International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 205-213 http://medscipublisher.com/index.php/ijmms 206 2 The Pathological Basis of Alzheimer's Disease 2.1 Core pathological features One of the main features of Alzheimer's disease (AD) is the appearance of extracellular β -amyloid protein (Aβ) plaques and intracellular aggregation of neurofibrillary tangles formed by hyperphosphorylated tau protein. Aβ peptides aggregate in the brain parenchyma to form plaques, while tau proteins undergo abnormal hyperphosphorylation, generating tangling structures that impair the normal function and structural integrity of neurons (McGrowder et al., 2021). These two protein abnormalities are at the core of the pathogenesis of AD and are closely related to synaptic dysfunction, nerve cell death, and gradual cognitive decline (Zhang et al., 2021). The relationship between Aβ and tau is complex and mutually reinforcing. Studies have shown that the deposition of Aβ accelerates the hyperphosphorylation and aggregation of tau. The pathological changes of tau cause Aβ to have a toxic effect on nerve cells, making neuronal damage more severe (Hong et al., 2025; Lou and Xu, 2025). This combined effect not only promotes the progress of AD, but also provides a scientific basis for the development of corresponding biomarkers and treatment methods (Ossenkoppele et al., 2022). 2.2 Pathological changes begin several years before cognitive impairment The pathological changes of AD, including Aβ deposition and tau protein hyperphosphorylation, begin many years (or even decades) before the appearance of clinical symptoms (Uchida et al., 2025). Long-term follow-up studies have shown that accumulation of Aβ can be detected 15-20 years before cognitive decline, followed by tau pathology and neurodegeneration. During this preclinical stage, molecular and structural changes in the brain gradually develop in silence, and these changes can be captured by highly sensitive biomarkers in cerebrospinal fluid, blood and neuroimaging (McGrowder et al., 2021). The initial stage of the pathological process is the golden period for intervention, which also indicates that early screening is very necessary. Identifying these abnormalities before the appearance of clinical symptoms can help delay or prevent diseases, demonstrating the important role of biomarkers in screening high-risk populations (Uchida et al., 2025). 2.3 Pathological stage determines the expression patterns and detection Windows of biomarkers The pathological development of Alzheimer's disease is sequential, and different stages will affect the content of biomarkers and the difficulty of detection. In the early stage of the disease, biomarkers related to Aβ (such as decreased cerebrospinal fluid Aβ42 levels or increased amyloid PET signaling) will first show abnormalities, and then the levels of phosphorylated tau (p-tau) and markers reflecting neurodegeneration will rise (Uchida et al., 2025). For instance, p-tau231 and p-tau217 in the blood are highly sensitive to early Aβ changes, among which p-tau217 is significantly associated with disease progression and long-term cognitive decline (Ashton et al., 2022). As the disease progresses to different stages, the types and degrees of changes in biomarkers will also change accordingly. Early markers are most suitable for preclinical identification, while other markers such as neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are more obvious in the later stage of the disease, reflecting persistent neuronal damage and inflammatory responses (Smirnov et al., 2022; Guo, 2025; Heneka et al., 2025). The timing and sequence of the appearance of these biomarkers are of great significance for the accurate staging, prognosis judgment and disease monitoring of AD, and are conducive to achieving more targeted early diagnosis and intervention strategies. 3 Research Progress on Biomarkers of Alzheimer's Disease 3.1 Cerebrospinal fluid (CSF) biomarkers Biomarkers in cerebrospinal fluid, especially Aβ42, total tau (t-tau) and phosphorylated tau (p-tau), are regarded by many as an important basis for the early detection of Alzheimer's disease (AD). These indicators directly reflect pathological changes such as Aβ deposition and tau hyperphosphorylation, which can effectively distinguish AD from other types of dementia and accurately predict the risk of progressing from mild cognitive impairment to AD (Papaliagkas et al., 2023; Barthsamlemy et al., 2023). Because cerebrospinal fluid is in direct
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