I think at this point the verdict is clear – mainstream scientific press is beyond redemption. I am not even sure how such abysmal reporting on study findings is not considered “reckless endangerment” by reporting to the public the exact opposite of what the actual scientific study found. The fiasco is further amplified due to the press article also directly promoting another lie – that estrogen is low in (peri)menopause – when in reality its levels (and especially the estrogen/progesterone (P4) ratio) are higher in menopause, and the latter is exactly what the study reported as well. In fact, the study directly induced Alzheimer Disease (AD) by modulating the levels of estrogen (E) – estradiol (E2), to be precise – and P4 so that they mimic the levels found in perimenopause, and the resulting high E2/P4 ratio produced the symptoms of AD in the animal model. Further corroborating Ray’s ideas and the bioenergetic theory as well, the study also found that the causal effects of elevated perimenopausal E2/P4 ratio on AD are driven by said ratio suppressing oxidative metabolism (OXPHOS) and thus severely depleting ATP levels in the brain. In other words, estrogen is a metabolic inhibitor/poison when its effects are left unopposed due to low levels of estrogen antagonist steroids (e.g. P4 and/or androgens, in both women and men). It gets better – the study reversed AD symptoms and neurological changes by supplementing P4 at a human-equivalent dose of 0.3mg/kg-0.6mg/kg for 50 days. The P4 treatment lowered the E/P4 ratio, boosted P4 levels in the brain, and restored OXPHOS and ATP levels. Furthermore, the study also found that an elevated E/P4 ratio activates the same genes that are involved in not only AD, but also in Parkinson Disease (PD), Huntington Disease (HD), prion disease (mad cow disease), and even amyotrophic lateral sclerosis (ALS). Thus, one could extend the study conclusion to state that an elevated E/P4 ratio drives virtually all chronic, degenerative neurological diseases and that P4 supplementation could be a viable treatment for all those conditions we have been told are “incurable”.
While does not mention it, there is a solid mechanism of action behind P4’s benefit observed in the study. P4 is an aromatase inhibitor and lowers estrogen synthesis, thus both lowering E and raising P4 levels (dual effect). P4 is also an estrogen receptor antagonist, so not only will it lower estrogen synthesis/levels, but will also block estrogen’s effects in the cell. It rarely gets better than that in terms of therapeutic effects for a specific substance. Other anti-estrogenic substances such as the vitamins E/K/A/D, aspirin, pregnenolone, DHT, etc would also likely be good options for keeping estrogen levels/signalling under control, and would probably be synergistic if combined with progesterone. A certain product featuring progesterone dissolved in vitamin E (by Ray himself) comes to mind here:-)
“…Alzheimer’s disease, a devastating neurodegenerative disorder, disproportionately affects women, particularly as they transition through midlife hormonal shifts. Although decades of research have associated estrogen decline during menopause with cognitive decline, the exact molecular underpinnings have remained elusive. The new findings from Sun, Peng, Hart et al. provide a detailed mechanistic insight, demonstrating how the ratio of oestradiol to progesterone rather than absolute levels critically governs neural metabolic balance through ERRα signaling.”
“…ERRα is a nuclear receptor overseeing the regulation of genes responsible for mitochondrial biogenesis and energy production in cells, especially in neurons with high metabolic demands. The research team discovered that during the perimenopausal window, an aberrant hormonal milieu—caused by disproportionate decreases in oestradiol relative to progesterone—triggers maladaptive changes in ERRα expression and activity. This disturbance significantly impairs mitochondrial function and disrupts ATP generation, leading to neuronal energy deficiency, a hallmark observed in Alzheimer’s pathology.”
https://www.nature.com/articles/s41467-025-66726-4
“…The perimenopausal transition in women is marked by elevated, erratic, and unpredictable E2 levels and a sharp reduction in P4 levels20,21,53. To investigate how these endocrine changes impact brain function, a perimenopausal state was artificially induced in laboratory mice using 4-vinylcyclohexene diepoxide (VCD), a chemical that selectively destroys small preantral ovarian follicles by accelerating follicular atresia while preserving the overall ovarian anatomy54,55. Young adult mice (postnatal day 70–75, P70–75) were utilized to minimize the confounding effects of chronological ageing (Fig. 2a). Following VCD treatment, elongation of the oestrous cycle duration became apparent by the 6th–7th cycle after completion of the treatment (Fig. 2a). This phenomenon was accompanied by persistent elevations in circulating levels of follicle-stimulating hormone (FSH) (Fig. 2b). While consistent reductions in circulating E2 and P4 levels were observed by Cycle 14 in all VCD-treated animals, a subset of animals at Cycle 7 exhibited marked increases in E2 (Fig. 2c) or decreases in P4 levels (Fig. 2d), resulting in aberrantly high E2:P4 ratios (≥ 2.5 pg/ng) (Fig. 2e). This condition, termed “higher oestradiol–lower progesterone imbalance,” characterized the onset of the perimenopausal state transition, which generally began at Cycle 6–7, while the full menopausal state (characterized by general reductions in both E2 and P4 levels) was successfully induced by Cycle 14.”
“…Furthermore, the animals displayed mild anxiety-like behaviour, as indicated by the significantly reduced time spent in the centre zone during the open-field test (Fig. 2i, Supplementary Fig. 3g). Importantly, the decline in behavioural performance at the onset of the perimenopausal state transition (Cycle 7) was most strongly correlated with the E2:P4 ratio (Fig. 2f–g, 2i) rather than with the circulating levels of E2 or P4 alone (Supplementary Fig. 3b–d, 3g). Immunohistochemical analysis further supported the negative impact of elevated E2:P4 ratios (≥ 2.5 pg/ng) on brain cellular integrity, revealing significant neurite loss in the Cornu Ammonis area 1 (CA1) of the hippocampus (Fig. 2j, Supplementary Fig. 3h–j). These anatomical changes were accompanied by impairments in neurophysiological function. Field excitatory postsynaptic potentials (fEPSPs) recorded from the Schaffer collateral pathway showed significant deficits in VCD-treated animals (Fig. 2k, left 246 panel), along with diminished long-term potentiation (LTP) (Fig. 2k, right panel). Together, these findings demonstrated that aberrantly elevated E2:P4 ratios during the perimenopausal state transition were associated with cognitive and memory impairments, mild anxiety-like behaviour, neurite loss in the hippocampus, and reduced synaptic plasticity, underscoring the detrimental effects of hormonal imbalances on brain function.”
“…To further investigate the underlying molecular mechanism, we conducted a bulk transcriptomic analysis of the cerebral cortex from VCD-treated animals, which exhibited a greater oestradiol–lower progesterone imbalance during the perimenopausal state transition (E2:P4 ≥ 2.5 pg/ng in oestrous Cycle 7; Fig. 259 2e). Principal component analysis (PCA) effectively distinguished the transcriptomic profiles of VCD-treated animals from those of vehicle-treated controls (Fig. 3a). This analysis revealed 346 upregulated and 544 downregulated transcripts in the VCD-treated group (Fig. 3b). While the upregulated DEGs did not cluster into any meaningful pathways, the downregulated DEGs were strongly enriched in pathways associated with mitochondrial energetics, including OXPHOS and the citrate cycle (TCA cycle). Furthermore, these genes were also involved in pathways related to neurodegenerative disorders such as Parkinson’s disease, prion disease, Huntington’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (Fig. 3c-d). These findings highlighted the central role of defective OXPHOS in the pathogenesis of age-related neurodegenerative diseases.”
“…As previously observed (Fig. 4), activated PR signalling plays a coregulatory role in guiding ERα signalling to regulate the ERRα-PGC1α axis via cholesterol homeostasis. The 3xTg mice exhibited a high E2:P4 ratio, and a decreased ERα–PR interaction was accompanied by increased levels of Aβ monomers, dimers, and oligomers, as well as phosphorylated tau (S202/T205), in cortical tissues (Fig. 7i, Supplementary Fig. 17c). These findings suggested that reversing the high E2:P4 ratio during the early perimenopausal state (Cycles 7–8) by elevating P4 levels could mitigate the adverse effects of hormonal imbalance on subcellular signalling, AD-related pathology, and cognitive decline. Pharmacokinetic profiling after P4 administration revealed a short plasma half-life following intraperitoneal injection (4–8 mg/kg), with peak levels occurring at 15 minutes and a rapid decline thereafter83 [Supplementary Fig. 18a(2)-b(2)]. Although P4 injections had no effect on endogenous E2 levels [Supplementary Fig. 18a(3)-b(3)], they effectively reduced the E2:P4 ratio below the defined imbalance threshold (≥2.5 pg/ng) for approximately 8 hours [Supplementary Fig. 18a-b(4)]. This time window allowed for the implantation of subcutaneous minipumps, which maintained effective P4 concentrations over an extended period. Using a protocol combining intraperitoneal injection (4 mg/kg) followed by subcutaneous infusion (11.7 ± 0.7 mg/kg over 48 hours), we found that P4 treatment normalized plasma E2:P4 ratios (Fig. 7k, Supplementary Fig. 18c) and restored P4 levels in brain tissues (Fig. 7k, Supplementary Fig. 18d). Subsequent extended P4 supplementation over 60 days, which coincided with Cycles 14–15, improved memory and cognitive functions in 3xTg mice with an initial high E2:P4 ratio, whereas no significant effects were observed in vehicle-treated mice with balanced E2:P4 ratios (Fig. 7l, Supplementary Fig. 19a–b). Brain tissues harvested from P4-treated 3xTg mice showed significant improvements in neurite length (Fig. 7m), reduced levels of phosphorylated tau (Fig. 7m-n, Supplementary Fig. 19c), and decreased Aβ immunoreactivity, accompanied by enhanced ERα–PR interactions (Fig. 7n, Supplementary Fig. 19d). Transcriptomic and metabolomic profiling revealed that P4 supplementation restored cholesterol and NAAG biosynthetic networks (Fig. 7o, Supplementary Fig. 20a–g). P4 treatment upregulated the expression of cholesterol biosynthetic genes (Dhcr7, Dhcr24) and pyruvate decarboxylation genes (Pdha1), which are key targets of P4-regulated ERα signalling 551 (Fig. 7o). This phenomenon re-established the relative abundance of cholesterol-bound ERRα (Fig. 7p, left panel) and preserved the expression of SDH, a critical metabolic enzyme involved in TCA cycle activity (Fig. 7p, right panel). Neurophysiological analyses further demonstrated that P4 supplementation improved the maximal respiratory capacity and ATP-linked respiration in the brain (Supplementary Fig. 20h). Additionally, fEPSPs in the Schaffer collateral pathway were significantly enhanced (Fig. 7q), indicating restored synaptic function.”
