rich in vitamin B12, folate, antioxidants, and active substances like isoflavones into the diet. Additionally, engaging in regular physical activity and considering hormone therapy could be beneficial.^16,17 Estrogen, a hormone found throughout the body, including the central nervous system (CNS), plays a crucial role in cognitive function and mood. Its effects can be understood through the modulation of various neurotransmitter systems, such as acetylcholine, catecholamines, serotonin, and GABA, in both animals and humans. Furthermore, estrogen receptors (ER) are located in several brain areas that are essential for cognitive processes, including learning and memory, as well as the formation of the hippocampus, amygdala, and cerebral cortex. ¹⁸

Estrogen has been shown to reduce the risk of AD in postmenopausal women and to mitigate issues related to amyloid-β (Aβ) in animal models of AD. Furthermore, it can decrease Aβ secretion from neuronal tissue. The use of HRT has been found to improve cognitive function, potentially delaying the development of Aβ. HRT can slow the accumulation of Aβ by reducing its release, which is a key component of amyloid plaques, into the brain parenchyma. ¹⁹ However, starting HRT after a nine-year gap has been found to double the risk of breast cancer. To minimize cancer risks, it is recommended that individuals undergoing HRT have annual or semi-annual physical examinations and mammograms. ²⁰ An alternative to HRT is the administration of phytoestrogens, which are plant-based hormones, particularly found in soybeans. ²¹ These natural hormones possess a molecular structure that is similar to that of human hormones and are referred to as bio-identical hormones. ²² Phytoestrogens have a chemical structure closely resembling that of 2-phenylnaphthalenes, which are analogous to the estrogen structural formula. Depending on various factors—including metabolic conditions, endogenous estrogen levels, gender, and menopausal status—phytoestrogens can function either agonistically (supporting estrogen-like effects) or antagonistically (exhibiting opposing effects). ²³ Research indicates that phytoestrogens can significantly enhance cognitive performance. ¹⁴ Estrogen also plays a role in promoting synaptogenesis in the hippocampus, influencing amino acids and cholinergic nerves. One commonly consumed food in Indonesia that contains phytoestrogens is tempeh. ²⁴

Consuming tempeh at the age of 60 can have positive effects on cognitive activity, including memory and concentration, due to its isoflavone content, which has an estrogenic effect. ²⁴ Isoflavones are dominant phytoestrogens that are structurally similar to the hormone estrogen and functionally comparable to 17β-estradiol. Estrogen is distributed throughout the body, including the CNS. ²⁵ ERs play a role in cognitive processes such as learning and memory, as well as the formation of the hippocampus, amygdala, and cerebral cortex. ²⁶ Isoflavones exert estrogen-like effects by binding to ERs, potentially mimicking some neuroprotective actions of estrogen in postmenopausal women. However, the effects of isoflavones are significantly weaker than those of pharmacological estrogen, and their clinical impact on women with AD remains limited and inconsistent. ²⁷ To prevent cognitive decline, it is beneficial to consume vitamin B12 and folic acid. ²⁸ Tempeh is a good source of isoflavones, vitamin B12, and folic acid. Additionally, vitamins B6, B12, and folic acid play crucial roles in maintaining nerve health. ²⁹ Studies have shown that elderly individuals with high vitamin B6 intake tend to have better cognitive scores. ³⁰ Supplementation with folic acid at specific doses can help prevent a decline in cognitive function among older adults. ²⁸ Vitamin B12 and folic acid protect the body from arterial damage caused by homocysteine by converting it into cysteine, which is then excreted in the urine. ³¹ Homocysteine is a sulfur-containing amino acid formed from the demethylation of methionine. Elevated levels of homocysteine are associated with an increased risk of heart attacks, strokes, AD, and decreased cognitive function.^31–34 Vitamin B12 is essential for normal nerve cell activity, DNA replication, and the production of red blood cells, white blood cells, and blood platelets. ³⁵ Furthermore, vitamins B12, B6, and folic acid are involved in converting folate into its active form and in the proper metabolism of all cells, particularly those in the digestive tract, bone marrow, and nervous tissue. ³⁶ A previous study that supplemented the diets of postmenopausal women with soy isoflavones found a slight decrease in both systolic and diastolic blood pressure in the experimental group, indicating the potential benefits of soy isoflavones on blood pressure. This suggests that soy supplementation may be a viable alternative therapy to HRT for managing postmenopausal symptoms. ³⁷

In a prospective study, women experiencing climacteric symptoms were randomized to receive one of three treatments for three months: acupuncture, phytoestrogens (specifically soy isoflavones), or low-dose hormone therapy. Various assessments were conducted before and after treatment, including the Greene Climacteric Scale, blood pressure, lipid levels, glucose, insulin, and the homeostatic model assessment of insulin resistance. The results indicated that treatment with acupuncture and phytoestrogens was associated with a decrease in blood pressure. Additionally, phytoestrogens appeared to positively impact low-density lipoprotein cholesterol levels. ³⁸ However, the mechanisms through which phytoestrogens exert their effects are not yet fully understood. Future research is necessary to determine whether these effects occur via ERs or other mechanisms that have not been identified. ²¹ The effects of phytoestrogens are not fully understood, so future research is needed to understand the exact mechanism of action, whether through ERs or other hidden mechanisms that produce these effects. ³⁹ The complexity of the biological impacts of phytoestrogens, along with variations in metabolism and bioavailability, indicates that any interpretation of risks or benefits should be approached with caution. ⁴⁰ It is also important to ensure the safety of soy milk consumption regarding liver function, kidney health, and hematological parameters, which were assessed in this study through blood markers. Furthermore, research conducted on one-year-old ovariectomized mice showed that those consuming tempeh exhibited better cognitive function compared to those that consumed tofu, estradiol, or casein. ⁴¹ Mice that consumed tempeh exhibited the lowest serum Aβ levels compared to those that received estradiol and casein. ⁴² Additionally, menopause is linked to an increased risk of sleep disorders, particularly obstructive sleep apnea (OSA). The decline in estrogen and progesterone during the menopausal transition affects upper airway stability and ventilatory control, heightening the likelihood of OSA in postmenopausal women. ⁴³ OSA is characterized by intermittent hypoxia and disrupted sleep, both of which can lead to neuronal damage and exacerbate cognitive decline. ⁴³ Research indicates that postmenopausal women with untreated OSA have a higher risk of developing memory impairment, executive dysfunction, and even dementia. ⁴⁴ Thus, sleep disturbances like OSA are significant, yet often underestimated, contributors to cognitive decline in menopausal women and should be considered in strategies aimed at preserving cognitive function during aging.^45,46

Pre-elderly women, perimenopause, and menopause

Women experience hormonal changes throughout their life cycle. ⁴⁷ The regulation of sex steroids in women is largely driven by luteinizing hormone, which stimulates the conversion of cholesterol to androstenedione in theca cells of the ovaries. ⁴⁸ Androstenedione is then converted to estradiol by the enzyme aromatase (CYP19A1) in granulosa cells, a process that is stimulated by follicle-stimulating hormone. This mechanism is known as the ‘2-cell, 2-gonadotropin’ model of follicular steroidogenesis.^48,49 Estradiol is the primary active estrogen in humans and circulates in the bloodstream mostly bound to sex hormone-binding globulin.^47–49 It plays a crucial role in promoting the development of breast and uterine tissue and also influences the distribution of adipose tissue as well as bone mineral accretion. ⁵⁰ As women reach middle age (typically over 45 years), they enter perimenopause, which is a transitional phase leading to menopause. During perimenopause, estrogen levels gradually decline, causing menstrual cycles to become erratic or irregular. This transition occurs at different rates for each woman. ⁵¹ Eventually, the ovaries produce less estrogen and stop releasing ova, marking the typical physiological progression of the female reproductive cycle into menopause. ⁵² Ovaries begin to produce less estrogen, and when women enter menopause, they can no longer release ova. This is a normal physiological aspect of the female reproductive cycle. Decreased levels of endogenous estrogen are associated with a higher prevalence of arterial hypertension, coronary artery disease, myocardial infarction, and stroke. ⁵² Women transitioning into premenopause or menopause may experience a reduction in estrogen hormones, which can increase their risk of vascular inelasticity and non-communicable diseases. Our understanding of both fast (nongenomic) and chronic (genomic) estrogen signaling has advanced significantly, particularly with the identification of a new G protein-coupled estrogen receptor (GPER). This receptor is similar to the classic receptors ERα and ERβ, which are abundant in the cardiovascular system.^19,52–54 Data from preclinical and clinical studies using nonselective compounds that activate GPER—including selective ER modulators such as tamoxifen and raloxifene, selective ER downregulators like Faslodex™ (fulvestrant/ICI 182,780), vitamin B3 (niacin), green tea catechins, and soy flavonoids such as genistein or resveratrol—suggest that GPER activation may offer therapeutic benefits for the primary and secondary prevention of coronary artery disease. ⁵⁵ Protective factors that can enhance endogenous estrogen levels include HRT in the form of ethinyl estradiol (synthetic) or naturally through phytoestrogens. Additionally, increasing nutritional factors such as folic acid, vitamin B12, vitamin B6, and antioxidants can also be beneficial (Figure 1).

Figure 1.

Risk and protective factors of menopausal women.

Menopausal women experience several declines in bodily functions, primarily due to reduced estrogen hormone levels, which can lead to decreased blood vessel elasticity. This reduction may increase the risk of developing non-communicable diseases related to impaired blood vessel function, such as diabetes mellitus, cardiovascular disease, and high blood pressure. These conditions can be exacerbated by unhealthy lifestyle choices, including alcohol consumption, smoking, and excessive intake of coffee and tea. Furthermore, diminished blood vessel elasticity in menopausal women may negatively impact cognitive function, resulting in decreased production of amyloid-β and choline. To mitigate these declines, it is beneficial to engage in light to moderate exercise, address estrogen hormone deficiencies either naturally or through HRT, and improve nutritional habits by consuming foods rich in folic acid, vitamin B6, vitamin B12, and antioxidants.^{47,49,51,54,56}

Protective factors of decreased endogenous estrogen in menopausal women

Isoflavones as hormone replacement therapy

HRT is considered beneficial for reducing the risk of cardiovascular disease in postmenopausal women. ⁵⁶ Soy isoflavones can act as selective ER modulators, ⁵⁷ interacting with ERs and making them particularly effective for preventing menopausal symptoms, such as hot flashes and cognitive issues. ⁵⁸ Isoflavones also have the potential to improve cardiovascular health by maintaining endothelial integrity and increasing the release of nitric oxide and prostacyclin, which contribute to endothelium-dependent vasodilation.^58,59 For women experiencing perimenopause, isoflavones may be the best therapeutic option. The Women's Health Initiative Memory Study indicated that many women begin HRT around the age of 72, about 15 years after menopause. ⁶⁰ The study put forth the hypothesis of a “critical period,” suggesting that starting hormone therapy earlier—during perimenopause or immediately after menopause—could have beneficial effects on cognitive function.^60–64 A cross-sectional study involving 428 women revealed that those who began HRT before the age of 56 scored higher on cognitive function tests, specifically the Mini-Mental State Examination, compared to those who started therapy after turning 56. ⁵⁸ Isoflavones are known to inhibit the proliferation and contraction of vascular smooth muscle by activating cAMP and cGMP-dependent pathways while reducing calcium influx. Additionally, isoflavones have demonstrated the ability to reduce oxidative stress, inhibit angiogenesis, and decrease vascular inflammation. ⁶⁵ Supplementation with soy protein that includes isoflavones for six months significantly improved cardiovascular risk markers during early menopause when compared to soy protein without isoflavones. ⁶⁶ In Asian countries where soy is consumed daily, soybeans are believed to be associated with a lower risk of cardiovascular disease. ⁶⁷ A meta-analysis has indicated that soy isoflavones, which are a type of phytoestrogen, can influence glucose homeostasis in menopausal women. The results suggested a significant trend favoring the use of soy isoflavones, particularly highlighting the role of genistein in improving glucose metabolism due to its low heterogeneity. ⁶⁸ Genistein acts as a relatively selective agonist for ERβ and shares structural similarities with estrogen. ERβ is present in brain regions associated with memory and learning. When genistein binds to ERβ, it provides neuroprotective effects and may help mitigate memory impairments associated with AD. Estrogen is neuroprotective and could induce synaptic and dendritic remodeling as well as stimulate glial activity. ⁶⁹ Estrogen in the hippocampus could increase the density of N-methyl-D-aspartate receptors and increase the sensitivity of nerves to be mediated by these receptors. Estrogen in neuroblastoma cells has a neuroprotective effect and reduces the increase in Aβ peptides. ⁷⁰

Nutritional content of tempeh

Tempeh has beneficial effects on health, and making tempeh is relatively easy. Hence, it could be made into various menu variants and functional foods, which refer to healthy food that is beneficial for health. ⁷¹ Foods rich in antioxidants are considered functional because of their properties that benefit human health. ⁷² Naturally, antioxidants are found in many food sources, especially fruits, vegetables, and spices. Some examples of well-known natural antioxidants are vitamin C (ascorbate acid), vitamin E (tocopherol), beta-carotene, and polyphenol. ⁷³

Soybeans in tempeh are a food rich in antioxidants and are a traditional fermented soybean product from Indonesia.^74,75 While tempeh is primarily made from soybeans (Glycine max (L.) Merr.), there are variations made with other legumes such as corn, red beans, black beans, and green beans. ⁷⁶ The main ingredient used in making tempeh is Rhizopus microsporus var. oligosporus, which secretes enzymes—such as cellulase, esterase, α-amylase, β-glycosidase, and protease—that break down the macromolecules in soybeans into micronutrient molecules and produce various secondary metabolites. ⁷⁷ Tempeh is high in vitamins, protein, antioxidants, probiotics, and calcium. ⁷⁸ The fermentation process enhances the availability of many vitamins and minerals. In 100 grams of tempeh, we could find 20.8 grams of protein, 13.5 grams of carbohydrates, and 8.8 grams of fat. The vitamins contained in 100 grams of tempeh include vitamin B1 (0.19 mg), vitamin B2 (0.59 mg), and vitamin B3 (5.9 mg), with these amounts generally exceeding those found in non-soybean versions of tempeh (Table 1).

Table 1.

Nutrition content of soybean tempeh (100 g).

	Content value	Percentage (%) of RDA*
Vitamin B6	0.447 mg	29.8%
Vitamin B1	0.19 mg	19%
Vitamin B2	0.59 mg	59%
Vitamin B3	4.90 mg	32.67%
Vitamin B12	1.7 mcg	42.5%
Vitamin B5	2.324 mg	46.48%
Protein	20.80 g	34.67%
Folic acid	25.1 mcg	6.275%
Isoflavone	2.485 mcg	6.21%

*RDA: recommended dietary allowances

Some microorganisms are produced during the fermentation of tempeh, including Clostridium beijerinckii and Lactococcus taiwanensis, which are contaminants originating from raw soybeans and become activated during tempeh production. ⁷⁹ Acetobacter indonesiensis and Acetobacter aceti produce acetic acid, which helps prevent the growth of pathogenic bacteria. Meanwhile, Lactobacillus fermentum, Lactobacillus delbrueckii, and Lactobacillus mucosae produce lactic acid to aid in controlling heat, inhibiting the growth of harmful bacteria, and serving as probiotics.^79,80

Multiple biomechanisms of tempeh and metabolism pathway of isoflavone

Soybeans are a notable source of isoflavones, which are primarily found in a glycosylated form, known as isoflavone glycosides. During the fermentation process of tempeh, the fungus Rhizopus spp. produces the enzyme beta-glucosidase. This enzyme hydrolyzes isoflavone glycosides, converting them into isoflavone aglycones, which are not bound to sugar molecules. The main isoflavone aglycones found in tempeh include genistein, daidzein, and glycitein. ⁸¹ Isoflavone aglycones have higher bioavailability in humans and exhibit more potent antioxidant activity compared to isoflavone glycosides, ⁸² consequently, tempeh can be regarded as a superior source of antioxidants compared to unfermented soybeans. Antioxidant activity tends to be greater in tempeh extracts than in soybean extracts.^75,83,84

Furthermore, 3-hydroxyanthranilic acid, which is produced from the metabolism of the amino acid tryptophan by fungi, has been identified as an antioxidant molecule exclusive to tempeh and not present in unfermented soybeans. This compound has previously been reported to possess antioxidant properties and to induce apoptosis in human carcinoma cell lines. ⁸⁵ Foods that contain antioxidants, such as tempeh, can stimulate cellular activity by activating the antioxidant response related to nuclear factor erythroid 2-related factor 2 (Nrf2). Antioxidants achieve this by interacting with Keap1 (Kelch-like ECH-associated protein 1) and modifying specific amino acid residues, particularly cysteine 151 (Cys151). This interaction facilitates the release and activation of Nrf2, allowing it to enter the nucleus. The Nrf2-mediated signaling pathway serves as a vital cellular defense mechanism against oxidative stress, which is associated with various conditions, including cardiovascular disease, neurodegenerative diseases, cancer, and aging. Nrf2 regulates the expression of genes that encode cellular antioxidant and detoxification enzymes, such as catalase, glutathione peroxidase, glutathione reductase, superoxide dismutase, peroxiredoxins, and NAD(P)H quinone dehydrogenase. ⁷⁵

Isoflavones are secondary plant metabolites that are biogenetically derived from the 2-phenylchroman flavonoid skeleton.^86,87 They are absorbed in the form of glycosides and aglycones (also called flavonoid aglycones) through passive diffusion across the gastrointestinal epithelial cell membrane. The aglycone is the biologically active form of isoflavones, including genistein and daidzein, as well as S-equol, a metabolite of daidzein found in soy products. Naringenin serves as a precursor for genistein, while liquiritigenin, a flavanone, acts as a precursor for daidzein. Additionally, S-equol is produced by intestinal bacteria in approximately 50% of the human population.^87–89 Flavonoids undergo metabolism in a series of coordinated steps involving various microbial groups. They also influence the quantity and composition of gut microbiota, potentially reducing the risk of intestinal diseases. After absorption, flavonoids enter the bloodstream and bind to albumin, which transports them to the liver. Once there, they undergo conjugation with glucuronic acid, sulfation, methylation, or oxidation before being distributed to cells throughout the body. ⁹⁰ In terms of their neuroregulatory effects within the microbiota-gut-brain axis, flavonoids have both direct and indirect effects. Direct effect: Flavonoids provide neuroprotective benefits by reducing oxidative stress and neuroinflammation, while promoting synaptogenesis and neurogenesis. They also help improve cognitive function and memory disorders. ⁹¹ Within cells, flavonoids stimulate Keap1/Nrf2 signaling, enhancing their antioxidant properties and supporting the integrity of the blood-brain barrier. Indirect effect: Flavonoids can inhibit the growth and colonization of pathogenic bacteria, such as Escherichia coli and Staphylococcus aureus. They also serve as metabolic substrates for beneficial bacteria, such as Lactobacillus and Bifidobacterium, contributing to the stability of intestinal microbiota by promoting the production of short-chain fatty acids. ⁹⁰

Isoflavone action in brain regions

Isoflavones, including genistein, daidzein, and S-equol, play a significant role in brain development. ⁹² They have beneficial effects on both the CNS and the cardiovascular system. S-equol, a metabolite of daidzein, has excellent intestinal absorption and is notable for its ability to penetrate the blood-brain barrier, as demonstrated by SwissADME testing and high-parallel artificial membrane permeability tests (PAMPA). ⁹³ These tests evaluate the permeability of S-equol, genistein, daidzein, and other polyphenols through the gastrointestinal tract and the blood-brain barrier. ⁹⁴ Isoflavones also influence DNA methylation and histone modification. Genistein functions as a DNA methyltransferase (DNMT) inhibitor, decreasing the expression levels of DNMT.^95,96 Research involving rats that consumed 300 mg of genistein per kg of body weight for four weeks indicated that genistein alters DNA methylation patterns. ⁹⁷ Additionally, soy isoflavones affect the proliferation of neurons and glial cells. Administering a daily intraperitoneal injection of 50 mg/kg of daidzein for 13 days led to metabolic changes in the rats, such as decreased high-density lipoprotein cholesterol levels, improved glucose tolerance, changes in insulin and adiponectin levels, increased leptin, and elevated endogenous estrogen (E2) levels. These alterations are associated with increased cell proliferation, reduced apoptosis, and gliosis, which reflect the brain's response to a high-fat diet. ⁹⁷ Isoflavones can also induce and modulate various signaling pathways through ERs, GPER1, and other receptors. This signaling activates proliferation and promotes the viability of hippocampal neuronal cell lines, influencing brain-derived neurotrophic factor signaling related to migration, differentiation, and synaptogenesis in neurons and glial cells. ⁹² Isoflavone exposure in the cerebral cortex may enhance cognitive performance in rats by increasing the activities of acetylcholinesterase, superoxide dismutase, and glutathione peroxidase. ⁹⁸ Genistein has been shown to improve cognitive deficits in mice experiencing cognitive dysfunction due to chronic sleep deprivation by activating the antioxidant Nrf2 and its downstream targets in the cortex. ⁹⁹ Additionally, exposure to genistein also activated insulin receptor substrate 1 and ER46 in the cerebral cortex of ovariectomized aged female rats. ⁹²

Conclusion

Isoflavones are a subclass of flavonoids known for their neuroprotective properties, which can impact various cellular mechanisms related to cognitive function, especially in postmenopausal women. These compounds interact with ERα and ERβ, the GPER1, and possibly other signaling pathways that support neuronal survival and synaptic plasticity. By modulating these receptors, isoflavones enhance cell proliferation, promote neuronal health, and protect against neurotoxicity induced by Aβ, particularly in the hippocampus, which is critical for memory and learning. In addition to mimicking estrogenic activity, isoflavones may help reduce oxidative stress, inflammation, and homocysteine levels—factors known to contribute to cognitive decline and the progression of AD. Tempeh, a traditional fermented soy product rich in isoflavones, presents a promising dietary intervention, especially for populations at risk of estrogen deficiency and cognitive impairment, such as postmenopausal women. Overall, the findings suggest that isoflavones derived from tempeh could serve as a safe, accessible, and culturally relevant alternative to HRT for preserving cognitive health and preventing neurodegenerative changes associated with aging. However, further longitudinal and interventional studies are necessary to clarify the clinical efficacy and safety of tempeh-derived isoflavones in human populations.