Sex Differences in Alzheimer's Disease (AD)

Longevity Argument

Women live longer than men, and age is the leading biological risk factor for AD → more women with AD

Greater Tau Burden

Women show higher accumulation of tau pathology than men

APOE4 effect

Female APOE4 carriers exhibit more amyloid than tau deposition and faster cognitive decline than males

Later diagnosis

Women are often diagnosed at later stages, possibly due to compensatory cognitive mechanisms

Biological Factors

• Sex hormones

• Sex chromosomes

Sex Hormones

Decline in estrogen during menopause affects brain metabolism and neuroprotection

Sex chromosomes

X-linked gene expression differences

Societal Factors

• Gender roles

• Lower education levels (historically)

• Occupational differences

Lifestyle and health factors

• Physical inactivity

• Depression

• Poor sleep

• Diet

• Vascular/metabolic diseases

Menopause as a vulnerability window

Not a direct cause

Sex as a Biological Variable (SABV)

Considering sex (biological differences) as a key variable in all stages of research - from design to analysis and interpretation

What are the consequences of ignoring sex?

Can mask important biological effects and lead to biased understanding of disease mechanisms and ineffective drug development

Optimal SABV Research Design

1. Include both sexes in study samples

2. Stratify by hormonal status (eg cycling, menopausal, or ovariectomised in animal models)

3. Model hormonal profiles to reflect human conditions

4. Analyse sex-by-hormone interactions rather than simply “male vs female” comparisons

What can understanding sex-specific mechanisms improve?

• Target identification (eg estrogen pathways for neuroprotection)

• Treatment efficacy and safety

• Personalised medicine for both men and women

PD Prevalence

More common in men than women

PD Potential Mechanisms

• Estrogen’s neuroprotective role may protect dopaminergic neurons in females

• Mitochondrial function, oxidative stress, and dopamine metabolism may differ between sexes

PD Risk Factors

• Environmental exposures

• Hormonal influences

• Immune system differences

Example of animal model application in PD

Compare PD pathology and motor symptoms in male vs female rodents, controlling for hormonal cycles

Example of Human studies application in PD

Stratify clinical data by sex and hormonal status to assess treatment outcomes and disease progression

Female-specific risks in AD

• Reduced lifetime exposure to ovarian hormones

• Hypertensive pregnancy disorders

Reduced lifetime exposure to ovarian hormones factors

• Age at menarche

• Menopause

• No. of pregnancies

• No of lifetime menstrual cycles

What happens to the hormones during menopausal symptoms?

Hormones start declining significantly

Menopause

The absence of a menstrual period for 12 months and marks the end of a woman’s reproductive years, occurring for most between 45-55 years

Menopause Types

• Induced (chemotherapy, surgical)

• Spontaneous (natural, endocrine disorders)

Ages at Menopause

• 45+ years

• <45 years

Healthy Cell Bias of Estrogen Action

Suggests that estrogen is beneficial to healthy neurons by enhancing their energy production and protecting them from damage, but can be detrimental to compromised neurons