Alzheimer’s disease – the journey of a healthy brain into organ failure

Abstract

As the most common dementia, Alzheimer’s disease (AD) exacts an immense personal, societal, and economic toll. AD was first described at the neuropathological level in the early 1900s. Today, we have mechanistic insight into select aspects of AD pathogenesis and have the ability to clinically detect and diagnose AD and underlying AD pathologies in living patients. These insights demonstrate that AD is a complex, insidious, degenerative proteinopathy triggered by Aβ aggregate formation. Over time Aβ pathology drives neurofibrillary tangle (NFT) pathology, dysfunction of virtually all cell types in the brain, and ultimately, overt neurodegeneration. Yet, large gaps in our knowledge of AD pathophysiology and huge unmet medical need remain. Though we largely conceptualize AD as a disease of aging, heritable and non-heritable factors impact brain physiology, either continuously or at specific time points during the lifespan, and thereby alter risk for devolvement of AD. Herein, I describe the lifelong journey of a healthy brain from birth to death with AD, while acknowledging the many knowledge gaps that remain regarding our understanding of AD pathogenesis. To ensure the current lexicon surrounding AD changes from inevitable, incurable, and poorly manageable to a lexicon of preventable, curable, and manageable we must address these knowledge gaps, develop therapies that have a bigger impact on clinical symptoms or progression of disease and use these interventions at the appropriate stage of disease.

3D bioengineered neural tissue generated from patient-derived iPSCs develops time-dependent phenotypes and transcriptional features of Alzheimer’s disease

“…Since iPSC reprogramming rejuvenates cells and erases donor aging signatures, concerns were raised about the ability to model age-related diseases with iPSC-derived neuronal cultures [59]. It is well-established that AD develops over decades [60]. Thus, genetic factors may produce endophenotypes early in life; therefore, they can be captured in iPSC-derived neural cultures.…”

“…It is well-established that AD develops over decades [60]. Thus, genetic factors may produce endophenotypes early in life; therefore, they can be captured in iPSC-derived neural cultures.…”

Therapeutic roles of plants for 15 hypothesised causal bases of Alzheimer’s disease

“…This pathology has come to be associated with aberrant metabolism of the amyloid precursor protein (APP) [30]. These findings have led to the amyloid cascade hypothesis, in which an imbalance between production and clearance of Aβ peptides initiates the complex pathological cascade of AD [31,32]. A variant of the cascade view is the amyloid-β oligomer (AβO) hypothesis, which postulates that the brain damage of AD is instigated by toxic soluble amyloid oligomers Tyler and Tyler Natural Products and Bioprospecting (2022) 12:34 [33].…”

Heart failure and late-onset Alzheimer’s disease: A Mendelian randomization study

“…In general, heart failure is commonly treated with HF-related medications and many of them have been reported to have protective effects on cognitive decline and AD ( Barthold et al, 2020 ; Poly et al, 2020 ; Nguyen et al, 2022 ; Olmastroni et al, 2022 ). Additionally, it is widely reported that AD pathology might begin 20 years before the clinical diagnosis of AD (e.g., Figure 1; Golde, 2022 ). Thus, patients of HF may have less chance to develop late-onset AD because HF is a leading cause of short survival in many western populations.…”