Dementias of the Alzheimer Type: Views Through the Lens of Evolutionary Biology Suggest Amyloid-Driven Brain Aging Is Balanced Against Host Defense

Abstract

We propose that Alzheimer’s disease (AD) and related neurodegenerative conditions can be best understood within an evolutionary framework as a trade-off with host defense, with the apoE allele system as an example. This chapter reviews this hypothesis and evaluates the relevant evidence. We focus the “Darwinian lens” on two major features of human aging: First, inflammatory changes with mild amyloid deposits and modest synapse loss that arise in shorter lived species during aging; second, we contrast these mild changes with the more aggressive neurodegenerative changes of AD found only in humans. To some extent, mild AD-like changes arise at later ages in primate species with widely differing life spans from lines that diverged 50 or more million years ago. We discuss the changing role of host defense in modern human populations that are under greatly reduced natural selection from infectious agents.

Glossary

Amyloids and Aβ peptides

Amyloid refers to a large group of proteins or peptides that are rich in β-helical sheets of amino acids and are prone to form insoluble aggregates within tissues. The aggregates that are among the classical diagnostic features of Alzheimer’s disease are known as Amyloid beta, or Aβ. There are several varieties, all of which are derived from a much larger precursor protein (APP, or the β-APP). The two Aβ peptides that have been most investigated are Aβ 1–40 (with forty amino acids) and Aβ 1–42 (forty-two amino acids). The name amyloid is derived from a chemical test for starch (an iodine test) used by the famous pathologist Rudolph Virchow in the mid-nineteenth century to determine the nature of waxy material he found in livers of some autopsied subjects. Virchow was prescient in using the suffix “–oid” (like starch), as this and all other types of amyloids turned out to be proteins. Amyloids, however, co-precipitate with hyaluronan sulfate proteoglycans, hence the positive iodine test!

Aging

Aging can be defined as a collection of gradual and insidious declines in multiple cellular physiological functions, which reduce responses to stress, increase the risk of chronic disease, and accelerate the probability of death during later adult ages

Amino acid residues

Proteins consist of strings of amino acids. When amino acids are linked, molecules of water are lost and the resulting amino acids are referred to as amino acid residues

APOE

This is the accepted abbreviation for a gene that codes for the apolipoprotein E protein. By convention, the abbreviations for genes are both capitalized and italicized; the related protein is also capitalized, but not italicized. Human populations have three different forms (alleles) of this gene, each differing slightly by amino acid sequence. The most common allele is E4, where E stands for epsilon. The least common allele, E2, is associated with lesser risk for Alzheimer’s disease. E4 is the major risk factor for late-onset Alzheimer’s disease

APP

Abbreviation for β-amyloid precursor protein (see Aβ peptides, above)

Astrocytes

The name of this major brain cell represents its typical star-like shapes. They provide neurons with lipids carried by apolipoprotein E

Entorhinal cortex

This is the part of the medial temporal cortex of the brain that connects the hippocampus to other areas of the cerebral cortex and is therefore an essential hub in the networks involved in learning and memory

Epigenetic drift

Epigenetics literally means “on top of” the genes. It involves chemical changes to the basic nucleotide base pairs of the DNA and of its associated proteins known as histones. In so doing, these chemical alterations change the expression of genes during cell differentiation and in certain pathological conditions. These chemical marks and their associate alterations in gene expression gradually change during aging, a process known as epigenetic drift

Epistatic gene interaction

Genes do not work in a vacuum. They are dependent upon interactions with other genes, variations at which can modulate the phenotype of the organism. For a fuller account of the origins and evolution of this concept, its terminology and its classifications, consult [94]

Lipid-binding terminus

Proteins and fatty substances (lipids) can be bound together in the same molecule. Characteristic sequences of amino acids have evolved to provide specificity for such interactions. These sequences can occur at different regions of the protein. For the case of apolipoprotein E (APOE), this binding occurs near the carboxyl end (C-terminus)

Neurite

A neurite is a projection from a neuron. These can be axons, the long neurites along which impulses are conducted from the cell body to other cells, or they can be dendrites, the short, branched extensions that transmit signals across the synapse

PiB

Abbreviation for Pittsburgh (Pi) Compound B, a radioactive compound related to a dye that has long been used to stain deposits of amyloid for the microscopic detection of amyloids. When used with positron emission tomography (PET scans), PiB detects deposits of amyloid in the brains of living patients and thus can help with the diagnosis of Alzheimer’s disease in very early stages. Thus, PiB can also document the effects of therapies designed to reverse or slow the rate of progression of the disease

Plasticity

In evolutionary biology, plasticity usually refers to the process of one genotype leading to various phenotypes depending on the environment. A broader use has developed among biogerontologists to represent the different timing of aging processes within phylogenetic clades, as shown in Fig. 19.1

Public allele system

This term represents a polymorphic gene (one with several variants, each of which has frequencies greater that ~1 %) that is widely found in different human populations. Its effects upon a given phenotype are generally predictable, as in the classic example of sickle-cell hemoglobin (see trade-offs)

Selective advantage

This term applies to alleles or groups of alleles or to certain phenotypes whose gene actions lead to a greater probability of survival in a given environment

TNFα

This gene encodes a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF) superfamily

Trade-offs

This term is used here to refer to gene actions that can exhibit differential effects on phenotypes depending upon the environment or the stage of the life cycle. A classic example is sickle-cell hemoglobin, in which heterozygotes have resistance to malaria, whereas homozygotes suffer painful tissue damage