Alzheimer’s disease: The article presents a thorough examination of Alzheimer’s disease (AD), emphasizing early detection as critical due to the disease's progression through stages from normal cognition to mild cognitive impairment (MCI) and eventually dementia. The review underscores the importance of identifying AD in its preclinical stages to prevent irreversible neuronal damage and the need for precise diagnostic methods that go beyond invasive and costly procedures like lumbar puncture and PET imaging.

The review discusses various non-cognitive signs that may indicate the onset of AD, such as behavioral and psychological symptoms, sleep disorders, sensory impairments, and physical changes. It suggests that these signs, though not definitive, could serve as early predictors of cognitive decline. The article also highlights the role of the gut microbiome and the potential of blood-based biomarkers in the early diagnosis of AD.

Historical shifts in diagnostic approaches are detailed, showing a move from reliance on clinical evidence to the incorporation of biological indicators. The review outlines the evolution of diagnostic criteria, the introduction of biomarkers, and the potential impact of artificial intelligence in discovering new, minimally invasive biomarkers.

Specific non-cognitive signs are explored in depth, including behavioral symptoms of dementia, circadian rhythm disruptions, sensory impairments, and the gut microbiome's influence on AD. The review points to the correlation between these symptoms and the pathological changes in AD, suggesting a complex interplay between early signs and disease progression.

Advancements in biomarker research are highlighted, with a focus on neuroimaging, blood-based markers, metabolomics, exosomal microRNA, and the potential role of pathogens and endocrine dysregulation. The review suggests that these diverse biomarkers, when integrated, could significantly enhance early detection and disease management.

The correlation between non-cognitive symptoms and pathological changes is a key point of discussion, with the review drawing attention to the bidirectional relationship between sleep disturbances and AD, and the association between sensory impairments and brain regions affected early in the disease.

In conclusion, the review stresses the necessity of early detection for effective intervention and the potential of non-cognitive symptoms and biomarkers in identifying AD before cognitive decline becomes apparent. It acknowledges the challenges of integrating these indicators into clinical practice and calls for further research to confirm their reliability and applicability in early diagnosis.

The article concludes with a series of questions that highlight the need for further investigation into the use of non-cognitive manifestations as early indicators, the relationship between these symptoms and the underlying pathology of AD, and the potential of integrating these indicators with biofluid biomarkers to improve diagnostic accuracy. AlphGalileo/SP