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.

Keywords: Alzheimer’s Disease; Amyloid; Neurodegeneration; Organ failure; Proteinopathy; Risk factors; Tau.

Fig. 1

The lifelong journey of a healthy brain into AD and brain organ failure. The factors that contribute to the development, and alter risk for, AD are depicted below a hypothetical lifespan of someone who gets symptomatic AD at 80 years of age. The blue coloring indicates the time and strength of those factors that are active or emerge variably during the lifespan. Pathology onset begins some 25–30 years before symptoms emerge and shows a characteristic sequence of changes beginning with Aβ deposition followed by cellular dysfunction, tau pathology and neurodegeneration. Age related co-morbidities can have increasing impact on disease course in late life. Brain and cognitive reserve can alter symptom emergence and progression without altering underlying pathology

Fig. 2

AD Genes and Loci associated with AD risk. AD genes are indicated in bold text whereas loci implicated by genome wide association studies (GWAS) are underlined. Y-axis indicates bidirectional risk, and the x-axis indicates the frequency of these mutations of variants. Note that several AD genes have both harmful and protective mutations or variants. For most loci implicated by GWAS, the genes and functional variants that are driving the association remain unknown. GWAS loci are derived from Kunkle et al. Nature Genetics 2019. 51(3):414–430 [32]

Fig. 3

Functional impact of genes linked to AD or risk for AD. Pivotal support for the ACH comes from genetic pathological, biomarker and experimental studies that link genes that cause EOFAD or alter risk for AD to Aβ aggregation and accumulation. Mutants and variants that increase risk alter Aβ in a manner that promotes deposition as amyloid. Conversely other variants appear to decrease the likelihood of Aβ aggregation and accumulation. AD genes, enriched in microglial cells, may modulate Aβ deposition, responses to aggregated Aβ or tau pathology, or both. Mutations in tau associated with FTD reinforce the notion that tau aggregation and accumulation is an important feature of AD

Fig. 4

Enigmatic aspects of the ACH. This schematic illustrates some of the gaps in our knowledge regarding certain aspects of the ACH. Uncertainty remains about how Aβ aggregate accumulation drives downstream changes. Similarly, there is uncertainty regarding how tau accumulation leads to neurodegeneration. It is likely that the mechanism that link Aβ and tau together and to neurodegeneration are complex. One concept that is not commonly discussed is that the presence of either amyloid or tau pathology and both pathological and compensatory response may make the brain more vulnerable to additional insults. Such vulnerability might explain why clinical progression is so variable, and how co-morbidities may impact the clinical phase of disease