NOVEL SYNAPTIC, BLOOD-BASED, AND NEUROIMAGING BIOMARKERS IN ALZHEIMER’S DISEASE AND RELATED DEMENTIAS: INSIGHT INTO PATHOPHISIOLOGY AND CLINICAL IMPLEMENTATION

Alzheimer’s disease (AD) and related dementias require accurate biomarkers to support early diagnosis, improve differential classification, and enable access to emerging therapies. This thesis examined novel biomarker candidates through different approaches - cerebrospinal fluid-based, blood-based, and neuroimaging - providing novel perspectives on their potential clinical and research applications. A systematic review and meta-analysis demonstrated that synaptic proteins such as neurogranin, SNAP-25, and GAP-43 are consistently elevated in the cerebrospinal fluid (CSF) of individuals with AD compared to cognitively unimpaired controls. These biomarkers were subsequently investigated in Memory Clinic cohort, yielding novel pathophysiological insights into their relationship with amyloid-β and tau. Importantly, relevant findings were further replicated in an independent cohort. Blood-based biomarkers were investigated in real-world memory clinic populations, with plasma p-tau217 showing high diagnostic accuracy and outperforming other fluid measures in distinguishing AD from non-AD dementias. Plasma NfL provided additional value in detecting neurodegeneration across conditions. Combined use of these markers offers the potential to reduce reliance on invasive CSF procedures while maintaining diagnostic precision. Finally, the utility of the recently developed amygdala atrophy scale (AAS), a novel visual MRI-based rating tool, was evaluated. The AAS proved effective in identifying cases with features of limbic-predominant age-related TDP-43 encephalopathy (LATE), distinguishing them from Alzheimer’s disease, while also capturing distinct clinical and imaging profiles and offering prognostic value. Overall, this thesis provides novel insights into Alzheimer’s disease and related dementias by exploring biomarkers from complementary perspectives, enhancing understanding of disease mechanisms and informing clinical practice