Review for 10.1186/s12876-025-03814-1 (2025)

Title: Metabolic Dysfunction-Associated Steatotic Liver Disease, Metabolic Alcohol-Related
Liver Disease, and Incident Dementia: a nationwide cohort study MASLD, MetALD, and
dementia risk
Version: 2 Date: 22 Feb 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-While the introduction mentions the differences between Asian and Western populations (e.g.,
lower obesity prevalence, higher viral hepatitis burden, faster aging), it could benefit from
further elaboration on how these demographic and epidemiological factors might specifically
influence dementia risk. Additionally, a clearer explanation of why studying this relationship
in an Asian context is important could help the reader understand the unique contributions of
the study.
-The introduction could briefly mention potential mechanisms linking MASLD, MetALD,
and dementia. For instance, inflammatory and metabolic factors commonly associated with
MASLD, such as insulin resistance and lipid metabolism disturbances, could be explained as
potential pathways contributing to dementia risk. Including these mechanisms would enrich the
scientific depth of the introduction.
-The criteria for defining "moderate alcohol intake" in MetALD are clear (30-60 grams for
males, 20-50 grams for females), but it would be beneficial to mention whether this was based
on self-reported data or clinical measurements. Self-reported alcohol consumption data may
introduce recall bias, which could be addressed or acknowledged in the limitations.
-While the study adjusts for multiple confounders (age, sex, BMI, comorbidities, smoking,
physical activity), the methods could be enhanced by briefly explaining why these specific
covariates were chosen. For example, mentioning prior research showing these variables'
influence on dementia risk would provide additional justification.
-While the discussion includes biological mechanisms for MASLD and its association with
dementia (e.g., oxidative stress, chronic liver inflammation), the potential mechanisms for
how MetALD specifically contributes to VaD could be expanded. MetALD involves alcohol
consumption, which could have a compounded neurotoxic effect. A more detailed explanation
of how alcohol exacerbates vascular damage in the context of MetALD, leading to VaD, would
be beneficial.
-The concept of a "latent period" before increased dementia risk appears (especially for
MetALD) is intriguing. However, further clarification is needed on why this latent period exists
and why the association with AD appears to reverse initially. Exploring why AD progression
may take longer to manifest compared to VaD, in the context of metabolic dysfunction, would
offer a deeper understanding of the findings.
-While the "obesity paradox" is acknowledged, it could be beneficial to expand on this in the
context of the study. For example, the potential impact of sarcopenic obesity (where excess fat
is paired with muscle loss) could be discussed. It would be interesting to examine how changes
in body composition (rather than just BMI) might affect the risk of dementia in individuals with
MASLD and MetALD.
-The discussion mentions the exclusion of genetic or biological factors in the analysis but could
benefit from a brief exploration of how such factors may play a role in the relationship between
MASLD/MetALD and dementia. For instance, how genetic predispositions to liver disease or
neurodegenerative conditions might influence dementia risk could be mentioned as a future
direction for research.