Toward refining Alzheimer's disease into overlapping subgroups

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive anterograde amnesia, cerebral atrophy, and eventual death. Current treatment has limited efficacy and cannot decelerate the disease progression. Clinical trials targeting the removal of the neuropathological hallmarks of AD, including accumulation of amyloid plaques or neurofibrillary tangles, have failed to modify disease progression. Without new or innovative hypotheses, AD is poised to become a public health crisis within this decade. We present an alternative hypothesis-that AD is the result of multiple interrelated causalities. The intention of this manuscript is to initiate a discussion regarding these multiple causalities and their overlapping similarities. The idea of creating subgroups allows for better identification of biomarkers across a narrower patient population for improved pharmacotherapeutic opportunities. The interrelatedness of many of these proposed subgroups indicates the complexity of this disorder. However, it also supports that no one single factor may initiate the cascade of events.

Keywords: cellular senescence; hyperexcitable neuronal networks; metabolic syndrome; mitochondrial cascade hypothesis; sleep disturbances; traumatic brain injury; two‐hit vascular hypothesis.

FIGURE 1

Overlapping genetic and environmental subgroups. Genetic screening for determination of early and late‐onset AD subgroups can identify individuals at risk for developing dementia before symptoms appear. Individuals who screen positive can implement life‐style risk‐reduction strategies that are known to have long‐term pro‐cognitive benefits. In addition, annual positron emission tomography (PET) monitoring for accumulation of proteinopathies may provide therapeutic opportunities for health‐span and lifespan extensions in these at‐risk individuals. Without readily identifiable biomarkers, environmental factors are more difficult to screen, thereby delaying a diagnoses until overt signs of dementia are present. The environmental subgroups discussed are arranged adjacent to potentially overlapping pathologies. This highlights environmental subgroups with possible comorbidities that may require multiple therapeutic strategies for individualized patient care. Furthermore, genetic subgroup pathologies may exacerbate particular environmental subgroups as indicated by their inset symbol. AD, Alzheimer's disease; APOE, apolipoprotein E gene; APP, amyloid precursor protein; BBB, blood–brain barrier; MetS, metabolic syndrome; PS1/2, presenilin 1 or 2; TBI, traumatic brain injury; TOMM40, translocase of outer mitochondrial membrane 40 gene; TREM2, triggering receptors expressed on myeloid cells 2 gene