Medical risk factors, ApoE haplotype, and Alzheimer's disease: a large-scale analysis.

Background: The multifactorial nature of Alzheimer's disease (AD) has become increasingly evident. In addition to well-established features like neurodegeneration, amyloid-beta and tau deposition, or glial changes, other processes-such as metabolic, circulatory, and inflammatory factors-may also play a key role in driving or accelerating AD-related pathology and cognitive decline. These factors represent important targets for slowing disease progression.

Objectives: Although many studies have examined individual risk factors and meta-analyses have been performed, a large-scale, comprehensive comparison using formal medical data from a single, unified cohort is needed.

Design: A retrospective case-control study leveraging comprehensive health database.

Setting: Data were obtained from the UK-Biobank, a large (∼500 K people) population-based biomedical database in the United Kingdom.

Participants: The study included participants aged 40-69 at enrollment between 2006 and 2010, comprising 3,843 individuals who were clinically diagnosed with AD by August 2022 and 387,275 individuals without dementia or cognitive-impairment diagnoses.

Measurements: ICD-10-coded diagnoses, recorded at least 10 years prior to AD diagnosis, were analyzed. Logistic regression was used to estimate the impact and significance of various medical conditions and their interactions with genetic risk factors, while accounting for demographic determinants.

Results: The analysis identified 45 medical factors (96 ICD-10 entities) across multiple systems-particularly metabolic, circulatory, gastrointestinal, and sensorimotor-that significantly differentiated individuals with clinical AD from cognitively unimpaired individuals. Interaction analyses revealed that circulatory and metabolic factors had a weaker influence on AD risk in Apolipoprotein E ε4 carriers, suggesting a gene-environment interaction in disease susceptibility.

Conclusions: These findings enhance the understanding of system-level risk factors for clinical AD, highlight the relevance of less frequently reported factors in the AD prevention literature-such as gastrointestinal and sensorimotor disorders-and underscore the complex interplay between genetic susceptibility and vascular risk factors.