The causes and consequences of Alzheimer's disease: phenome-wide evidence from Mendelian randomization.

Alzheimer's disease (AD) has no proven causal and modifiable risk factors, or effective interventions. We report a phenome-wide association study (PheWAS) of genetic liability for AD in 334,968 participants of the UK Biobank study, stratified by age. We also examined the effects of AD genetic liability on previously implicated risk factors. We replicated these analyses in the HUNT study. PheWAS hits and previously implicated risk factors were followed up in a Mendelian randomization (MR) framework to identify the causal effect of each risk factor on AD risk. A higher genetic liability for AD was associated with medical history and cognitive, lifestyle, physical and blood-based measures as early as 39 years of age. These effects were largely driven by the APOE gene. The follow-up MR analyses were primarily null, implying that most of these associations are likely to be a consequence of prodromal disease or selection bias, rather than the risk factor causing the disease.

Focal axonal swellings and associated ultrastructural changes attenuate conduction velocity in central nervous system axons: a computer modeling study.

The constancy of action potential conduction in the central nervous system (CNS) relies on uniform axon diameter coupled with fidelity of the overlying myelin providing high-resistance, low capacitance insulation. Whereas the effects of demyelination on conduction have been extensively studied/modeled, equivalent studies on the repercussions for conduction of axon swelling, a common early pathological feature of (potentially reversible) axonal injury, are lacking. The recent description of experimentally acquired morphological and electrical properties of small CNS axons and oligodendrocytes prompted us to incorporate these data into a computer model, with the aim of simulating the effects of focal axon swelling on action potential conduction. A single swelling on an otherwise intact axon, as occurs in optic nerve axons of Cnp1 null mice caused a small decrease in conduction velocity. The presence of single swellings on multiple contiguous internodal regions (INR), as likely occurs in advanced disease, caused qualitatively similar results, except the dimensions of the swellings required to produce equivalent attenuation of conduction were significantly decreased. Our simulations of the consequences of metabolic insult to axons, namely, the appearance of multiple swollen regions, accompanied by perturbation of overlying myelin and increased axolemmal permeability, contained within a single INR, revealed that conduction block occurred when the dimensions of the simulated swellings were within the limits of those measured experimentally, suggesting that multiple swellings on a single axon could contribute to axonal dysfunction, and that increased axolemmal permeability is the decisive factor that promotes conduction block.