Author: Katie Kavanagh
Editor: Nirvan Marathe
Artist: Yasmin Yong
Lecanemab is the most recent treatment targeting the root cause of Alzheimer’s disease, aiming to prevent amyloid-β buildup, therefore decreasing cognitive decline. This treatment boasts a 27% reduction in cognitive decline after 18 months, a result that appears to be significant; however, upon closer inspection of the statistics, it is evident that lecanemab only results in a 9.3% reduction of cognitive decline in women, despite constituting two-thirds of the Alzheimer’s population. This blatant neglect of the majority group at risk of the disease makes it evident that we should be looking into specific and personalised treatments for Alzheimer’s to ensure everyone affected, especially those most at risk, receive appropriate care.
Lecanemab is a monoclonal antibody that targets oligomeric b-amyloid peptides to prevent the formation of the β-amyloid plaques that are characteristic of Alzheimer’s disease. This treatment is based on the amyloid cascade hypothesis theorising that Alzheimer’s pathology begins with the formation of β-amyloid plaques, which then cause intracellular neurofibrillary tau tangles to form, furthering cognitive decline. Lecanemab is administered via infusion once every two weeks at a dose of 10 mg/kg body weight. The original report of the CLARITY-AD trial claims that the treatment was effective, leading to a 27% decrease in cognitive decline. However, upon stratifying the data by gender, it is revealed that lecanemab only reduces cognitive decline by 9.3% in women, a figure that is negligible in daily life.
Alzheimer’s disease impacts 55 million people worldwide, a number that is expected to almost double every 20 years. Increasing age is the biggest risk factor for developing this disease; however, it does not impact all people equally, as women are 2 times more likely to develop Alzheimer’s disease than men. It is well established that women live longer than men; although, this longevity alone is not sufficient to account for this drastic inequality, and it is hypothesised that this bias is due to a combination of social and biological factors. Social factors such as increased years of education, physical activity, and social engagement are believed to play a protective role in late-life dementia; however, due to the historical absence of women from these roles, they are excluded from this protection. Biological factors such as pregnancy and menopause exclusively impact females, and both increase the risk of mild cognitive impairment. Oestrogen is believed to play a protective role in the brain, preventing the formation of β-amyloid plaques but during menopause, oestrogen levels rapidly decrease, removing this protective feature.
The imbalance of risk of Alzheimer’s is even more prevalent when the race, ethnicity, or genotype of these women are considered. Black American women, Hispanic women, and female APOE ɛ4 carriers are especially susceptible to developing Alzheimer’s disease compared to non-Hispanic White women and non-APOE ɛ4 carriers. This risk according to race and ethnicity is largely due to the aforementioned social factors, such as fewer years of formal education and increased oxidative stress due to carer roles, which often fall on Black American women. The APOE ɛ4 genotype is the biggest genetic risk factor that increases the risk of Alzheimer’s 4-fold for women with one copy of the allele, and by up to 15-fold for women with two copies of the allele. Lecanemab has also been shown to have very little efficacy on APOE ɛ4 carriers, many of whom are female. Targeting the vast inequalities within the development of Alzheimer’s, the response to treatment, and the paucity of data stratified for sex, race, or ethnicity is essential for future diagnoses and treatments of Alzheimer’s disease and suggests the potential value of personalised medicine.
Alzheimer’s disease is a highly prevalent neurodegenerative disorder, which is only expected to increase due to the world’s ageing population. Finding treatments for Alzheimer’s disease is a necessity and has been described as “the greatest unmet need facing modern medicine“. Due to clear discrepancies in risk, progression, and response to treatment of Alzheimer’s disease resulting from sex, race, and genotype, personalised treatments and medicines should be prioritised to protect those who need them most.
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