Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria

Abstract

During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.

Plasma Amyloid as Prescreener for the Earliest Alzheimer Pathological Changes

“…Amyloid pathology without cognitive impairment has been defined as the earliest Alzheimer pathological changes 3, 4, 5. Individuals with these earliest Alzheimer changes (ie, abnormal amyloid status) are at increased risk of future cognitive decline6, 7, 8 and clinical progression to dementia 7, 9, 10, 11.…”

Search for Alzheimer's disease biomarkers in blood cells: hypotheses-driven approach

“…NFTs are deposits of paired helical filaments composed mainly of hyperphosphorylated τ protein, a microtubule-stabilizing protein that maintains neuronal cell structure and axonal transport. Nevertheless, neither senile plaques nor NFTs are absolute hallmarks of AD dementia, because cognitively intact aged individuals may exhibit both pathological changes upon postmortem brain examination or as assessed by positron emission tomography amyloid and τ imaging agents (amyloid-PET and τ-PET) [2][3][4][5].Clinical AD manifests by aggravating dysfunction and weakening functional cognitive processes, linked to brain neuron loss that is both progressive and permanent [4], and that within several years leads to total dependence on the caregiver and eventually to death. Advances in our knowledge of AD have shown that clinical symptoms usually develop after a long preclinical pathogenic process, lasting for decades, making early AD detection in asymptomatic patients a subject of great interest [4,5].…”

“…The turning point for the acceptance of these biomarkers as indicators of preclinical AD were the results of the longitudinal study in carriers of rare familial AD (FAD) autosomal-dominant mutations in protein-encoding genes participating in the production of Aβ, over two decades before the onset of dementia symptoms [9]. Presently preclinical AD can be diagnosed based on the presence of both Aβ and τ biomarkers in the CSF or brain [5]. However, FAD is not fully representative for sporadic AD, the latter being more complex and heterogeneous.…”

“…As indicated by the US FDA, for clinical applications, the biological samples in which the biomarker is to be measured should be easy to obtain in a safe procedure, preferably noninvasive, and the laboratory methods must be reliable, stable and cost-effective. In this light, while the recent development of brain imaging technologies and PET AD tracers as well as assays addressing the 'AD signature' in CSF reflect significant progress in AD diagnosis [4,5], these biomarkers do not fulfill all optimal diagnostic criteria for clinical practice (Table 1). Overall, it becomes clear that progress in AD diagnostics relies on identifying novel diagnostic biomarkers for AD, especially for the early disease phase, that are more cost-effective and in more easily available diagnostic tissues, such as blood ( Table 1).…”

Nutritional strategies in the management of Alzheimer\'s disease: systematic review and meta-analysis

“…The AD is a continuum pathological disorder of the brain characterized by a progressive synaptic lost, dysfunction and neuronal death, caused by the deposition of pathologic markers inducers of lesions in the brain tissue, amyloidopathy and tauopathy (13). Recent studies have focused in the comprehension of this hallmarks, neuritic plaques composed by amyloid β peptide (Aβ) and extracellular neurofibrillary tangles (NFT) by hyperphosphorylated Tau protein, with a preferential distribution along the medial temporal-lobe structures (entorhinal-hippocampal region) (14,15).…”