Dementia and cholesterol: investigating links and impacts of hormone replacement therapy

By Pooja Toshniwal PahariaReviewed by Lily Ramsey, LLMOct 25 2023

In a recent study published in Nutrition, researchers determined the relationships between hormone replacement therapy (HRT), serum cholesterol levels, and dementia incidence among post-menopausal women in Taiwan.

Study: Cholesterol Levels, Hormone Replacement Therapy, and Incident Dementia among Older Adult Women. Image Credit: adriaticfoto/Shutterstock

Background

Post-menopausal females are increasingly experiencing dementia due to various underlying causes, including abnormal protein buildup and compromised neurovasculature.

Studies indicate that HRT with estrogen may protect post-menopausal women from dementia, although the link between serological cholesterol and dementia incidence is not fully understood.

Low cholesterol levels may be linked to cell membrane development and maintenance of membranes, including cranial membranes. Elevated serum cholesterol might result in atherosclerosis and narrow blood vessels, impairing cognitive function.

Studies indicate that post-menopausal females with lowered estrogen levels may be susceptible to Alzheimer's disease-related dementia; however, the evidence is inconclusive since not all previous studies support this finding.

About the study

In the present retrospective study, researchers evaluated the impact of HRT and serum cholesterol levels on dementia development among post-menopausal females.

Non-demented females aged above 40 years, registered with the History-based Artificial Intelligence Clinical Dementia Diagnostic System (HAICDDS) database, were recruited between September 2015 and August 2021. 

The participants were followed longitudinally to assess dementia conversion. Cox regression modeling was performed to investigate the effects of statistical quartiles of low-density lipoprotein-cholesterol (LDL-C) and total cholesterol (TC) levels on dementia conversion, adjusting for gender, age, comorbidities, educational attainment, neuropsychological symptoms, neuropsychiatric evaluations, HRT, medications, systolic blood pressure, fasting blood glucose, and creatinine levels.

The primary study objective was a systematic record of HAICDDS members with cognitive impairments (CIs) or dementia.

The team enrolled disease-free individuals and those with Alzheimer’s disease (AD)- and Lewy body disease (LBD)-associated brain degeneration, cognitive impairment resulting from cerebrovascular diseases, or other diseases of the brain linked to cognitive decline. Neuropsychologists interviewed participants and informants.

Neuropsychiatric assessments included the Montreal Cognitive Assessment (MoCA), the Cognitive Abilities Screening Instrument (CASI), the Clinical Dementia Rating (CDR) scale, and the activities of daily living (ADL) function, based on the History-based Artificial Intelligence ADL (HAIADL) scores. Psychological and behavioral symptoms were evaluated using the Neuropsychiatric Inventory (NPI) to assess CI and dementia severity.

Dementia diagnosis was based on the National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria, global CDR scores of 0.5 and higher, and CDR scale sum of boxes (CDR-SB) scores of 4.5 and higher.

Results

Initially, 10,581 HAICDDS members were identified, of whom those without follow-up information (n=6,015), menstruating females, and those with prior dementia history (n=3,799) were excluded from the analysis.

As a result, 787 individuals were analyzed. Among the participants, 539 (69%) did not convert to dementia (non-converters), of whom 68 (13%) received HRT. Contrastingly, 248 (32%) individuals developed dementia (converters), of whom 28 (11%) were HRT recipients.

The mean durations of follow-up were 3.3 and 2.9 years for converters and non-converters, respectively.  Compared to the lowermost statistical quartile of total cholesterol levels (below 153), the hazard ratio (HR) values for dementia conversion were 0.6 for all quartiles. However, HRT and LDL-C did not influence dementia incidence. 

Compared to non-converters, the HR values for dementia conversion, except for TC contribution, age (HR, 1.1), education (HR, 1.1), CASI score (HR, −1.0), HAIADL scores (HR, 1.1), no physical activity (HR, 1.3), and systolic blood pressure (HR, 1.0) showed significant associations with dementia conversion. Worse neuropsychiatric symptoms tended to increase dementia conversion (HR, 1.0).

The converters had older age, lower educational attainment, poorer cognition, lower daily function performance, prior diabetes history, and used anti-diabetic medications. Physical exercise, hyperlipidemia, higher LDL-C, and TC reduced dementia conversion.

Conclusions

Based on the study findings, post-menopausal females with low cholesterol levels have a significantly higher risk of developing dementia, especially those with advanced age, diabetes, low level of education, poorer cognitive performance, and reduced ability to perform routine activities.

Lipid raft disruptions and demyelination are involved in synaptic function and plasticity and are crucial to memory and learning. Low cholesterol caused by drugs or toxins may disrupt lipid rafts, affecting memory consolidation and cognitive function, ultimately leading to dementia.

Furthermore, low cholesterol levels may interfere with myelin regeneration, disrupting signal transformation and consolidation.

Therefore, the "Lower LDL-C, the better" policy to prevent cardiovascular diseases must be re-evaluated for the potential adverse impacts of low serum cholesterol levels on dementia.