More Evidence to Focus on Tau in Alzheimer’s Disease

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A extensive reference map of the metabolic brain-related effects in Alzheimer’s disease (AD) offers strong evidence of changes in bioenergetic pathways, the metabolism of cholesterol, neuroinflammation and other pathways. This is the result of a huge multicenter trial.

AD is the most prevalent form of dementia and its is expected to increase in the coming years. The neurodegenerative disorder is defined by neurofibrillary tau-protein neurofibrillary tangles as well as the accumulation of beta-amyloid. A wide array of evidence supports metabolic impairment as the primary cause of these pathologies. Metabolic transporters and enzymes are among the most frequently targeted proteins in pharmaceutical interventions across all disorders, highlighting the translational potential of systematically discovering metabolic changes in AD. This research provides the first comprehensive map of the metabolic brain changes associated with AD, AD associated neuropathologic manifestations, and cognitive decline.

The analysis involved brain samples from 500 participants, comprising 352 women and 148 males with a mean age at death of 91. Participants were screened for physiologic and cognitive function every year after signing to participate in the study.
The neuropathology of the deceased was determined following autopsy.
The statistical associations between eight metabolic profiles and AD-related traits were used to assess the metabolic changes associated with AD. All models used in the analysis took into account AD-related confounders (age, gender, years of schooling and body mass index and copies of APOE4) as well as postmortem intervals.
Untargeted metabolic profiling was conducted on samples from the dorsolateral prefrontal cortex brain region. Metabolomics tests were examined in relation to eight AD-related characteristics that cover late-life cognitive assessments as well as postmortem pathology. These included diagnosis at the time of death; level of cognition proximate to death; cognitive decline during life; b-amyloid load tau tangle load; global burden of AD pathology (global NP) the NIA-Reagan score and neuropathologic diagnosis, derived on the basis of the combination of Braak stage and CERAD score (NP diagnosis).

Of the 500 participants, 220 had AD (with or with out a secondary cause) at the time of their death. 119 had mild cognitive impairment and 153 did not have cognitive impairment and eight had different forms.
298 out of 667 metabolites (44.7 percent) were significantly associated with one or more AD characteristics at a the rate of 5% false discovery. The majority of 298 metabolites had been linked to one of three AD traits such as cognitive impairment (n=201) or tau tangles (n=188), or the global burden of disease (n=183). The lowest number of associations among the eight AD characteristics was 34 metabolites that were associated with b–amyloid.
While B-amyloid has been the subject of most therapeutic approaches however, a conditional analysis suggests that tau pathology is a driver of brain metabolic changes. It is believed to be responsible for the accumulation of tau tangles and tangle-driven pathogenesis. This study suggests that tau tangles’ metabolic associations are mostly independent of b-amyloid load, however, metabolic associations associated with b-amyloid load are confounded by tau tangle loads.

Cross-sectional studies are not able to evaluate the causality of these connections despite the numerous new discoveries about the changes in metabolism in AD. The changes in metabolism that are observed in AD could either directly contribute to the development of disease or have a reverberating impact on brain pathologic changes. The study did not have the statistical power necessary to determine the true nature and extent of the effect.
Postmortem tissue samples can be subject to significant biological and technical variation. This is evident in the association between 307 of 667 metabolisms as well as the postmortem interval (PMI) which is the time period between death and preservation. Despite statistical corrections for PMI interval the degradation of certain substances prior to preservation of samples is not controlled in this type of study.

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