Multisystem failure, tipping points, and risk of Alzheimer's disease

Abstract

Introduction: Medical conditions including obesity, diabetes, hyperlipidemia, and depression significantly increased risk of Alzheimer's disease (AD). However, effect of their duration, influenced by non-modifiable factors like chromosomal sex and apolipoprotein E (APOE) genotype, remains unclear.

Methods: Data from 5644 UKBiobank participants were analyzed using Cox regression model to identify critical tipping points based on age of onset, risk factor (RF) duration and their interaction with sex and APOE genotype.

Results: Hypertension or diabetes before age 62 exerted greater AD risk than APOEε4 alone. Obesity before age 62 increased AD risk by 54%, with the risk nearly tripling between ages 62-72. Hyperlipidemia and depression were associated with age-independent risk increases of 33% and 69%, respectively. After age 72, APOEε4 became the dominant RF.

Discussion: Duration of AD-risk-factors can have a greater impact than APOEε4. Identification of critical age-related tipping points highlights temporal dynamics of AD progression and role of multisystem failure in AD progression.

Highlights: AD risk factors impact AD onset, especially diagnosed between ages 62 and 72. Later diagnoses of hypertension, diabetes, and obesity delayed AD onset. Hyperlipidemia and depression increased AD risk by 33% and 69%, age-independent. APOEε4 carriers regardless of sex exhibited a higher risk increasing with age. Trajectories differed between APOEε4 carriers and non-carriers across sex.

Keywords: AD prevention strategies; AD‐risk‐factors; APOE genotype; Alzheimer's disease (AD); Cox proportional hazard model (CPHM); UK Biobank; chromosomal sex; depression; hyperlipidemia (HLP); hypertension (HTN); late onset Alzheimer's disease (LOAD); modifiable risk factors; obesity; type 2 diabetes (T2D); unmodifiable risk factors.

FIGURE 1

Overview of the extended Cox proportional hazard model (CPHM) proposed to evaluate the impact of multiple diagnoses throughout participants’ lifespan on Alzheimer's disease (AD) diagnosis. UK Biobank longitudinal diagnosis data of 5644 participants were included as input to the model along with the related sex and apolipoprotein E (APOE) genotype. (A) Risk factor diagnoses are modeled as time‐dependent covariates x_i(t) while sex and APOEε4 carrier status are modeled as time‐fixed covariates X_i. (B) Time‐varying representation of diagnoses included in the Cox model, where each participant can be associated with up to five risk factor diagnoses (i.e., covariates) before the end‐point occurrence (i.e., AD or last follow‐up diagnosis).

FIGURE 2

Study design and summary of the UK Biobank (UKB) matched cohort main features. (A) Study design and UKB participants selection. (B) Covariate balance before and after pair‐matching. The love plot illustrates the standardized mean differences of covariates before (pink) and after (light blue) 3:1 pair‐matching. The balance improves post‐matching, as indicated by the reduced absolute standardized mean differences across covariates. (C) Age of each risk factor diagnosis by sex and apolipoprotein E (APOE) ε4 carrier status, grouped by Alzheimer's disease (AD) diagnosis. (D) Distribution of risk factor diagnoses by sex and APOEε4 carrier status, grouped by AD status. Bars are normalized within each AD group to facilitate comparison. (E) Distribution of number of comorbidities by sex and APOEε4 carrier status, grouped by AD diagnosis. CHF, congestive heart failure; LiverMild, mild liver disease; LiverSevere, moderate to severe liver disease; MI, myocardial infarction; CHF, congestive heart failure; NDD, neurodegenerative disease; Paralysis, hemiplegia or paraplegia; PUD, peptic ulcer disease; Pulmonary, chronic pulmonary disease; PVD, peripheral vascular disease; Renal, moderate to severe renal disease; RF, risk factor; Rheumatic, rheumatologic disease; Stroke, cerebrovascular disease.

FIGURE 3

Estimated hazard ratios (HRs) and 95% confidence intervals for the associations between Alzheimer's disease (AD) risk factors and non‐modifiable risk factors with AD onset in (A) Cox regression model and (B) Cox regression model stratified by time intervals. APOE, apolipoprotein E; n.s., not significant.

FIGURE 4

Trajectories stratified by sex and apolipoprotein E (APOE) genotype for type 2 diabetes (T2D), hyperlipidemia (HLP), hypertension (HTN), obesity (OBESITY), depression (DEP), and absence of AD‐risk‐factors (No risk factors). (A) All cohort trajectories. (B) Female APOEε4 carrier. (C) Female APOEε4 noncarrier. (D) Male APOEε4 carrier. (E) Male APOEε4 noncarrier.