Recent update on the heterogeneity of the Alzheimer’s disease spectrum

Abstract

Alzheimer's disease (AD), the most common form of dementia worldwide, is a mixed proteinopathy (β-amyloid, tau and other proteins). Classically defined as a clinicopathological entity, AD is a heterogeneous, multifactorial disorder with various pathobiological subtypes showing different forms of cognitive presentation, currently referred to as the Alzheimer spectrum or continuum. Its morphological hallmarks are extracellular β-amyloid (amyloid plaques) and intraneuronal tau aggregates forming neurofibrillary tangles and neurites, vascular amyloid deposits (cerebral amyloid angiopathy), synapse and neuronal loss as well as neuroinflammation and reactive astrogliosis, leading to cerebral atrophy and progressive mental/cognitive impairment (dementia). In addition to "classical" AD, several subtypes with characteristic regional patterns of tau pathology have been segregated that are characterized by distinct clinical features, differences in age, sex distribution, disease duration, cognitive status, APOE genotype, and biomarker levels. In addition to four major subtypes based on the distribution of tau pathology and brain atrophy (typical, limbic predominant, hippocampal sparing, and minimal atrophy), several other clinical variants (non-amnestic, corticobasal, behavioral/dysexecutive, posterior cortical variants, etc.) have been identified. These heterogeneous AD variants are characterized by different patterns of key neuronal network destructions, in particular the default-mode network that is responsible for cognitive decline. Other frequent age-related co-pathologies, e.g., cerebrovascular lesions, Lewy and TDP-43 pathologies, hippocampal sclerosis, or argyrophilic grain disease, essentially influence the clinical picture and course of AD, and can challenge our understanding of this disorder including the threshold and causal relevance of each individual pathology. Unravelling the clinico-morphological heterogeneity among the AD spectrum entities is important for better elucidation of the pathogenic mechanisms affecting the aging brain that may enable a broader diagnostic coverage of AD as a basis for implementing precision medicine approaches and for developing preventive and ultimately disease-modifying therapies for this devastating disorder.

Concordance of Alzheimer’s Disease Subtypes Produced from Different Representative Morphological Measures: A Comparative Study

“…Moreover, due to the absence of nearly half of the data for beta-amyloid and tau, it is difficult to analyze the matched subtypes more deeply from a pathological perspective. (3) Studies on AD continuum show that molecular pathology and neurodegeneration show different spatial relationships in the whole course of AD, so different subtype results may be presented using mode-varying imaging methods in different stages of AD [ 6 , 36 ]. In the future, the influences of different GM features on the definitions of AD subtypes can be further explored.…”

“…As proved by some studies, the gray matter (GM) change in brain region is closely associated with tau pathology in AD patients with abnormal amyloids [ 4 ]. Therefore, GM atrophy pattern-based morphometric measures have received increasing attention in the studies of biologically defined AD subtypes [ 5 , 6 ].…”

Current advances in our understanding of circular RNA (circRNA) in Alzheimer’s disease (AD); the potential utilization of synthetic circRNAs as a therapeutic strategy in the clinical management of AD

“…Heterogeneity of AD and a requirement for "precision" or "individualized" medicine AD is a distinctly heterogeneous, multifactorial neurological disorder with variation of neuropathology and patient symptoms stemming from a number of areas. These include familial genetics and family history, ethnicity, inter-current illness, multiple parameters associated with gender and aging, the environment, diet and lifestyle and other factors associated with the intrinsic complexity of the disease itself, neurodiagnostic variation in neuroimaging, and neuropathologically via the pre-clinical, clinical and Braak staging of the disease, multiple interactive parameters including CSF and plasma Aβ40/ Aβ42 ratios and the anatomical location of Aβ accumulation (Dong et al, 2017;DeTure and Dickson, 2019;Habes et al, 2020;Jellinger et al, 2022). Other parameters of AD diversity and heterogeneity include the abundance, speciation and inflammatory potential of different senile plaque (SP) and neurofibrillary tangle (NFT) isoforms and densities in anatomical regions of the brain implicated in behavior, cognition and memory (Dong et al, 2017;DeTure and Dickson, 2019;Habes et al, 2020;Lemercier et al, 2021;Bellenguez et al, 2022;Jellinger 2022).…”

“…Currently the "precision medicine" approach has been to investigate early pathophysiological changes of AD to fully capture the complexity of the disease, and has been essential to develop timely screening, detection, diagnostic, prognostic and therapeutic interventions in significantly heterogeneous AD patient populations. Importantly "precision medicine" delineates which therapeutic approach or treatment strategy would be the most effective for a specific individual, at a specified disease stage, across multiple medical research fields that include molecular-genetics, imaging technologies, neuroscience, neurology and psychiatry and the identification of miRNA-and/or mRNA-based biomarkers in the CSF and blood (Hampel et al, 2019;Lemercier et al, 2021;Giampietri et al, 2022;Jellinger 2022;Yamamoto et al, 2022). "Precision medicine" achieves the greatest success when multiple interdisciplinary diagnostic parameters are integrated to yield the most accurate diagnostic analysis of the AD patient who can be subsequently treated using an individualized combination therapy approach or multi-target-directed methodologies.…”

Wearable and Portable GPS Solutions for Monitoring Mobility in Dementia: A Systematic Review

“…Dementia encompasses a spectrum of disorders which are broadly characterised by an individual's progressive loss of cognitive ability. The most common type is Alzheimer's disease, which is associated with the accumulation of amyloid plaques and cellular neurofibrillary tangles [4]. Other dementias vary in their aetiology, onset and specific symptom profile with sub-types including vascular dementias, dementia with Lewy bodies and dementias in disorders such as Huntington's and Parkinson's disease.…”