Genome-Wide Association Scan Identifies Risk Factors and Endophenotypes for Late-Onset Alzheimer's Disease

Core Concepts

Large-scale biobank data and genome-wide association studies can be leveraged to systematically identify genetic risk factors and distinct biological processes underlying various risk factors for late-onset Alzheimer's disease.

Abstract

The authors introduced BADGERS, a powerful method to perform biobank-wide association scans using genome-wide association study (GWAS) summary statistics. They applied BADGERS to two independent datasets for late-onset Alzheimer's disease (AD) and identified 48 significant associations with various traits in the UK Biobank.
Key findings:

Family history, high cholesterol, and numerous traits related to intelligence and education showed strong and independent associations with AD.
Family history and high cholesterol were strongly associated with classic AD neuropathologies, including neuritic plaques and neurofibrillary tangles.
In contrast, intelligence and education-related traits predicted pre-clinical cognitive phenotypes but not AD neuropathologies.
The associations with family history and high cholesterol were substantially reduced after removing the APOE region, while the associations with cognition and education were largely unchanged.
These results suggest that various AD risk factors may affect the disease course at different time points and via distinct biological processes. While some risk factors (e.g., high cholesterol and APOE) may directly contribute to the accumulation of pathologies, other factors (e.g., intelligence and education) may buffer the adverse effect of brain pathology on cognition.

Stats

Family history of Alzheimer's disease and dementia showed the most significant associations with late-onset Alzheimer's disease.
Having any dementia diagnosis was also strongly and positively associated with Alzheimer's disease risk.
Better performance in cognition tests, such as fluid intelligence score and time to complete cognitive tests, was associated with lower Alzheimer's disease risk.
Higher education attainment, such as having a university degree or A-levels, was associated with lower Alzheimer's disease risk.
High cholesterol was positively associated with Alzheimer's disease risk.

Quotes

"Family history showing strong associations with AD is not a surprise, and many other associations are supported by the literature as well. The protective effect of higher educational and occupational attainment on the risk and onset of dementia is well studied."
"These results suggest that various AD risk factors may affect the disease course at different time points and via distinct biological processes. While some risk factors (e.g., high cholesterol and APOE) may directly contribute to the accumulation of pathologies, other factors (e.g., intelligence and education) may buffer the adverse effect of brain pathology on cognition."

Key Insights Distilled From

Biobank-wide association scan identifies risk factors for late-onset Alzheimer’s disease and endophenotypes

by Yan,D., Hu,B... at www.biorxiv.org 11-12-2018

https://www.biorxiv.org/content/10.1101/468306v3

Deeper Inquiries

What other modifiable lifestyle factors beyond education and cholesterol could be targeted for Alzheimer's disease prevention

In addition to education and cholesterol, several other modifiable lifestyle factors could be targeted for Alzheimer's disease prevention. One key factor is physical activity. Regular exercise has been shown to have a protective effect on brain health and cognitive function. Studies have indicated that physical activity can help reduce the risk of developing Alzheimer's disease by promoting neuroplasticity, reducing inflammation, and improving overall brain health.
Another important lifestyle factor is diet. A diet rich in antioxidants, omega-3 fatty acids, and other nutrients has been associated with a lower risk of cognitive decline and Alzheimer's disease. Consuming a Mediterranean diet, which includes plenty of fruits, vegetables, whole grains, and healthy fats, has been linked to better cognitive function and a reduced risk of dementia.
Furthermore, maintaining social connections and engaging in mentally stimulating activities can also play a role in reducing the risk of Alzheimer's disease. Social interaction and cognitive engagement have been shown to support brain health and resilience against cognitive decline.
Addressing risk factors such as smoking, excessive alcohol consumption, and poor sleep quality are also important in Alzheimer's disease prevention. Smoking and heavy alcohol use have been linked to cognitive impairment and an increased risk of dementia. Poor sleep quality and sleep disorders have been associated with cognitive decline and an increased risk of Alzheimer's disease.

How do the identified genetic risk factors interact with environmental and social determinants of health to influence Alzheimer's disease risk and progression

The identified genetic risk factors for Alzheimer's disease can interact with environmental and social determinants of health to influence disease risk and progression in several ways. Environmental factors such as exposure to air pollution, toxins, and pesticides can interact with genetic predispositions to increase the risk of developing Alzheimer's disease. For example, individuals with specific genetic variants may be more susceptible to the neurotoxic effects of environmental pollutants, leading to accelerated cognitive decline and disease progression.
Social determinants of health, such as education level, socioeconomic status, and access to healthcare, can also interact with genetic risk factors to impact Alzheimer's disease outcomes. Higher levels of education and socioeconomic status have been associated with a reduced risk of dementia, potentially due to increased cognitive reserve and access to better healthcare resources. These social determinants can modify the expression of genetic risk factors and influence the trajectory of the disease.
Additionally, lifestyle factors such as diet, exercise, and mental stimulation can interact with genetic vulnerabilities to either mitigate or exacerbate Alzheimer's disease risk. Individuals with a genetic predisposition to the disease may benefit more from a healthy lifestyle, including a nutritious diet, regular physical activity, and cognitive engagement, to reduce their risk of developing Alzheimer's disease or delay its onset.

What are the underlying neurobiological mechanisms by which intelligence and education-related traits protect against cognitive decline in the presence of Alzheimer's disease pathology

The protective effects of intelligence and education-related traits against cognitive decline in the presence of Alzheimer's disease pathology may be mediated by several underlying neurobiological mechanisms.

Cognitive Reserve: Intelligence and education are associated with higher cognitive reserve, which refers to the brain's ability to cope with damage or pathology. Individuals with higher cognitive reserve may have more efficient neural networks, greater synaptic density, and enhanced brain connectivity. This cognitive reserve can help compensate for the effects of Alzheimer's disease pathology, allowing individuals to maintain cognitive function despite brain changes.

Neuroplasticity: Intelligence and education are linked to increased neuroplasticity, the brain's ability to reorganize and form new neural connections. This enhanced neuroplasticity may enable individuals to adapt to and compensate for Alzheimer's-related brain changes, preserving cognitive function and delaying the onset of symptoms.

Lifestyle Factors: Intelligence and education are often associated with healthier lifestyle choices, such as engaging in mentally stimulating activities, maintaining social connections, and following a nutritious diet. These lifestyle factors can promote brain health, support neurogenesis, and protect against cognitive decline in the presence of Alzheimer's disease pathology.

Stress Response: Higher levels of education and intelligence may be linked to better stress management and coping strategies. Chronic stress has been associated with cognitive decline and neurodegeneration, so individuals with higher education and intelligence levels may be better equipped to handle stress and its detrimental effects on the brain.

Overall, intelligence and education-related traits contribute to cognitive resilience and may help individuals maintain cognitive function and delay the progression of Alzheimer's disease by enhancing cognitive reserve, promoting neuroplasticity, supporting healthy lifestyle choices, and improving stress management.