For the first time, the Xiangya Hospital team confirmed that there is no causal relationship between Alzheimer's disease and age-related macular degeneration

*For medical professionals only

Alzheimer's disease (AD) is the most common neurodegenerative disease, and the "age spots" formed β the deposition of amyloid (Aβ) in the brain are one of the typical pathological features of
AD.

Coincidentally, large amounts of Aβ
are also present in hydranous warts, a typical pathological feature of age-related macular degeneration (AMD).

Since AD and AMD are both highly prevalent in the elderly population and share common histopathological features and pathophysiological mechanisms, the relationship between the two has become a research hotspot in recent years [1].

Recently, Shen Lu's team from Xiangya Hospital affiliated to Central South University published important research results in Alzheimer's & Dementia, a top journal in the field of AD [2].

They found through the Mendelian randomization analysis study (MR) that there was no statistically causal relationship between genetic susceptibility to late AMD and AD risk (OR=0.
999, P=0.
948); Conversely, AD also has no causal relationship for late AMD (OR=0.
973, P=0.
133).

This shows that there is currently no evidence to support a two-way causal relationship between advanced AMD and AD, suggesting that the possibility of clinical correlation between these two diseases is very low, and the diagnostic and therapeutic ideas that link the two together may need to be adjusted and updated, which is of great significance for pathological mechanism research and clinical practice
.

Screenshot of the first page of the paper

Previous studies suggest that AMD and AD may have common risk factors and pathophysiological mechanisms
.
Coupled with the high correlation of clinical symptoms, research on the causal relationship between the two has been continuously carried out, but the conclusions reached have always been debated, and it is urgent to clear the clouds
.

For example, meta-analysis studies have shown that patients with AMD are at higher risk of developing AD [3]; For people with cognitive impairment with AD, the risk of advanced AMD is also correspondingly increased [4].

Of course, there are also cohort studies that have come to completely different (opposite) conclusions, and there is actually no significant association between late AMD and AD [5]; Some prospective studies have also found that the risk of AD in AMD patients is also not significantly increased [6].

In order to solve the problem of inconsistency in the above conclusions, MR, which can avoid residual confounding and reverse causal interference, naturally becomes a more reliable analysis tool
.
Compared with traditional observational studies, MR uses genetic information as a substitute index, is less susceptible to bias, and the analysis of causality is more robust
.

For this reason, the research team designed a two-sample MR research method
based on the three core assumptions of instrumental variables predicting exposure, independent of known confounders, and only affecting outcomes by exposure.
By combining single nucleotide polymorphism (SNP) exposure and SNP result correlation, the impact of exposure on outcomes can be determined and the genetic evidence between the two can be assessed using holistic data, aiming to reveal a causal relationship
between late AMD and AD.

ADtaxi recalls "Remember" Cheng Che vol.
22 Listen to Craig Ritchie, Professor of Geriatric Psychiatry at the University of Edinburgh, interpret the risk analysis and risk factors of AD and cognitive evidence

Specifically, the research team obtained an abstract-level dataset from the International AMD Genomics Consortium, which included 16,144 cases of advanced AMD (first diagnosed after age 50 with at least one fundus atrophy and/or macular choroidal neovascularization) and 17,832 control populations (non-intermediate and advanced AMD, including early AMD and non-AMD populations), and estimated β coefficients and standard errors [7].

。 Then, for the selection of AD populations, the research team included genome-wide data (GWAS) containing 21,982 cases and 41,944 controls for preliminary analysis [8].

Finally, a larger GWAS database (including a total of 71,880 cases and 383378 controls) was used to strengthen the causality and validate the analysis results
.
All of the above groups are of European ancestry
.

The research team then ruled out potential confounding factors associated with AMD and AD (obesity, smoking, alcohol consumption, high blood pressure, serum cholesterol, and diabetes) or SNPs associated with education, depressive symptoms, and sleep, and further removed SNPs
of the apolipoprotein E (APOE) e2/3/4 genotype that may affect AMD and AD.

Finally, fixed-effect inverse variance weighting (IVW) is used as the main statistical method to comprehensively analyze the bidirectional causal relationship
between late AMD and AD.

The IVW method was used to study the bidirectional causality table between genetic susceptibility to late AMD and AD

The results showed that the genetic susceptibility to late AMD was not related to AD risk, and there was a consistent zero association across different AD datasets (see table above, P values were all greater than 0.
05).

Similarly, there was no statistically significant causal relationship between genetic susceptibility to AD and risk of late AMD (see table above, both P values greater than 0.
05).

Bidirectional MR analysis scatterplot between late AMD and AD

The X-axis represents a genetic association with exposure and the Y-axis represents a genetic association
with the risk of outcome.

The slope of each line represents a causal estimate of the corresponding outcome risk for each method, showing a causal relationship
with no statistical difference.

The A/B diagram represents AMD's causal relationship to AD; The C/D diagram represents the causal relationship between AD and AMD

In addition, the causality estimation of IVW analysis and all sensitivity analyses was consistent (see figure above), which supported the robustness of
causality in MR analysis.

Overall, this study is the first to apply the MR method to evaluate a bidirectional causal relationship between late AMD and AD: there is neither genetic evidence that late AMD is associated with AD risk, nor results show that AD is associated with
late AMD.
It follows that the association between late AMD and AD should not be defined as causal
.

There were also some limitations in this study, such as the relatively single study population; No more specific stages or subtypes of AMD were distinguished in the study; Other non-genetic factors
that can influence AMD and AD are also not included.

However, in an environment where both blinding and dementia have become a serious global public health burden, even if the research team only provides a causal finding, the results of MR analysis are undoubtedly more solid and convincing than a large number of previous observational studies, and question the role of AD in the etiology of late AMD
.

It is not difficult to see that the pathological mechanism of neurodegenerative diseases is mysterious and complex, and the prevention and treatment of age-related diseases is even more
arduous.
Especially for the clinical treatment of AMD and AD, not taking the road of forced association may be a more reasonable clinical direction in the future
.

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