The present understanding of Alzheimer’s disease is illustrative of a broader issue with aging in general, in that while there is considerable evidence to pin down specific pathological mechanisms in cells and tissues, it is hard to prove exactly how these mechanisms interact. What is cause, what is consequence. What is important, what is merely a side-effect of other, important processes. At present there is some upheaval in the Alzheimer’s research community based on the failure of amyloid-β clearance to produce meaningful benefits in patients. This may or may not disrupt the present thinking on the condition, that early amyloid-β aggregation sets the stage for later neuroinflammation and tau aggregation. Amyloid-β may be a good early target, or it may turn out to be a side-effect of rising levels of chronic inflammation or persistent infection, and thus not a useful target at all.
Alzheimer’s disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There is currently no effective treatment for AD, which may be attributed in part to lack of a clear underlying mechanism. Studies within the last few decades provide growing evidence for a central role of amyloid β (Aβ) and tau, as well as glial contributions to various molecular and cellular pathways in AD pathogenesis.
AD pathogenesis involves pathogenic contributions from multiple components and alterations in behavior of various cell types within the central nervous system. Aβ is generated in neurons and then released to the extracellular space, where it can be degraded or cleared by microglia and astrocytes. Increased Aβ production or impaired Aβ degradation/clearance leads to Aβ accumulation. Tau is mainly expressed in neurons, and highly modulated through various post-translational modifications. Abnormal PTMs, liquid-liquid phase separation, and pathogenic tau seeds can cause tau aggregation and accumulation through different mechanisms. Tau pathology may be propagated during disease progression, and glial cells play an important role in the process of seeding and dispersion. Forms of Aβ aggregates, together with tau accumulation, can cause neuronal dysfunction and glial activation and the subsequent neuroinflammation; these events are regulated by various receptors expressed in neurons, microglia and astrocytes.
Genetic factors can cause or affect AD pathogenesis. Early-onset AD is mainly due to mutations in APP and PS1/PS2, which are involved in Aβ generation, while late-onset AD is largely associated with a group of genes enriched in glial cells, such as APOE and TREM2, which are important for Aβ clearance and glial function. Therefore, differential mechanisms may be involved in different forms of AD. In addition, other factors such as aging, metal ion, virus, and microbiota may also contribute to AD pathogenesis via various mechanisms. Mechanisms for late-onset AD are complex and subtypes of late-onset AD may exist. However, most of the available AD animal models carrying early-onset AD-associated mutations can only mimic early-onset AD. Development of animal models to recapitulate pathogenesis of late-onset AD may be beneficial to compare early and late stage forms of AD. This may uncover mechanisms specific to late-onset AD which represents over 90% of AD cases, and potentially provide new insights to therapeutic targets for treatment.