Menopause mediated Alzheimer’s vulnerability: Mechanistic and Functional Insights

Breeze, Bernadette (2026) Menopause mediated Alzheimer’s vulnerability: Mechanistic and Functional Insights. Doctoral thesis, University of East Anglia.

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Abstract

Alzheimer’s Disease (AD) is a leading cause of death in the UK and disproportionately affects women, imposing substantial social and economic burdens. Menopause, marked by profound hormonal changes, is linked to cognitive decline and increased dementia risk, though the mechanisms driving this vulnerability remain poorly defined. Utilising VCD as a model of menopause, this thesis investigated how VCD-induced ovarian failure influenced cognition, neuropathology, metabolism, and brain–gut interactions in the ATG16L-ΔWD mouse model of late-onset AD (LOAD), which exhibits hallmark AD features including TAU hyperphosphorylation, Aβ accumulation, and microglial dysfunction.

VCD treatment selectively exacerbated TAU pathology, independently of amyloid-beta, with genotype-specific effects that increased Aβ load. Tau hyperphosphorylation was associated with dysregulated kinase and phosphatase activity and occurred largely independently of estrogen receptor signalling or overt microglial activation. Metabolic analyses revealed hippocampal deficits in glycolysis, mitochondrial function, and oxidative phosphorylation, alongside blood-brain barrier disruption, consistent with the mitochondrial–neurovascular–metabolic framework of AD progression. These deficits coincided with synaptic vulnerability, including elevated proBDNF and reduced expression of Sema6c and Syngap1.

VCD also altered brain lipid composition, particularly n-3 PUFAs (DHA, DPA), affecting both total and phospholipid-bound pools and correlating with AD pathology. Dysregulated expression of elongases and desaturases (Elovl1–6, Fads1) suggests a mechanistic link between lipid-imbalance and synaptic or mitochondrial dysfunction. Gut–brain analyses further revealed selective shifts in microbial metabolic pathways and opposing regulation of peripheral and central mannose metabolism, indicating compartment-specific metabolic effects of menopause.

Collectively, these findings suggest that the VCD model of menopause amplifies AD susceptibility through converging mechanisms, including tauopathy, metabolic and lipid dysregulation, BBB impairment, synaptic dysfunction, and altered gut–brain metabolic signalling, particularly within the hippocampus. This work advances understanding of menopause-mediated neurodegeneration and identifies potential therapeutic targets to mitigate cognitive decline in women.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	Chris White
Date Deposited:	27 Jul 2026 07:37
Last Modified:	27 Jul 2026 07:37
URI:	https://ueaeprints.uea.ac.uk/id/eprint/103950
DOI:

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