Genomics: Insight

Alzheimer’s Disease (AD) and Societal Implications

An estimated 6.9 million Americans had AD and 119,399 died from it in 2021, making it one of the three leading neurological causes of death worldwide.1 AD is a progressive neurodegenerative disorder that leads to a gradual decline in cognitive functions, primarily affecting individuals over the age of 65, who may experience significant impairments in daily activities, profound memory loss, and notable changes in personality and behavior. Individuals require increasing levels of assistance as cognitive decline progresses, placing emotional, physical, and financial demands on caregivers. While no cure exists, available treatments help manage symptoms and delay progression. The rising number of AD cases pressure long-term care and healthcare services, with costs projected to reach $1 trillion in 2050.2

So, how do genetic variants and socio-environmental variables, such as sleep deprivation, neighborhood resources, and employment type collectively influence the risk and progression of Alzheimer’s disease? In this review, we will discuss the genetic risk factors associated with AD, how they interact with environmental exposures to increase risk, and the impact of social disparities.

APOE ɛ4’s Role in AD Development

The APOE gene codes for the protein APoE, which can bind to Aβ proteins and promote Aβ plaques associated with cognitive decline. APOE has the main allelic variants ɛ2, ɛ3, and ɛ4 at a gene locus, with APOE ɛ4 being the greatest genetic risk factor for AD and increasing the risk for both familial and sporadic early and late-onset AD. Heterozygous carriers (APOE ɛ3/4) experience an estimated 3 times higher risk, and homozygous carriers (APOE ɛ4/4) experience an estimated 15 times higher risk.3

A study by Saunders et al. demonstrated that patients with late-onset Alzheimer’s as well as both probable and confirmed sporadic Alzheimer’s have a higher frequency of the APOE €4 gene. The 3 control groups involved in this study were 91 European or American unrelated grandparents from the Centre d'Etude du Polymorphisme Humain (CEPH) reference families, 21 white spouses of probable AD patients, and a representative control series from a similar population in the literature. The four AD groups were 36 individuals from late-onset AD families, 16 from early-onset AD families, 69 probable sporadic AD patients, and 176 confirmed sporadic AD subjects; all patients were diagnosed at Duke, University of Toronto, Massachusetts General Hospital, and Harvard. The study showed that all Alzheimer’s groups except the early-onset group demonstrated higher APOE €4 frequencies than the CEPH controls. The APOE €4 frequencies of the late-onset AD series are significantly different from the CEPH controls (p = 0.000017), and the APOE €4 frequencies of both sporadic-probable and sporadic-probable AD were significantly different from the CEPH controls (p = 0.00031 and p < 0.00001, respectively).4

Gene-environment Interactions of APOE ɛ4
The combination of APOE ɛ4 and exposure to certain environmental factors can affect the risk of developing AD. A study by Cacciottolo et al. found that older women with long-term exposure to fine particulate matter (PM2.5) have a higher risk of developing AD, especially if they are also APOE ε4 gene carriers. The participants were community-dwelling women aged 65 to 79 across 48 states and dementia-free at enrollment. Among 3,647 women of European ancestry with APOE alleles ε3/3, ε3/4, or ε4/4, higher PM2.5 exposure was linked to an increased risk of all-cause dementia, with the hazard being 68% for APOE ε3/3 carriers, 91% for ε3/4 carriers, and 295% for ε4/4 carriers.5

Mayeux et al. found that individuals with the APOE ε4 allele and a history of head injury have a higher risk of AD. The study included 113 AD patients and 123 healthy elderly individuals, all from the same region in northern Manhattan. The odds ratio for developing AD was highest in individuals with both APOE ε4 and a head injury (OR = 10.5), followed by those with the APOE ε4 gene alone (OR = 2.0), compared to those with only head injury or without either risk factor (OR = 1.0).6

"The combination of APOE ɛ4 and exposure to certain environmental factors can affect the risk of developing AD."

Socio-environmental Factors Related to AD Risk

Sleep Deprivation and AD Risk
Aβ is a key marker of AD, as shown in studies with transgenic mice models, where Aβ plaques are linked to memory deficits and neurodegeneration. Sleep is vital for regulating Aβ levels in the brain, as neurons release more Aβ during wakefulness and less during sleep, making quality sleep important for reducing Aβ accumulation. Aβ plaques in brain areas that regulate sleep impair sleep and contribute to cognitive decline.7 A study by Kang et al. indicates that sleep deprivation leads to an increase in brain interstitial fluid (ISF) Aβ levels. The study results show that the average ISF Aβ levels during sleep deprivation were 16.8% higher compared to the ISF Aβ levels of the controls.8 Additionally, the results show that the infusion of αCRF9–41, a corticotropin-releasing factor (CRF) receptor antagonist, into the hippocampus during sleep deprivation led to a 33.7% increase in ISF Aβ levels compared to controls.9 CRF receptor signaling is typically involved in increasing Aβ levels, but αCRF9–41 blocks CRF receptor signaling. Aβ levels increased despite the CRF receptor signaling pathway being blocked, highlighting that sleep deprivation alone is sufficient to cause significant Aβ accumulation.

APOE plays a key role in the clearance of Aβ. Studies show that extended wakefulness increases Aβ accumulation in the hippocampus while reducing APOE expression.10 Sleep deprivation alters hormone levels, particularly thyroid hormones, which regulate APOE expression.11 Reduced levels of thyroxine, a thyroid hormone essential for metabolism and brain function, observed in sleep-deprived animals, impair the function of APOE and its receptors in clearing Aβ. Excessive APOE expression may also compete with Aβ for receptor binding, hindering its clearance. This indicates that sleep deprivation both increases Aβ accumulation and impairs APOE-mediated clearance, contributing to the progression of cognitive decline and neurodegeneration in Alzheimer’s disease.

Neighborhood Resources, Family Dynamics, Employment Type, and Education Levels Associated with AD Risk and Cognitive Decline
Neighborhood differences, occupational types, and education levels contribute to variations in the likelihood of developing Alzheimer’s disease and other dementias. A study by DM Alhasan et al. shows that neighborhoods with fewer resources and employment in rural or small urban industries strongly correlate with higher AD incidence.15 The study examined older adults (≥50 years old) across 1,081 census tracts in South Carolina from 2010 to 2014. In these settings, factors such as suboptimal nutrition, chronic stress, and pollutants may contribute to biological vulnerabilities and accelerate cognitive decline. Specifically, rural areas (19.3% of the population) and small urban areas (22.3%) showed an increased AD risk. While neighborhood conditions are often difficult to modify at an individual level, family dynamics, such as household size and daily interactions, may serve as more actionable protective factors. Li et al. found that, in family environments with both support and occasional conflict, people perform better cognitively than those in disengaged or high-conflict households. Frequent, meaningful social engagement, even if not always harmonious, can help preserve cognitive function.21

Occupational complexity also increases AD risk. Majoka and Schimming report that individuals engaged in manual labor, which typically involves lower intellectual stimulation, heighten the risk of AD compared to jobs requiring more complex cognitive tasks like problem-solving, language, or mathematics.16 The  “cognitive reserve” hypothesis suggests that the brain builds resilience through mentally engaging activities over the lifespan.17 Thus, a richer cognitive reserve may delay the onset of AD symptoms, even in the presence of underlying neuropathology.18

The 2020 Lancet Commission on Dementia Prevention, Intervention, and Care estimated that up to 40% of worldwide dementia cases could be prevented or delayed by addressing modifiable risk factors, like educational attainment and limited social engagement.19 The Chicago Health and Aging Project (CHAP) has shown that individuals with fewer years of formal education are at higher risk of developing cognitive impairment and dementia.20 These differences often persist even after adjusting for known genetic risks like the APOE ε4 allele; therefore, occupational factors and education levels are critical in influencing AD risk.

Conclusion

Alzheimer’s disease risk, particularly among APOE ε4 carriers, is influenced by a range of socio-environmental factors including air pollution, head injury, and sleep deprivation. Recent air quality alerts in Los Angeles, driven by ongoing wildfires, emphasize the compounded danger of these environmental exposures for high-risk groups. Several epidemiological studies have demonstrated that individuals with APOE ε4 face accelerated disease onset under poor air conditions; however, these interactions are not yet fully explored in large-scale clinical datasets. Nonetheless, the global burden of AD indicates an urgent need for systems that address both genetic predispositions and environmental hazards; therefore, policies to reduce pollution are a strong priority for mitigating disease risk.

References

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