Alzheimer Disease Clinical Trials Targeting Amyloid: Lessons Learned From Success in Mice and Failure in Humans.

BACKGROUND: The goal of slowing or halting the development of Alzheimer disease (AD) has resulted in the huge allocation of resources by academic institutions and pharmaceutical companies to the development of new treatments. The etiology of AD is elusive, but the aggregation of amyloid-ß and tau peptide and oxidative processes are considered critical pathologic mechanisms. The failure of drugs with multiple mechanisms to meet efficacy outcomes has caused several companies to decide not to pursue further AD studies and has left the field essentially where it has been for the past 15 years. Efforts are underway to develop biomarkers for detection and monitoring of AD using genetic, imaging, and biochemical technology, but this is of minimal use if no intervention can be offered. REVIEW SUMMARY: In this review, we consider the natural progression of AD and how it continues despite present attempts to modify the amyloid-related machinery to alter the disease trajectory. We describe the mechanisms and approaches to AD treatment targeting amyloid, including both passive and active immunotherapy as well as inhibitors of enzymes in the amyloidogenic pathway. CONCLUSION: Lessons learned from clinical trials of amyloid reduction strategies may prove crucial for the leap forward toward novel therapeutic targets to treat AD.

APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer's disease: a systematic review.

Possession of the ε4 allele of apolipoprotein E (APOE) is the primary genetic risk factor for the sporadic form of Alzheimer's disease (AD). While researchers have extensively characterized the impact that APOE ε4 (APOE4) has on the susceptibility of AD, far fewer studies have investigated the phenotypic differences of patients with AD who are APOE4 carriers vs. those who are non-carriers. In order to understand these differences, we performed a qualitative systematic literature review of the reported cognitive and pathological differences between APOE4-positive (APOE4+) vs. APOE4-negative (APOE4-) AD patients. The studies performed on this topic to date suggest that APOE4 is not only an important mediator of AD susceptibility, but that it likely confers specific phenotypic heterogeneity in AD presentation, as well. Specifically, APOE4+ AD patients appear to possess more tau accumulation and brain atrophy in the medial temporal lobe, resulting in greater memory impairment, compared to APOE4- AD patients. On the other hand, APOE4- AD patients appear to possess more tau accumulation and brain atrophy in the frontal and parietal lobes, resulting in greater impairment in executive function, visuospatial abilities, and language, compared to APOE4+ AD patients. Although more work is necessary to validate and interrogate these findings, these initial observations of pathological and cognitive heterogeneity between APOE4+ vs. APOE4- AD patients suggest that there is a fundamental divergence in AD manifestation related to APOE genotype, which may have important implications in regard to the therapeutic treatment of these two patient populations.

APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice.

The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer's disease (AD). However, the reason for the association between APOE4 and AD remains unclear. While much of the research has focused on the ability of the apoE4 protein to increase the aggregation and decrease the clearance of Aß, there is also an abundance of data showing that APOE4 negatively impacts many additional processes in the brain, including bioenergetics. In order to gain a more comprehensive understanding of APOE4's role in AD pathogenesis, we performed a transcriptomics analysis of APOE4 vs. APOE3 expression in the entorhinal cortex (EC) and primary visual cortex (PVC) of aged APOE mice. This study revealed EC-specific upregulation of genes related to oxidative phosphorylation (OxPhos). Follow-up analysis utilizing the Seahorse platform showed decreased mitochondrial respiration with age in the hippocampus and cortex of APOE4 vs. APOE3 mice, but not in the EC of these mice. Additional studies, as well as the original transcriptomics data, suggest that multiple bioenergetic pathways are differentially regulated by APOE4 expression in the EC of aged APOE mice in order to increase the mitochondrial coupling efficiency in this region. Given the importance of the EC as one of the first regions to be affected by AD pathology in humans, the observation that the EC is susceptible to differential bioenergetic regulation in response to a metabolic stressor such as APOE4 may point to a causative factor in the pathogenesis of AD.

Human Lupus Plasma Pro-Atherogenic Effects on Cultured Macrophages Are Not Mitigated by Statin Therapy: A Mechanistic LAPS Substudy.

Background and Objectives: Atherosclerotic cardiovascular disease (CVD) remains a major cause of morbidity and mortality in persons with systemic lupus erythematosus (SLE, lupus). Atherosclerosis, which involves interplay between cholesterol metabolism and cellular inflammatory pathways, is primarily treated with statins since statins have lipid-lowering and anti-inflammatory properties. The Lupus Atherosclerosis Prevention Study (LAPS) was designed to investigate the efficacy of statins against CVD in SLE patients. LAPS demonstrated that 2 years of atorvastatin administration did not reduce atherosclerosis progression in lupus patients. In this LAPs substudy, we use cultured macrophages to explore the atherogenic properties of plasma from LAPS subjects to explain the mechanistic rationale for the inability of statins to reduce CVD in lupus. Materials and Methods: THP-1 differentiated macrophages were treated for 18 h with 10% SLE patient plasma obtained pre- and post-atorvastatin therapy or placebo. Gene expression of the following cholesterol transport genes was measured by qRT-PCR. For efflux-ATP binding cassette transporter (ABC)A1 and ABCG1, 27-hydroxylase, peroxisome proliferator-activated receptor (PPAR)γ, and liver X receptor (LXR)α; and for influx-cluster of differentiation 36 (CD36) and scavenger receptor (ScR)A1. Results: Macrophages exposed to plasma from both statin-treated and placebo-treated groups showed a significant decrease in cholesterol efflux proteins ATP binding cassette (ABC) transporters A1 and ABCG1, an increase in 27-hydroxylase, an increase in the LDL receptor and a decrease in intracellular free cholesterol. No change in influx receptors ScRA1 and CD36, nor nuclear proteins LXRα and PPARγ was observed. Conclusions: Statins do not normalize pro-atherogenic changes induced by lupus and these changes continue to worsen over time. This study provides mechanistic insight into LAPS findings by demonstrating that statins are overall ineffective in altering the balance of cholesterol transport gene expression in human macrophages. Furthermore, our study suggests that statins as a CVD treatment may not be useful in attenuating lipid overload in the SLE environment.

Amyloid toxicity in Alzheimer's disease.

A major feature of Alzheimer's disease (AD) pathology is the plaque composed of aggregated amyloid-ß (Aß) peptide. Although these plaques may have harmful properties, there is much evidence to implicate soluble oligomeric Aß as the primary noxious form. Aß oligomers can be generated both extracellularly and intracellularly. Aß is toxic to neurons in a myriad of ways. It can cause pore formation resulting in the leakage of ions, disruption of cellular calcium balance, and loss of membrane potential. It can promote apoptosis, cause synaptic loss, and disrupt the cytoskeleton. Current treatments for AD are limited and palliative. Much research and effort is being devoted to reducing Aß production as an approach to slowing or preventing the development of AD. Aß formation results from the amyloidogenic cleavage of human amyloid precursor protein (APP). Reconfiguring this process to disfavor amyloid generation might be possible through the reduction of APP or inhibition of enzymes that convert the precursor protein to amyloid.