The Role of Lipid Variability in Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias

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Prevention strategies for Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRDs) are of utmost importance due to the rising prevalence of these conditions.

While there has been extensive research on various risk factors for AD/ADRD, one area that has not been thoroughly examined is lipid variability, which refers to fluctuations in blood lipid levels over time.

Understanding the association between lipid variability and the development of AD/ADRD could provide valuable insights into potential preventive measures.

In this study, we aimed to investigate the variation of multiple lipid types and their association with the development of AD/ADRD in a large population-based cohort. We analyzed data from a geographically defined population and explored the relationship between lipid variability and incident AD/ADRD, while accounting for confounding factors such as baseline lipid levels and adherence to lipid-lowering treatment.

The findings of our study revealed a significant association between high variability in total cholesterol and triglyceride levels and the incidence of AD/ADRD. Importantly, this association remained significant even after adjusting for baseline cholesterol levels and lipid-lowering treatment. However, we did not observe a similar association for variability in LDL-C and HDL-C levels.

These results are consistent with previous studies that have shown an association between lipid variability and cardiovascular outcomes. Total cholesterol variability has been identified as a predictor of cardiovascular and coronary events, myocardial infarction, stroke, and all-cause mortality.

Similarly, LDL-C, HDL-C, and triglyceride variability have been linked to coronary and cardiovascular events, stroke, and myocardial infarction, independent of mean lipid levels and lipid-lowering treatment. Moreover, variations in fasting blood glucose, systolic blood pressure, and BMI have also been associated with adverse health outcomes, including all-cause mortality, myocardial infarction, and stroke.

Interestingly, an additive effect was observed when considering the number of high-variation parameters, indicating a higher risk of both cardiovascular and dementia outcomes. This suggests that lipid variability may be a marker of increased risk for adverse vascular and neurological events.

It is worth noting that our study focused on individuals above the age of 60, as the prevalence of AD/ADRD is relatively small among those below this age threshold. The mechanisms underlying the association between increased lipid variability and the risk of AD/ADRD are not yet fully understood. However, one possible explanation is endothelial dysfunction, which is considered an early marker for atherosclerosis.

Endothelial dysfunction has been associated with increased risk of cognitive impairment and lower cerebral blood flow, which could contribute to the development of AD/ADRD in later life. Additionally, atherosclerosis has been found to increase the risk of Alzheimer’s disease, and total cholesterol variability may lead to plaque instability, further increasing the risk of cerebrovascular damage.

The relationship between lipids and AD/ADRD has yielded inconsistent results, often dependent on the timing of lipid measurements. High total cholesterol levels during midlife have been associated with an increased risk of Alzheimer’s disease later in life. However, high total cholesterol levels during late life have been associated with a decreased risk of Alzheimer’s disease.

To account for potential age-related differences, we stratified our sample into two age groups: 60-69 years old and 70+ years old. Among those aged 70+, the highest quintile of total cholesterol variability showed a borderline significant association with incident AD/ADRD, while quintiles 2 and 3 exhibited significant associations.

The reasons why quintiles 2 and 3 had significant associations, but not quintile 5, remain unclear. Additionally, only the highest quintile of triglyceride variability remained significantly associated with AD/ADRD among those aged 70+. It is possible that triglyceride variability serves as a biomarker of AD/ADRD rather than a direct risk factor.

This hypothesis is supported by the observation that individuals in the highest quintile of triglyceride variability had the lowest BMI and triglyceride levels, and lower BMI is associated with decreased triglyceride levels, which is also associated with the early phases of Alzheimer’s disease.

Nevertheless, our analyses accounted for baseline lipid levels and BMI, and sensitivity analyses excluding individuals with early events or follow-up censoring did not attenuate the results, supporting the robustness of the findings.

In contrast to total cholesterol and triglycerides, LDL-C and HDL-C variability did not show a significant association with incident AD/ADRD in our study. Few studies have investigated the relationship between LDL-C and HDL-C variability and AD/ADRD. However, prior research has indicated an association between LDL-C variability and decreased cognitive function and lower cerebral blood flow.

It is plausible that LDL-C variability contributes to AD/ADRD through its impact on cerebral blood flow and cognitive function. On the other hand, both low and high levels of plasma HDL-C have been associated with an increased risk of AD/ADRD. The lack of a significant relationship between HDL-C and LDL-C variability and AD/ADRD risk in our study may be attributed to decreased sensitivity of these lipid profiles to early stages of dementia, as well as the influence of other factors related to aging and frailty.

Notably, the association between HDL-C and LDL-C variability and AD/ADRD risk may depend on APOE haplotypes, which play a crucial role in lipid homeostasis and have a significant impact on AD risk. Unfortunately, our study lacked access to APOE haplotype information, and future studies should consider stratification and adjustment by APOE haplotypes to further explore the association between lipid variability and AD/ADRD, as well as the role of different lipid-lowering treatments in this context.

While our study provides valuable insights into the association between lipid variability and AD/ADRD, there are some limitations that should be acknowledged. First, the inclusion criteria resulted in a sample that differed from the excluded individuals, potentially introducing selection bias.

Additionally, the use of ICD codes for AD/ADRD diagnosis may lead to underdiagnosis, and our outcomes may predominantly reflect more severe forms of the disease. Furthermore, we did not differentiate between different dementia subtypes, as our analysis focused on the entire spectrum of AD/ADRD.

The lack of data on APOE haplotypes and specific types of lipid-lowering medications is another limitation. The extraction of lipid levels from electronic health records (EHR) may also introduce variability, as the collection of lipid data in routine clinical practice may not be as standardized as in prospective cohort studies.

Moreover, the assessment of lipid variation using variability independent of mean (VIM) does not account for directionality. Lastly, the observed association between lipid variability and AD/ADRD may be influenced by factors related to frailty, as lipid variation could be a consequence of AD/ADRD or other health conditions associated with frailty. Future studies should consider baseline cognitive data and explore the impact of lipid variation on AD/ADRD risk with adjustment for frailty-related factors to further elucidate these associations.

In conclusion, our study highlights the significance of lipid variability, specifically high variability in total cholesterol and triglyceride levels, as a potential risk factor for the development of AD/ADRD. These findings contribute to the growing body of evidence suggesting that lipid profiles and their fluctuations over time play a crucial role in neurovascular health and the pathogenesis of AD/ADRD.

Understanding the mechanisms underlying the association between lipid variability and AD/ADRD may provide new avenues for preventive strategies and therapeutic interventions aimed at reducing the risk and progression of these devastating neurodegenerative diseases. Further research is warranted to elucidate the complex interactions between lipid variability, APOE haplotypes, and other genetic and environmental factors that may modulate the risk of AD/ADRD.

Additionally, prospective studies that incorporate longitudinal lipid measurements, cognitive assessments, and APOE haplotype information are needed to confirm and expand upon our findings. Ultimately, the identification of lipid variability as a potential risk factor for AD/ADRD opens up new possibilities for personalized interventions and preventive measures that may help mitigate the global burden of these conditions.


reference link : https://n.neurology.org/content/early/2023/07/05/WNL.0000000000207595

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