More Evidence to Focus on Tau in Alzheimer's Disease

Susan Kreimer

December 01, 2021

Key Takeaway

  • A comprehensive reference map of metabolic brain changes in Alzheimer's disease (AD) provides strong evidence of alterations in bioenergetic pathways, cholesterol metabolism, neuroinflammation, osmoregulation, and other pathways, results of a large, multicenter trial reveal.

  • This research was published as a preprint and has not yet been peer reviewed.

Why This Matters

  • AD is the most common cause of dementia, and prevalence rates are projected to rise significantly in the coming decades. The neurodegenerative disorder is marked by the deposition of β-amyloid and accumulation of neurofibrillary tangles of phosphorylated tau protein in the brain. A large body of evidence implicates metabolic impairment as the root cause of these pathologies. Metabolic enzymes and transporters are among the most commonly targeted proteins in pharmaceutical interventions across all diseases, emphasizing the translational potential of systematically identifying metabolic alterations in AD. The new research offers the first comprehensive reference map of metabolic brain changes related to AD, AD-associated neuropathologic manifestation, and cognitive decline.

Study Design

  • The analysis involved brain samples from 500 participants, including 352 women and 148 men, with a mean age at death of 91. Following enrollment in the study, participants underwent annual assessments for physiologic and cognitive function.

  • Neuropathology was assessed after autopsy.

  • To assess AD-related metabolic changes, statistical associations between metabolic profiles and eight AD-related traits were computed. All statistical models accounted for AD-related confounders (age, sex, years of education, body mass index, and copies of APOE4) as well as postmortem interval.

  • Untargeted metabolic profiling was performed on samples from the dorsolateral prefrontal cortex brain region. Metabolomics measurements were analyzed in relation to eight AD-related traits covering late-life cognitive assessments and postmortem pathology: clinical diagnosis at the time of death; level of cognition proximate to death; cognitive decline during lifetime; β-amyloid load; tau tangle load; global burden of AD pathology (global NP); NIA-Reagan score; and neuropathologic diagnosis, inferred on the basis of a combination of Braak stage and CERAD score (NP diagnosis).

Key Results

  • Of the 500 participants, 220 were diagnosed with AD (with or without a secondary cause of dementia) at the time of death, 119 had mild cognitive impairment, 153 were without cognitive impairment, and eight had other forms of dementia.

  • A total of 298 of 667 metabolites (44.7%) were significantly associated with one or more AD traits at 5% false discovery rate. The majority of the 298 metabolites were associated with one of three AD traits: cognitive decline (n = 201), tau tangles (n = 188), and global burden of pathology (n = 183). Only 34 metabolites were associated with β-amyloid, which was the lowest number of associations among the eight AD traits.

  • While β-amyloid has been the focus of most therapeutic approaches, conditional analysis suggests tau pathology is a driver of metabolic changes in brain. It is considered to influence the accumulation of tangles of phosphorylated tau as well as tangle-driven pathogenesis. This analysis suggests that metabolic associations of tau tangles are largely independent of β-amyloid load, while metabolic associations of β-amyloid load are confounded by tau tangle load.

Limitations

  • Despite numerous novel insights into metabolic alterations in the brain seen in AD, such cross-sectional studies cannot evaluate the causal direction of the identified associations. In other words, an observed metabolic change in AD could be a factor that directly contributes to disease development, or it could be a downstream effect of pathologic changes in the brain. The study lacked the necessary statistical power to determine the true direction of effect.

  • Second, postmortem tissue samples are susceptible to substantial biological and technical variation, as observed in the association of 307 of 667 metabolites with postmortem interval (PMI), ie, the time between death and sample preservation. Despite the statistical correction for PMI interval, degradation of certain metabolites prior to sample preservation is a factor that cannot be controlled in this type of study.

Study Disclosures

  • No disclosures

This is a summary of a preprint study by Jan Krumsiek and colleagues from Weill Cornell Medicine, New York, New York, posted on bioRxiv provided to you by Medscape. The research has not yet been peer reviewed. The full text of the study can be found on https://www.biorxiv.org/content/10.1101/2021.11.15.468698v1.full

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