Evolution of Human Susceptibility to Alzheimer's Disease: A Review of Hypotheses and Comparative Evidence

Evolutionary Anthropology Issues News and Reviews · 2025-01-13 · 2 citations

Primates rely on memory to navigate both physical and social environments and in humans, loss of memory function leads to devastating consequences. Alzheimer's disease (AD) is a neurodegenerative disease which begins by impacting memory functioning and is ultimately fatal. AD is common across human populations and its prevalence is predicted to rise with increases in the aging population. Despite this, the full AD phenotype has not been observed in any other nonhuman primate species. While a significant amount of research has been devoted to understanding the immediate mechanisms involved in AD pathogenesis in humans, less research has focused on why humans are particularly vulnerable to neurodegenerative diseases like AD. Here we explore hypotheses on the evolution of distinct human susceptibility to AD and place these in the context of findings from comparative neuroanatomical and molecular studies and discuss recent evidence for evolutionary changes protective against AD in the primate lineage.

Evolutionary specializations of the human limbic system

Evolution of Nervous Systems · 2025-09-25

Inhibitory systems in brain evolution: pathways of vulnerability in neurodevelopmental disorders

Brain Behavior and Evolution · 2024-08-13 · 4 citations

BACKGROUND: The evolution of the primate brain has been characterized by the reorganization of key structures and circuits underlying derived specializations in sensory systems, as well as social behavior and cognition. Among these, expansion and elaboration of the prefrontal cortex has been accompanied by alterations to the connectivity and organization of subcortical structures, including the striatum and amygdala, underlying advanced aspects of executive function, inhibitory behavioral control, and socioemotional cognition seen in our lineages. At the cellular level, the primate brain has further seen an increase in the diversity and number of inhibitory GABAergic interneurons. A prevailing hypothesis holds that disruptions in the balance of excitatory to inhibitory activity in the brain underlies the pathophysiology of many neurodevelopmental and psychiatric disorders. SUMMARY: This review highlights the evolution of inhibitory brain systems and circuits and suggests that recent evolutionary modifications to GABAergic circuitry may provide the substrate for vulnerability to aberrant neurodevelopment. We further discuss how modifications to primate and human social organization and life history may shape brain development in ways that contribute to neurodivergence and the origins of neurodevelopmental disorders. KEY MESSAGES: Many brain systems have seen functional reorganization in the mammalian, primate, and human brain. Alterations to inhibitory circuitry in frontostriatal and frontoamygdalar systems support changes in social behavior and cognition. Increased complexity of inhibitory systems may underlie vulnerabilities to neurodevelopmental and psychiatric disorders, including autism and schizophrenia. Changes observed in Williams syndrome may further elucidate the mechanisms by which alterations in inhibitory systems lead to changes in behavior and cognition. Developmental processes, including altered neuroimmune function and age-related vulnerability of inhibitory cells and synapses, may lead to worsening symptomatology in neurodevelopmental and psychiatric disorders. BACKGROUND: The evolution of the primate brain has been characterized by the reorganization of key structures and circuits underlying derived specializations in sensory systems, as well as social behavior and cognition. Among these, expansion and elaboration of the prefrontal cortex has been accompanied by alterations to the connectivity and organization of subcortical structures, including the striatum and amygdala, underlying advanced aspects of executive function, inhibitory behavioral control, and socioemotional cognition seen in our lineages. At the cellular level, the primate brain has further seen an increase in the diversity and number of inhibitory GABAergic interneurons. A prevailing hypothesis holds that disruptions in the balance of excitatory to inhibitory activity in the brain underlies the pathophysiology of many neurodevelopmental and psychiatric disorders. SUMMARY: This review highlights the evolution of inhibitory brain systems and circuits and suggests that recent evolutionary modifications to GABAergic circuitry may provide the substrate for vulnerability to aberrant neurodevelopment. We further discuss how modifications to primate and human social organization and life history may shape brain development in ways that contribute to neurodivergence and the origins of neurodevelopmental disorders. KEY MESSAGES: Many brain systems have seen functional reorganization in the mammalian, primate, and human brain. Alterations to inhibitory circuitry in frontostriatal and frontoamygdalar systems support changes in social behavior and cognition. Increased complexity of inhibitory systems may underlie vulnerabilities to neurodevelopmental and psychiatric disorders, including autism and schizophrenia. Changes observed in Williams syndrome may further elucidate the mechanisms by which alterations in inhibitory systems lead to changes in behavior and cognition. Developmental processes, including altered neuroimmune function and age-related vulnerability of inhibitory cells and synapses, may lead to worsening symptomatology in neurodevelopmental and psychiatric disorders.

Williams Syndrome and Autism

2024-07-01

Abstract Certain human disorders, such as Williams syndrome (WS) and autism spectrum disorders (ASD), are known to affect social behaviors. WS is a rare neurodevelopmental disorder caused by deletion of approximately 25 genes on chromosome band 7q11.23, and WS individuals are typically described as hypersocial. ASD is a much more common group of heterogeneous disorders generally characterized by hyposociality. In WS total brain volume is decreased, while in ASD total brain volume is increased, in early development. Both disorders are characterized by microstructural changes throughout the brain, and this chapter focuses on changes in the prefrontal cortex and amygdala, regions which have been subject to recent evolutionary change in humans. This chapter reviews the neuroanatomical profiles of these two disorders in an evolutionary context before concluding with a brief discussion of how animal and stem cell models can be used to explore the cellular and molecular mechanisms underlying their neuroanatomical profiles.

Comment on “Human TKTL1 implies greater neurogenesis in frontal neocortex of modern humans than Neanderthals”

Science · 2023-03-10 · 17 citations

Pinson et al . ( 1 ) concluded that the modern human TKTL1 gene is responsible for an increased number of cortical neurons. We show that the “putative Neanderthal variant” of TKTL1 is present in modern human backgrounds. We dispute their argument that this genetic variant is responsible for brain differences in modern humans as opposed to Neanderthals.

Infant Brain Development and Plasticity from an Evolutionary Perspective

Evolutionary psychology · 2022 · 10 citations

• Neuroscience
• Psychology
• Evolutionary biology

8. Before or After the Split? Hominid Neural Specializations

Berghahn Books · 2022-10-01

Brain aging, Alzheimer's disease, and the role of stem cells in primate comparative studies

The Journal of Comparative Neurology · 2022-08-05 · 5 citations

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is ultimately fatal. Currently, millions of Americans are living with AD, and this number is predicted to grow with increases in the aging population. Interestingly, despite the prevalence of AD in human populations, the full AD phenotype has not been observed in any nonhuman primate (NHP) species, and it has been suggested that NHPs are immune to neurodegenerative diseases such as AD. Here, we review the typical age-related changes and pathologies in humans along with the neuropathologic changes associated with AD, and we place this information in the context of the comparative neuropathology of NHPs. We further propose the use of induced pluripotent stem cell technology as a way of addressing initial molecular processes and changes that occur in neurons and glia (in both humans and NHPs) when exposed to AD-inducing pathology prior to cell death.

Reintroduction of the archaic variant of <i>NOVA1</i> in cortical organoids alters neurodevelopment

Science · 2021 · 142 citations

• Biology
• Genetics
• Computational biology

, which is exclusive to modern humans since divergence from Neanderthals, may have had functional consequences for our species' evolution.

Decreased density of cholinergic interneurons in striatal territories in Williams syndrome

Brain Structure and Function · 2020-03-18 · 6 citations