The process of memory entails the activation of numerous neural networks and biochemical pathways throughout the brain. The phenomenon of memory decline in relation to aging has been the subject of extensive research for several decades. The correlation between the process of aging and memory is intricate and has various aspects to consider. Throughout the aging process, there are various alterations that take place within the brain and, as expected, affect other functions that have already been linked to memory and its function such as involving microcirculation and sleep. Recent studies provide an understanding of how these mechanisms may be interconnected through the relatively new concept of the glymphatic system. The glymphatic system is strongly correlated to sleep processes. Sleep helps the glymphatic system remove brain waste solutes. Astrocytes expand and contract to form channels for cerebrospinal fluid (CSF) to wash through the brain and eliminate waste. However, the details have not been totally elusive, but the discovery of what we call the glymphatic system enables us to connect many pieces of physiology to understand how such factors are interconnected and the interplay between them. Thus, the purpose of this review is to discuss how the glymphatic system, sleep, memory, and aging are interconnected through a network of complex mechanisms and dynamic interactions.

Blood phospho-tau181 may offer a useful biomarker for Alzheimer’s disease. However, the use of either serum or plasma phospho-tau181 and their diagnostic value are currently under intense investigation. In a pilot study, we measured both serum and plasma phospho-tau181 (pT181-Tau) by single molecule array (Simoa) in a group of patients with Alzheimer’s disease and a mixed group of patients with other primary dementing and/or movement disorders. Classical cerebrospinal fluid biomarkers were also measured. Plasma (but not serum) pT181-Tau showed a significant increase in Alzheimer’s disease and correlated significantly with cerebrospinal fluid amyloid and pT181-Tau. Receiver operating curve analysis revealed a significant discrimination of Alzheimer’s from non-Alzheimer’s disease patients, with an area under the curve of 0.83 and an excellent sensitivity but a moderate specificity. Plasma pT181-Tau is not an established diagnostic biomarker for Alzheimer’s disease, but it could become one in the future, or it may serve as a screening tool for specific cases of patients or presymptomatic subjects.

Cerebrospinal fluid (CSF) biomarkers remain the gold standard for fluid-biomarker-based diagnosis of Alzheimer’s disease (AD) during life. Plasma biomarkers avoid lumbar puncture and allow repeated sampling. Changes of plasma phospho-tau-181 in AD are of comparable magnitude and seem to parallel the changes in CSF, may occur in preclinical or predementia stages of the disease, and may differentiate AD from other causes of dementia with adequate accuracy. Plasma phospho-tau-181 may offer a useful alternative to CSF phospho-tau determination, but work still has to be done concerning the optimal method of determination with the highest combination of sensitivity and specificity and cost-effect parameters.

The use and interpretation of diagnostic cerebrospinal fluid (CSF) biomarkers for neurodegenerative disorders, such as Dementia with Lewy bodies (DLB), represent a clinical challenge. According to the literature, the composition of CSF in DLB patients varies. Some patients present with reduced levels of amyloid, others with full Alzheimer Disease CSF profile (both reduced amyloid and increased phospho-tau) and some with a normal profile. Some patients may present with abnormal levels of a-synuclein. Continuous efforts will be required to establish useful CSF biomarkers for the early diagnosis of DLB. Given the heterogeneity of methods and results between studies, further validation is fundamental before conclusions can be drawn.

Analysis of classical cerebrospinal fluid biomarkers, especially when incorporated in a classification/diagnostic system such as the AT(N), may offer a significant diagnostic tool allowing correct identification of Alzheimer’s disease during life. We describe four patients with more or less atypical or mixed clinical presentation, in which the classical cerebrospinal fluid biomarkers amyloid peptide with 42 and 40 amino acids (Aβ₄₂ and Aβ₄₀, respectively), phospho-tau (τ_P-181) and total tau (τ_Τ) were measured. Despite the unusual clinical presentation, the biomarker profile was compatible with Alzheimer’s disease in all four patients. The measurement of classical biomarkers in the cerebrospinal fluid may be a useful tool in identifying the biochemical fingerprints of Alzheimer’s disease, especially currently, due to the recent approval of the first disease-modifying treatment, allowing not only typical but also atypical cases to be enrolled in trials of such treatments.

The glymphatic system is a brain-wide perivascular network that facilitates cerebrospinal fluid-interstitial fluid exchange and the clearance of metabolic waste. Growing experimental and clinical evidence suggests that glymphatic dysfunction may represent a convergent upstream mechanism linking aging, neuroinflammation, and neurodegeneration. In this narrative review, we synthesize human imaging, clinical, and translational evidence implicating glymphatic dysfunction across major neurodegenerative diseases and integrate these findings with emerging data supporting its role in chronic low-grade inflammation associated with aging (inflammaging). We further discuss how alterations in the gut microenvironment may remotely influence glymphatic function and contribute to neurodegeneration through the gut–brain axis. Although supported by extensive preclinical evidence, studies in humans increasingly demonstrate impaired glymphatic function in several neurodegenerative disorders, most assessed using diffusion tensor imaging along the perivascular space (DTI-ALPS) index. Glymphatic dysfunction is associated with cognitive decline, motor impairment, and disease progression. Aging-related alterations in astrocytic function, aquaporin-4 polarization, blood-brain barrier integrity, and perivascular fluid dynamics provide mechanistic links between inflammaging and glymphatic failure. Gut dysbiosis may further exacerbate these processes by promoting central nervous system inflammation and vascular dysfunction. Together, these findings identify the glymphatic system as a clinically relevant pathway in neurodegeneration that may be regulated by aging-associated neuroinflammatory mechanisms involving the gut-brain axis. Finally, we discuss lifestyle factors that influence glymphatic function and propose a unified framework positioning glymphatic dysfunction as a central integrator of impaired brain clearance, with potential implications for biomarker development, clinical assessment, and disease-modifying therapeutic strategies in neurodegenerative disorders.