Abstract
An accurate diagnosis of Alzheimer’s disease (AD) currently stands as one of the most difficult and challenging in all of clinical neurology. AD is typically diagnosed using an integrated knowledge and assessment of multiple biomarkers and interrelated factors. These include the patient’s age, gender and lifestyle, medical and genetic history (both clinical- and family-derived), cognitive, physical, behavioral and geriatric assessment, laboratory examination of multiple AD patient biofluids, especially within the systemic circulation (blood serum) and cerebrospinal fluid (CSF), multiple neuroimaging-modalities of the brain’s limbic system and/or retina, followed up in many cases by post-mortem neuropathological examination to finally corroborate the diagnosis. More often than not, prospective AD cases are accompanied by other progressive, age-related dementing neuropathologies including, predominantly, a neurovascular and/or cardiovascular component, multiple-infarct dementia (MID), frontotemporal dementia (FTD) and/or strokes or ‘mini-strokes’ often integrated with other age-related neurological and non-neurological disorders including cardiovascular disease and cancer. Especially over the last 40 years, enormous research efforts have been undertaken to discover, characterize, and quantify more effectual and reliable biological markers for AD, especially during the pre-clinical or prodromal stages of AD so that pre-emptive therapeutic treatment strategies may be initiated. While a wealth of genetic, neurobiological, neurochemical, neuropathological, neuroimaging and other diagnostic information obtainable for a single AD patient can be immense: (i) it is currently challenging to integrate and formulate a definitive diagnosis for AD from this multifaceted and multidimensional information; and (ii) these data are unfortunately not directly comparable with the etiopathological patterns of other AD patients even when carefully matched for age, gender, familial genetics, and drug history. Four decades of AD research have repeatedly indicated that diagnostic profiles for AD are reflective of an extremely heterogeneous neurological disorder. This commentary will illuminate the heterogeneity of biomarkers for AD, comment on emerging investigative approaches and discuss why ‘precision medicine’ is emerging as our best paradigm yet for the most accurate and definitive prediction, diagnosis, and prognosis of this insidious and lethal brain disorder.
Highlights
Senile dementia is the progressive, age-related loss of memory and cognition sufficiently severe to irreversibly affect social, behavioral, perceptual, occupational, and functional capabilities
The discovery, characterization, and quantification of biomarkers as measurable substances or cognitive disruptions in the ‘prospective Alzheimer’s disease (AD) patient’, whose presence are indicative of disease, are urgently needed so that: (i) AD may be more accurately diagnosed, especially at an earlier ‘prodromal’ stage and with the goal of preventive and or targeted therapeutic strategies that may be implemented at the earliest signs of AD onset; and (ii) more effective and reliable integration of multi-modal biomarkers for AD that can streamline, support, and strengthen the diagnostic and therapeutic decision-making
Peer-reviewed publications on biomarkers for AD have yielded almost ~53,000 original research reports and reviews since 1983 crossing the words ‘Alzheimer’s disease’ and ‘biomarkers’; [2,3,8,9,10]. These include observations on the classical and established AD biomarkers [11,12,13,14], including altered genetics, genetic mutations and gene modifications, end-stage neurotoxic and pathogenic metabolic products that accumulate in AD brains, such as multiple forms of tau aggregates and amyloid-beta (Aβ) aggregation species and plaques
Summary
Senile dementia is the progressive, age-related loss of memory and cognition sufficiently severe to irreversibly affect social, behavioral, perceptual, occupational, and functional capabilities. Microbial biomarkers and systems biology approaches to understand host–microbiome interactions have been suggested by multiple AD researchers that both: (i) predict the risk of developing AD well before the onset of cognitive decline; and (ii) stimulate and/or accelerate the development of classical AD neuropathology [24,34,39,41,42,43,44] Whether these viral, bacterial, or other microbial DNA- or RNA-based nucleic acids or associated lipoproteins, liposaccharides, peptidoglycans, bacterial-derived amyloids, and/or neurotoxins originate from the gastrointestinal (GI) tract microbiome, a potential brain microbiome, or some dormant pathological microbiome is currently not well understood [24,35,36,40,43,45]. Genetic and epigenetic signaling via miRNA-mRNA networks in the brain may be one of the most useful as potential biomarkers for early AD detection as they can detect subtle failure in multiple AD-relevant brain signaling systems and metabolic pathways [10,25,45,49,51]
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