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Although rodents are the primary animal model used for biomedical research, neurological and evolutionary differences from humans have contributed to a high failure rate of Alzheimer’s disease clinical trials. Nonhuman primates are a viable model of aging and neurodegeneration and can help address this major concern. Aging in primates is associated with gene expression changes, volumetric atrophy, cerebrovascular dysfunction, neuroinflammation, and mild cognitive decline. Moreover, primates exhibit the pathologic hallmarks of Alzheimer’s disease, amyloid-beta and tau lesions, in association with glial activation. In contrast, primates do not experience the extensive neuronal loss and dementia symptoms seen in Alzheimer’s disease patients. Understanding similarities and differences between humans and primates can contribute to a greater understanding of normal aging and neurodegenerative processes as well as improve the efficacy of models and therapeutics for Alzheimer’s disease.

Comparative neuroanatomical studies have contributed substantial information about the brains of large mammals and expanded our understanding of cortical organization among species. In this chapter, we review some features of the largest extant mammals and include, where evidence is available, details about the organization and characteristics of the cerebral cortex, neuron morphology, subcortical structures, and cerebellum. We conclude with a brief discussion of putative cognitive and behavioral specializations associated with these species.

Human brain evolution has involved reorganization of neural structure sizes, the distribution of cell types, axonal innervation patterns, and the expression of molecules and proteins. Microstructural specializations are evident with increased neuropil in the prefrontal cortex, modifications of neuromodulatory innervation of the neocortex and basal ganglia, and greater proportions of energetically costly long-range corticocortical projecting neurons. Some microstructural asymmetries in cortical regions associated with language and handedness might also be evolutionarily unique in the human brain.

Von Economo neurons (VENs) are projection neurons located in layer V of the anterior cingulate and frontoinsular cortex that have recently attracted the interest of the neuroscience community. Several studies have pointed to their complex evolutionary history and to their involvement in many neurological and psychiatric illnesses. Current evidence suggests that VENs represent a specialized neuronal type with a characteristic morphology that is present in several species across mammalian orders and most likely represent a population of pyramidal neurons present in ancestral mammals in the context of specific adaptive pressures. Within primates, VENs are observed only in the anthropoid lineage and are particularly vulnerable in human neuropsychiatric conditions characterized by deficits in social skills and emotional function. Moreover, recent evidence on the neurochemical phenotype, morphological features, and laminar and regional distribution of VENs suggests that this intriguing neuronal population could be critically involved in autonomic regulation.

The neuronal composition of the insula in primates displays a gradient, transitioning from granular neocortex in the posterior-dorsal insula to agranular neocortex in the anterior-ventral insula with an intermediate zone of dysgranularity. Additionally, apes and humans exhibit a distinctive subdomain in the agranular insula, the frontoinsular cortex (FI), defined by the presence of clusters of von Economo neurons (VENs). Studies in humans indicate that the ventral anterior insula, including agranular insular cortex and FI, is involved in social awareness, and that the posterodorsal insula, including granular and dysgranular cortices, produces an internal representation of the body's homeostatic state. We examined the volumes of these cytoarchitectural areas of insular cortex in 30 primate species, including the volume of FI in apes and humans. Results indicate that the whole insula scales hyperallometrically (exponent = 1.13) relative to total brain mass, and the agranular insula (including FI) scales against total brain mass with even greater positive allometry (exponent = 1.23), providing a potential neural basis for enhancement of social cognition in association with increased brain size. The relative volumes of the subdivisions of the insular cortex, after controlling for total brain volume, are not correlated with species typical social group size. Although its size is predicted by primate-wide allometric scaling patterns, we found that the absolute volume of the left and right agranular insula and left FI are among the most differentially expanded of the human cerebral cortex compared to our closest living relative, the chimpanzee.

Human evolution was marked by an extraordinary increase in total brain size relative to body size. While it is certain that increased encephalization is an important factor contributing to the origin of our species-specific cognitive abilities, it is difficult to disentangle which aspects of human neural structure and function are correlated by-products of brain size expansion from those that are specifically related to particular psychological specializations, such as language and enhanced "mentalizing" abilities. In this chapter, we review evidence from allometric scaling studies demonstrating that much of human neocortical organization can be understood as a product of brain enlargement. Defining extra-allometric specializations in humans is often hampered by a severe lack of comparative data from the same neuroanatomical variables across a broad range of primates. When possible, we highlight evidence for features of human neocortical architecture and function that cannot be easily explained as correlates of brain size and, hence, might be more directly associated with the evolution of uniquely human cognitive capacities.