Biomarkers and evolution in Alzheimer disease

Abstract

Brain regions and their highly neuroplastic long axonal connections that expanded rapidly during hominid evolution are preferentially affected by Alzheimer disease. There is no natural animal model with full disease pathology (neurofibrillary tangles and neuritic amyloid plaques of a severity seen in Alzheimer’s disease brains). Biomarkers such as reduced glucose metabolism in association neocortex, defects in long white matter tracts, RNA neurochemical changes, and high CSF levels of total and phosphorylated tau protein, which are helpful to identify MCI and preclinical Alzheimer disease patients, may also provide insights into what brain changes led to this disease being introduced during hominid evolution.

What is normal in normal aging? Effects of aging, amyloid and Alzheimer's disease on the cerebral cortex and the hippocampus

“…These areas include not only the temporal regions, but regions around the medial parietal cortex (the precuneus/posterior cingulate/retrosplenial cortex) – an area that is an important component of the DMN. One speculation is that areas characterized by high degree of life-long plasticity are those most vulnerable to detrimental effects of normal and pathological aging (Neill, 1995, Mesulam, 1999, Bufill and Carbonell, 2004, Rapoport and Nelson, 2011, Neill, 2012, Bufill et al, 2013). The pattern of effects may be explained by the special role of the medial temporal lobes and other parts of DMN in learning and memory, with high demands for life-long plasticity required for these cognitive functions (Aimone et al, 2010, Deng et al, 2010).…”

The Exceptional Vulnerability of Humans to Alzheimer’s Disease

“…Determining whether tau exon 8 is expressed in different primate species, for example, would help to affirm or refute its hypothesized protective role [87], as would studies of exon 8-bearing tau in cell cultures, organoids [102], and genetically modified animal models. A comparative evaluation of specific types of neurons especially vulnerable to tauopathy in AD [103] could also be informative; brain regions giving rise to long axonal connections have expanded in the evolution of hominids, and it has been proposed that enhanced neuroplasticity of these areas may render cells more susceptible to tangle formation, possibly due to increased remodeling of synaptic membranes, or the cytoskeleton [4]. An in depth analysis of regional vulnerability, tau variants and posttranslational modifications in humans and nonhuman primates is clearly needed.…”

Post-transcriptional regulatory elements and spatiotemporal specification of neocortical stem cells and projection neurons

“…In this way, the neocortex can be thought of as the evolutionary foundation for cognitive advances, including the uniquely human “theory of mind” and language. However, with these advances, human-specific ailments such as schizophrenia, autism spectrum disorders, Parkinson’s disease, Alzheimer’s disease, and Amyotrophic Lateral Sclerosis have also developed (Garey, 2010, Wegiel et al, 2010, Morgen et al, 2011, Ozdinler et al, 2011, Rapoport and Nelson, 2011, Yang et al, 2011). Therefore, understanding the molecular and cellular mechanisms underlying neocortical formation, maintenance, and dysfunction is critical not only for furthering basic neuroscience knowledge of brain development and architecture but also for better understanding neuropsychiatric disorders.…”