Metabolic Profiling of Cognitive Aging in Midlife

Abstract

Alzheimer's dementia (AD) begins many years before its clinical symptoms. Metabolic dysfunction represents a core feature of AD and cognitive impairment, but few metabolomic studies have focused on cognitive aging in midlife. Using an untargeted metabolomics approach, we identified metabolic predictors of cognitive aging in midlife using fasting plasma sample from 30 middle-aged (mean age 57.2), male-male twin pairs enrolled in the Vietnam Era Twin Study of Aging (VETSA). For all twin pairs, one twin developed incident MCI, whereas his co-twin brother remained to be cognitively normal during an average 5.5-year follow-up. Linear mixed model was used to identify metabolites predictive of MCI conversion or cognitive change over time, adjusting for traditional risk factors. Results from twins were replicated in an independent cohort of middle-aged adults (mean age 59.1) in the Wisconsin Registry for Alzheimer's Prevention (WRAP). Results in twins showed that higher baseline levels of four plasma metabolites, including sphingomyelin (d18:1/20:1 and d18:2/20:0), sphingomyelin (d18:1/22:1, d18:2/22:0, and d16:1/24:1), DAG (18:2/20:4), and hydroxy-CMPF, were significantly associated with a slower decrease in one or more domains of cognitive function. The association of sphingomyelin (d18:1/20:1 and d18:2/20:0) was replicated in WRAP. Our results support that metabolic perturbation occurs many years before cognitive impairment and plasma metabolites may serve as early biomarkers for prediction or monitoring of cognitive aging and AD in midlife.

The role of dietary patterns and erythrocyte membrane fatty acid patterns on mild cognitive impairment

“…This result validated that the dietary patterns with different consumption characteristics of fatty acid might affect FAPs. Our results supported that erythrocyte membrane metabolites, SM (26:0), SM (24:1), and SM (26:1), might function as early biomarkers for predicting or monitoring cognitive aging in elderly (13). Dietary pattern 1 affected FAP2, and this pattern might achieve the ultimate goal of neuroprotection through the very long-chain SMs.…”

“…They also get involved in the mechanisms leading to cognitive impairment or inflammation in elderly subjects (12). However, evidence indicates that saturated fatty acids (SFAs) with different carbon chain lengths have various effects on the process of Aβ generation, and fatty acids with longer chain (C20:0 and C26:0) are more likely to promote Aβ production (13). In addition, dietary fatty acid saturation is reported to be harmful to cognitive function in human studies (14).…”

Investigating associations between blood metabolites, later life brain imaging measures, and genetic risk for Alzheimer’s disease

“…Within the module, we identified four hub metabolites – two phospholipids and two DAGs. Both subclasses have been previously linked to AD and neurodegeneration (43,44), and increased serum concentrations have been hypothesised to represent alterations in membrane integrity and subsequent degradation (45,46), although some associations in the opposite direction have also been reported (32,47). Three module hubs were additionally associated with an AD PRS at the nominal level; this relationship appeared to be driven predominantly by APOE and may thus reflect pleiotropic pathways.…”

Sphingomyelins and ceramides: possible biomarkers for dementia?

“…This lack of certainty limits the ability to compare effect sizes, thereby forcing an increased reliance on statistical significance as the sole indication of association. Of note, a few longitudinal investigations tested hypotheses that were incomparable to those investigating clinical progression of diagnoses, such as longitudinal trajectories in hippocampal volume [16] and changes in cognitive test scores [16,24,29] over time.…”