Alzheimer’s disease: the forgotten burden on women

Alzheimer’s disease (AD) is a type of dementia where the progressive loss of neurons (brain cells) leads to memory loss and behavioural changes.[1–3] In 2022, dementia was the leading cause of death in the UK, accounting for 15% of all registered deaths in women.[1,2] Unsurprisingly, 50% of UK adults stated that AD was the health condition they most feared as they age.[4]

Did you know that AD disproportionately affects women?[5,6] In fact, women account for 65% of all diagnoses.[5,6]

Alzheimer’s disease symptoms

The early symptoms of AD include:[7]

1.????Memory loss affecting everyday life e.g., relying on memory notes

2.????Difficulties in planning or solving problems e.g., remembering to pay bills

3.????Problems with everyday tasks e.g., creating a shopping list or getting lost

4.????Losing track of appointments or time

5.????Issues with remembering words

6.????Constantly losing things and not being able to find them again

7.????Reduced ability to make decisions

8.????Changes in mood including confusion, depression, and anxiety

9.????Inability to hold conversations

The biology of Alzheimer’s disease

In patients with AD, senile or amyloid plaques and neurofibrillary tangles accumulate in the brain as the disease progresses.[1,2] The amyloid plaques occur due to the build-up of proteins known as Aβ peptides.[1,2] These deposits lead to inflammation and altered calcium signalling, causing neuronal death.[2] Neurofibrillary tangles are composed of phosphorylated tau protein.[1,2] Accumulation of neurofibrillary tangles in the brain prevents the formation of microtubules causing neurons to die and promoting inflammation.[2]

Risk factors for Alzheimer’s disease

About 70% of the risk for developing AD is genetic.[2] The most well-known gene involved in AD is the apolipoprotein E (APOE) gene which codes for a protein called ApoE which is involved in the breakdown of cholesterol.[2] For example, the APOE-?4 allele promotes β?amyloid peptides (Aβ) peptide deposition and thus the formation of amyloid plaques.[2] Individuals with this allele are more likely to develop AD, with this risk being greater in women than men.[1,2] Women with a single APOE??4 allele have an earlier age of disease onset, decreased brain volume, lower cognitive scores, and increased plaque burden.[1] This is comparable in severity to the symptoms seen in men with two copies of the APOE-?4 allele.[1]

The most well-known risk factor for AD is advancing age.[2,8] Individuals aged 75–84 years-old account for 19% of AD cases, whilst 30?35% of AD cases are in individuals older than 85 years.[2] The increased risk of AD may result from women living longer than men, with average life expectancies of 83 versus 79?years, respectively.[8,9] Twice the number of women over the age of 70 live alone and are therefore more likely to experience depression and loneliness, known risk factors for AD.[2,10,11]

Women who experience menopause at an older age are less likely to develop AD.[12] Since the hormone oestrogen is important for cognition, anxiety, appetite, and sexual behaviour it has been proposed that a drop in oestrogen might contribute to AD risk.[13] However, increasing oestrogen levels by hormone replacement therapy (HRT) offers no clear protective effect.[14]

Low cognitive activity is a risk factor for AD.[2,15] Traditionally, across the world men experience a better education and higher occupational status than women, resulting in women (particularly those over the age of 70) being at increased risk of AD.[15] Women are becoming increasingly educated, which may decrease this risk.[15]

Smoking, obesity, type 2 diabetes, hypertension (high blood pressure), and dyslipidaemia (high cholesterol) are all risk factors for AD.[2] These risk factors can be mitigated by lifestyle changes, and research suggests that 40% of the population would adopt a healthier lifestyle to reduce their risk of developing AD.[4] However, the extent that such lifestyle changes would have on risk reduction is sex?dependent.[16] In men, moderate or vigorous exercise, cognitive engagement, and social support are protective, whereas moderate activity and cognitive engagement are found to be protective for women.[16 ]Hypertension is a more pronounced risk factor in women than men whilst the opposite is true for smoking and alcohol consumption.[16,17]

Treatment for Alzheimer’s disease

Unfortunately, there is no cure for AD and current treatments aim to reduce symptoms.[18] About 30% of adults in the UK incorrectly believe that AD progression can be slowed down by medicines.[4]

Acetylcholinesterase (AChE) inhibitors increase the amount of the neurotransmitter (a chemical messenger) acetylcholine which is essential for neurons to communicate with each other.[19] In the UK, there are three AChE inhibitors available for the treatment of early to mid-stage AD.[20] Common side effects are nausea, vomiting or loss of appetite.[19]

Another group of drugs known as glutamate receptor antagonists, prevent the production of glutamate, a neurotransmitter.[19,20] These are prescribed to patients who are unable to tolerate AChE inhibitors or with moderate to severe AD.[19,20] They can also be prescribed with AChE inhibitors for patients with severe AD.[19,20] Side effects include headaches, dizziness, and constipation.[20]

Most therapies in clinical trials are disease-modifying therapies (designed to slow disease progression), 10% are cognitive enhancing, and 7% target neuropsychiatric symptoms.[21] Perhaps the most promising of these are antibodies that target the amyloid plaque build-up, some of which are in the final phases of clinical trials.[22]

The burden of Alzheimer’s disease

Women with AD typically have more severe depressive and abnormal motor symptoms than men.[23] In contrast, men had more severe apathy (disinterest) than women.[23] Brain autopsies of AD patients have shown that women have different AD pathology to men.[24] Primarily women have phosphorylated tau in their frontal cortex whilst men have a build-up of the protein, α-synuclein.[25]

Since there are no effective treatments or cures, clinical trials can provide hope.[26] However, women are significantly underrepresented in clinical trials and are twice as less likely to be eligible for screening compared to men.[15,27] This was found to be closely linked to education levels in older generations, with this disparity decreasing over time.[15] Women are more likely to be excluded from clinical trial enrolment due to comorbidities whereas men are more likely to be excluded due to treatment criteria.[27]

Women account for 60─70% of all caregivers for patients with AD.[28] About 20% of caregivers reduce their working hours from full-time to part-time, negatively impacting their finances, stress levels, and social lives which in turn increases their risk of developing AD.[2,28]

The barriers to finding a cure

About 99% of all drugs that enter clinical trials for the treatment of AD fail, discouraging further investment.[3] There is an urgent and unmet need for AD treatments, but the road to success will be time-consuming and difficult.[3] This high failure rate is partially due to the challenge of getting drugs past the brain’s protective barrier, the blood-brain-barrier.[3] There is a need for Phase 2 clinical trials (initial effectiveness and comprehensive safety testing), to prevent agents with low efficacy from reaching Phase 3 clinical trials (final stage testing) and thus minimising the waste of limited resources.[3] Additionally, more preclinical work is needed to understand the biology of AD to improve the chances of drug success.[3]

Despite 70% of UK adults stating that they would consider participating in clinical research for AD, women remain underrepresented.[4,29] Greater efforts are needed to increase the number of women participating in clinical trials since the disease pathology (origin and progression) differs between the sexes. It is therefore likely that any new treatments and/or cures will also be sex dependent.[1,25]

The need for large-scale action

In 2022, Alzheimer’s Research UK published a report with recommendations about how the increased risk of AD in women can be recognised.[30] This highlighted the urgent need for the UK government to recognise, educate, and raise awareness about how AD disproportionately affects women.[30] They emphasised the need for funding bodies, regulators, and peer-reviewed journals to have clear recommendations and guidelines surrounding the increased participation of women in clinical trials.[30]

The UK government has pledged as part of the Dementia Moonshot programme to double dementia research funding to ￡160 million/year by 2024, with an additional ￡95 million for clinical trials.[31,32] Former Prime Minister Boris Johnson called for an increase in volunteers both with and without a family history of dementia to enrol in preventative clinical trials to honour the memory of Dame Barbara Windsor, who died due to AD in 2020.[31] As part of this programme, research will be carried out to improve understanding about the mechanisms and factors that lead to increased risk of dementia in women.[33]

Conclusion

Women are more likely develop AD than men, with genetics, physiology, and lifestyle factors all contributing to this increased risk.[2,19] The burden of caring for loved ones with AD also falls disproportionately on women.[28] Symptoms and their severity differ between sexes, most likely due to differences in underlying pathology.[24,25] Current therapies target the symptoms, rather than slowing or preventing disease onset or progression.[19,20] There is an urgent need to understand the biological mechanisms that underlie this increased risk of AD in women, to allow for better preventive interventions and treatments.[3] Since the biology and disease progression differ by sex, it is imperative that more women are enrolled in clinical trials.[30]

References

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2.???????Silva, M. V. F. et al. Alzheimer’s disease: risk factors and potentially protective measures. J Biomed Sci 26, (2019).

3.???????Cummings, J., Feldman, H. H. & Scheltens, P. The “rights” of precision drug development for Alzheimer’s disease. Alzheimer’s Research & Therapy 2019 11:1 11, 1–14 (2019).

4.???????Perceptions of dementia - Dementia Statistics Hub. https://www.dementiastatistics.org/statistics/perceptions-of-dementia/.

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7.???????Memory Loss & 10 Early Signs of Alzheimer’s | alz.org. https://www.alz.org/alzheimers-dementia/10_signs.

8.???????Chêne, G. et al. Gender and incidence of dementia in the Framingham Heart Study from mid-adult life. Alzheimers Dement 11, 310–320 (2015).

9.???????Estimates of the very old, including centenarians, UK - Office for National Statistics. https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/ageing/bulletins/estimatesoftheveryoldincludingcentenarians/2002to2019.

10.?????People living alone aged 65 years old and over, by specific age group and sex, UK, 1996 to 2019 - Office for National Statistics. https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/families/adhocs/11446peoplelivingaloneaged65yearsoldandoverbyspecificagegroupandsexuk1996to2019.

11.?????Akhter-Khan, S. C. et al. Associations of loneliness with risk of Alzheimer’s disease dementia in the Framingham Heart Study. Alzheimers Dement 17, 1619–1627 (2021).

12.?????Fu, C. et al. Association of reproductive factors with dementia: A systematic review and dose-response meta-analyses of observational studies. EClinicalMedicine 43, (2022).

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14.?????Compton, J., van Amelsvoort, T. & Murphy, D. HRT and its effect on normal ageing of the brain and dementia. Br J Clin Pharmacol 52, 647 (2001).

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18.?????Breijyeh, Z. & Karaman, R. Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules 25, (2020).

19.?????Yiannopoulou, K. G. & Papageorgiou, S. G. Current and Future Treatments in Alzheimer Disease: An Update. J Cent Nerv Syst Dis 12, 117957352090739 (2020).

20.?????Alzheimer’s disease - Treatment - NHS. https://www.nhs.uk/conditions/alzheimers-disease/treatment/.

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22.?????Hao, Y., Dong, M., Sun, Y., Duan, X. & Niu, W. Effectiveness and safety of monoclonal antibodies against amyloid-beta vis-à-vis placebo in mild or moderate Alzheimer’s disease. Front Neurol 14, 375 (2023).

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24.?????Congdon, E. E. Sex differences in autophagy contribute to female vulnerability in Alzheimer’s disease. Front Neurosci 12, 372 (2018).

25.?????Koppel, J. et al. Psychotic Alzheimer’s disease is associated with gender-specific tau phosphorylation abnormalities. Neurobiol Aging 35, 2021–2028 (2014).

26.?????What are Clinical Trials | Alzheimer’s Association. https://www.alz.org/alzheimers-dementia/research_progress/clinical-trials/what-are-clinical-trials.

27.?????Abdelnour, C. et al. How gender and sex influence clinical trial recruitment in Alzheimer’s disease: Findings from Fundació ACE Barcelona Alzheimer Treatment and Research Center. Alzheimer’s & Dementia 16, e041772 (2020).

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