From Amyloid to Synaptic Dysfunction: Biomarker-Driven Insights into Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and represents a major public health challenge. With increasing life expectancy, the incidence of AD has also increased, highlighting the need for early diagnosis and improved monitoring. Traditionally, diagnosis has relied on clinical symptoms and neuroimaging; however, the introduction of biomarkers has revolutionized disease assessment. Traditional biomarkers, including the Aβ42/Aβ40 ratio, phosphorylated tau (p-Tau181, p-Tau217, and p-Tau231), total tau (t-tau), and neurofilament light chain (NfL), are fundamental for staging AD progression. Updated guidelines introduced the ATX(N) model, which extends biomarker classification to include additional promising biomarkers, such as SNAP-25, YKL-40, GAP-43, VILIP-1, progranulin (PGRN), TREM2, IGF-1, hFABP, MCP-1, TDP-43, and BDNF. Recent advancements have allowed for the detection of these biomarkers not only in CSF but also in plasma and neuron-derived exosomes, offering less invasive and more accessible diagnostic options. This review explores established and emerging biomarkers and emphasizes their roles in early diagnosis, patient stratification, and precision medicine.

Keywords: ATX(N) framework; Alzheimer’s disease; CSF; biomarkers; blood; diagnostic criteria; plasma.

Figure 2

Timeline of Alzheimer’s disease diagnostic criteria evolution (1984–2024). This timeline summarizes the key milestones in the development of the diagnostic criteria for AD, from the 1984 NINCDS-ADRDA criteria to the most recent 2024 revision [14,41,42,43,44,45]. Over the years, the definition of AD has evolved from a purely clinical construct to a biologically driven model. The 2011 and 2014 updates introduced the use of CSF biomarkers and imaging techniques to detect amyloid and tau pathologies. The 2018 NIA-AA Research Framework formalized AT(N) classification, categorizing biomarkers into three main groups: amyloid (A), tau (T), and neurodegeneration (N). In 2024, the revised NIA-AA criteria incorporated blood-based biomarkers and introduced an expanded ATX(N) model. The “X” category includes emerging biomarkers that capture additional pathological processes, such as neuroinflammation, synaptic dysfunction, and blood–brain barrier damage.

Figure 1

Biomarkers of Alzheimer’s disease across the blood–brain Barrier. Glial fibrillary acidic protein (GFAP), phosphorylated tau protein (p-TAU), growth-associated protein 43 (GAP-43), insulin-like growth factor 1 (IGF-1), brain-derived neurotrophic factor (BDNF), chitinase-3-like protein 1 (YKL-40), amyloid β 42 peptide (Aβ42), amyloid β 40 peptide (Aβ40), neurofilament light chain (NfL), synaptosomal-associated protein 25 (SNAP-25), triggering receptor expressed on myeloid cells 2 (TREM2), monocyte chemoattractant protein-1 (MCP-1), visinin-like protein 1 (VILIP-1), heart-type fatty acid-binding proteins (hFABPs), and TAR DNA-binding protein 43 (TDP-43).

Figure 3

The AT(X)N framework for the biological diagnosis and staging of Alzheimer’s disease. The framework includes three main categories of biomarkers: A (amyloid) for β-amyloid deposition (Aβ42, Aβ42/Aβ40 ratio, amyloid PET), T (tau) for tau pathology (p-Tau181, p-Tau217, p-Tau231, tau PET), and N (neurodegeneration) for neuronal damage (t-Tau, MTBR-Tau243, NfL, brain atrophy on MRI, FDG-PET). The X category includes emerging biomarkers that reflect other disease mechanisms, such as neuroinflammation (GFAP, sTREM2, YKL-40), synaptic dysfunction, and blood–brain barrier damage (e.g., sPDGFRβ), which are not captured by the traditional ATN model. β-amyloid 40 (Aβ40), β-amyloid 42 (Aβ42), cerebrospinal fluid (CSF), glial fibrillary acidic protein (GFAP), phosphorylated tau (isoforms 181, 217, 231) (p-TAU), total tau (t-Tau), alpha-synuclein seeding amplification assay (alfaSyn-SAA), FDG positron emission tomography (FDG-PET), neurogranin (Ng), neurofilament light chain (NfL), synaptosomal-associated protein 25 (SNAP-25), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), microtubule-binding region tau 243 (MTBR-Tau243), YKL-40, S100 calcium-binding protein B (S100B), synaptic vesicle glycoprotein 2A positron emission tomography (SV2A PET).

Figure 4

Promising biomarkers reflecting key pathophysiological processes in Alzheimer’s disease. The biomarkers of synaptic dysfunction include growth-associated protein 43 (GAP-43) and synaptosomal-associated protein 25 (SNAP-25). Biomarkers of neuroinflammation include monocyte chemoattractant protein-1 (MCP-1), progranulin (PGRN), triggering receptor expressed on myeloid cells 2 (TREM2), and chitinase-3-like protein 1 (YKL-40). Biomarkers of neuronal injury include visinin-like protein 1 (VILIP-1) and heart-type fatty acid binding protein (hFABP). Biomarkers of neuroprotection comprise brain-derived neurotrophic factor (BDNF), progranulin (PGRN), and insulin-like growth factor 1 (IGF-1). Finally, the biomarker of protein aggregation is TAR DNA-binding protein 43 (TDP-43).