The Amyloid-β Pathway in Alzheimer's Disease

Abstract

Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at the center of Alzheimer's disease (AD) pathophysiology. While the detailed molecular mechanisms of the pathway and the spatial-temporal dynamics leading to synaptic failure, neurodegeneration, and clinical onset are still under intense investigation, the established biochemical alterations of the Aβ cycle remain the core biological hallmark of AD and are promising targets for the development of disease-modifying therapies. Here, we systematically review and update the vast state-of-the-art literature of Aβ science with evidence from basic research studies to human genetic and multi-modal biomarker investigations, which supports a crucial role of Aβ pathway dyshomeostasis in AD pathophysiological dynamics. We discuss the evidence highlighting a differentiated interaction of distinct Aβ species with other AD-related biological mechanisms, such as tau-mediated, neuroimmune and inflammatory changes, as well as a neurochemical imbalance. Through the lens of the latest development of multimodal in vivo biomarkers of AD, this cross-disciplinary review examines the compelling hypothesis- and data-driven rationale for Aβ-targeting therapeutic strategies in development for the early treatment of AD.

Fig. 1. Traditional neuropathological phases of amyloid-β deposition in Alzheimer’s disease dementia.

Red areas in Phase 1 depicts the cortical regions with the initial accumulation of amyloid-β during the early pre-clinical stage. Continued deposition in the same areas are shown in darker colors in the subsequent stages, with the new areas showing amyloid-β in red in each phase. Neocortical regions with the early accumulation of amyloid-β in phase 1 include association cortices. Additional accumulation is seen in allocortical regions and midbrain (phases 2 and 3), with the cerebellum and brain stem having amyloid-β accumulation in late phase clinical stages. The change to darker shading indicates the continuous accumulation of Aβ. Adapted with permission from ref. [13].

Fig. 2. Hypothetical biomarker evidence-driven model of AD pathophysiology.

Hypothetical model of dynamic biomarkers of the AD is expanded to explicate the preclinical phase. Aβ is identified by cerebrospinal fluid Aβ42 assay or PET amyloid imaging. Synaptic dysfunction evidenced by [¹⁸F]-fluorodeoxyglucose positron emission tomography (FDG-PET) or functional magnetic resonance imaging (fMRI), with a dashed yellow line to indicate that synaptic dysfunction may be detectable in carriers of the ε4 allele of the apolipoprotein E gene before detectable Aβ deposition. Neuronal injury is evidenced by cerebrospinal fluid tau or phospho-tau, and brain structure is documented by structural magnetic resonance imaging. Biomarkers change from normal to maximally abnormal (y-axis) as a function of disease stage (x-axis). The temporal trajectory of two key indicators used to stage the disease clinically, cognitive and behavioral measures, and clinical function are also illustrated. Neurofilament light chain (NfL) and neurogranin are newer and potentially more accurate markers of neuronal injury. Figure adapted with permission from ref. [391].

Fig. 3. Amyloidogenic vs non-amyloidogenic pathway.

Amyloid Precursor Protein (APP) is a single transmembrane protein. For the non-amyloidogenic pathway (left), APP is cleaved by A Disintegrin And Metalloprotease (ADAM) family proteases to yield the membrane-tethered C83 fragment and extracellularly released soluble APP alpha (sAPPα). In the amyloidogenic pathway (right), APP is first cleaved by β-secretase (β-APP-cleaving enzyme-1 or BACE1). CTF-β fragment is subsequently cleaved by γ-secretase composed of Presenilin 1 or 2, Nicastrin, PEN2 and APH-1. This proteolytic processing releases amyloid-β into the extracellular space. APP intracellular domain (AICD) from the initial β-secretase cleavage is released into intracellular space. Adapted with permission from ref. [392].

Fig. 4. Amyloid-β aggregation species and evidence of reversible states: the amyloid-β cycle.

Aggregation species of Aβ can exist as monomers, dimers, oligomers, protofibril, fibril and amyloid plaques. These species exist in steady state where one form can convert to another in a bidirectional manner. The species are characterized by aggregate size, conformation state and solubility, with fibril and amyloid plaque being insoluble. Adapted with permission from ref. [108].

Fig. 5. The evidence-driven experimental model of Aβ-tau synergy.

Accumulation of neurofibrillary tangles made up of tau (red) and amyloid plaques composed of amyloid-β (blue) coincides in the neocortical areas in the brain of Alzheimer’s disease subjects supporting amyloid-β dependent tau propagation across neocortical regions. Inter-neuronal spreading of tau (bottom) is enhanced in AD brains with both plaques and tangle build-up. Adapted with permission from ref. [221].

Fig. 6. Techniques of in vivo Alzheimer’s disease amyloid-β pathway staging, along the clinical continuum, based on molecular imaging and innovative algorithms.

Neocortical distribution of [¹⁸F]-florbetapir is shown in a composite representation according to Aβ stages. Early composite (positive in stage 1 in green; left), intermediate composite (positive in stage 2 in blue; middle) and late composite (positive in stage 3 in red; right) can allow global and regional assessment of amyloid plaque deposition. Adapted with permission from: ref. [393].