How Circulating Metabolites Can Predict Alzheimer’s Pathogenesis How Circulating Metabolites Can Predict Alzheimer’s Pathogenesis

The study covered in this summary was published on as a preprint and has not yet been peer reviewed.

Key Takeaways

  • The investigators attempted to estimate the metabolic features of genetic liability to Alzheimer’s disease (AD) at seven different stages across the life span, with the aim of identifying early features of AD pathogenesis that may be potential targets to prevent the clinical onset of AD.

  • They designed a genetic instrument for AD liability and explored its association with circulating metabolites measured in two studies: the Avon Longitudinal Study of Parents and Children (ALSPAC) and the UK Biobank.

  • The results bolster a deep-seated influence of the APOE4 isoform on circulating lipids and fatty acids from early life to later adulthood. These lipid and fatty acid traits may be involved in early AD pathogenesis.

  • AD-associated metabolic disorders take root in childhood, multiple decades before the development of disease, and carry over into later adulthood when the diagnosis of AD more commonly occurs.

Why This Matters

  • Amid our aging population, the number of patients with AD — the most common form of dementia — continues to increase.

  • Neuropathological hallmarks of AD arise decades earlier than the onset of clinical symptoms, yet patients are often diagnosed late in the disease trajectory.

  • Although brain and cerebrospinal fluid (CSF) metabolites differentiate AD cases from controls with a high level of accuracy, they require invasive methods, such as lumbar puncture, to collect samples.

  • As a result, significant motivation remains for more easily identifying measured plasma AD biomarkers, as is starting to be shown for plasma amyloid-beta, which could enhance our understanding of early disease etiology.

Study Design

  • The researchers used genetic and metabolomic data of 5648 offspring from the ALSPAC birth cohort.

  • Linear regression models analyzed the association between higher AD liability, as measured by a genetic risk score (GRS), and plasma metabolites measured at 8, 16, 18, and 25 years of age.

  • The study involved 229 metabolites, most of which related to lipid/lipoprotein traits.

  • To evaluate the persistence of any AD liability effects into late adulthood, the investigators performed two-sample Mendelian randomization utilizing summary statistics from age-stratified genome-wide association studies of the same metabolites for 118,466 participants from the UK Biobank.

Key Results

  • GRS including the APOE4 isoform showed the most robust associations for cholesterol-related traits per doubling of genetic liability to AD, eg, for low-density lipoprotein cholesterol (LDL-C) at age 25 years (0.12 standard deviation [SD]; 95% CI, 0.09 – 0.14), with similar degrees of association across age groups in ALSPAC.

  • In the UK Biobank, the effect of AD liability declined with age tertile for several lipid traits (eg, LDL-C, youngest: 0.15 SD; 95% CI, 0.07 – 0.23; intermediate: 0.13 SD; 95% CI, 0.07 – 0.20; oldest: 0.10 SD; 95% CI, 0.05 – 0.16).

  • Across both groups, the effect of AD liability on high-density lipoprotein cholesterol (HDL-C) weakened with advancing age.

  • Fatty acid metabolites also exhibited positive associations in both cohorts, though lesser in magnitude compared with lipid traits.

  • Sensitivity analyses revealed that the APOE4 isoform was the catalyst behind these effects.


  • The modest analysis sample size for ALSPAC analyses, particularly at older ages, is a major limitation of this study. Nonetheless, the researchers’ use of an allele score method seemed to enable relatively high statistical power and precision of exposure-outcome estimates.

  • The lack of ancestral diversity in ALSPAC (96% white) and UK Biobank (only Europeans examined) limits the generalizability of results to diverse populations, although it does, however, limit the potential for confounding by population stratification. Future studies must delve into the extent to which APOE4 carrier status has an impact on the metabolome for other populations.

  • Despite the central-peripheral flux of metabolites via the blood–brain barrier, prior research has indicated that there is divergence between the AD molecular profiles of plasma and CSF. Hence, the degree to which assumptions regarding central AD pathophysiology can be drawn from this study are potentially limited.

  • Another limitation stems from the targeted nature of the Nightingale metabolomics platform, which concentrates on metabolites previously identified to be of clinical interest, most of which are lipids. An untargeted approach would facilitate the discovery of unknown biomarkers, including those beyond the lipid classes, of AD liability.

Study Disclosures

This is a summary of a preprint research study, “Effects of genetic liability to Alzheimer’s disease on circulating metabolites across the life course,” written by Hannah Compton from University of Bristol, United Kingdom on medRxiv, provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on

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