Why Are Humans Vulnerable to Alzheimer’s Disease?

Abstract

Alzheimer’s disease (AD) is a serious public health issue, and a treatment for the disease has been elusive. Evolutionary approaches to medicine may contribute to understanding why humans are vulnerable to AD and how to best approach research into clinical interventions. Since AD generally manifests late in life, it is often thought to be invisible to natural selection; however, an examination into APOE, the only unequivocal risk gene for AD, reveals that AD may, in fact, be subject to selection. Given this, antagonistic pleiotropy and environmental mismatch are explored as possibilities for our vulnerability to AD. In addition, the amyloid-β (Aβ) plaques and paired helical filament tau (PHFtau) neurofibrillary tangles that characterize AD are considered from the perspective of evolution. These disease hallmarks are generally thought to promote neurodegeneration in AD, but may in fact be harmless by-products of a pathological process such as oxidative stress, or even beneficial adaptations to protect the brain from actual harmful processes. The spread of misfolded Aβ and synaptic propagation of PHFtau is considered, as are comparative perspectives on AD-like patterns in nonhuman species. The implications of evolutionary thinking for clinical practice and research are evaluated, especially with regard to the caution that must be taken when directly targeting tau and amyloid, as many drug trials have recently attempted.

Glossary

APOE

A gene involved in the expression of a protein called apolipoprotein-E. This protein is implicated in transporting cholesterol through the bloodstream. There are three variants of the protein caused by different forms of the gene, known as E2, E3, and E4 or sometimes ε2, ε3, and ε4. The E3 allele is the most common. The E4 allele is associated with a higher risk of cardiovascular disease and AD than E3, whereas the E2 allele is associated with a reduced risk of AD relative to E3 [8, 82].

Amyloid-β

(pronounced “amyloid-beta”; a.k.a. beta-amyloid, Aβ) One of the proteins involved in the pathology of AD. It can take one of several forms including oligomers, which are small chainlike molecules, and plaques, which are large insoluble aggregates of Aβ that accumulate in the brains of Alzheimer’s patients. Its normal function is not well-understood, although it may be involved in immune response, cellular metabolism, or a number of other processes. Aβ is formed when a protein called amyloid precursor protein (APP) is cut by two other proteins, known as β-secretase (beta-secretase) and γ-secretase (gamma-secretase). Aβ in plaque or oligomeric form has traditionally been thought to be one of the causes of the neurodegeneration seen in Alzheimer’s disease.

Tau protein

The other protein whose abnormal processing forms the signature neurofibrillary tangle of Alzheimer’s disease. Normally, tau functions to stabilize microtubules, which support the cytoskeleton of neurons in the central nervous system. As part of its normal function, tau changes its shape via phosphorylation, a process wherein phosphate groups bind to tau and allow it to change configurations. In Alzheimer’s disease, tau becomes saturated with phosphates, a process called hyperphosphorylation, which promotes its misfolding into filamentous structures called paired helical filaments. These paired helical filaments, in turn, aggregate into neurofibrillary (i.e., “nerve fiber”) tangles, which, along with plaques, are a marker of Alzheimer’s disease. Tau tangles have been thought to play a role in neuron death.

Oxidative stress

A process caused by by-products of metabolism in which so-called reactive oxygen species or free radicals overwhelm the body’s ability to neutralize them, potentially causing damage to DNA and proteins. Reactive oxygen species are molecules or ions of oxygen that are missing one electron, making them highly reactive. Oxidative stress may play key roles in a number of neurodegenerative diseases, including Alzheimer’s disease.