Clinically, Alzheimer`s disease (AD) is a progressive, neurodegenerative disease leading to neurodegeneration and subsequently cognitive decline.(Lane et al., 2018) Neurodegeneration refers to the progressive loss of structure or functions of neurons in the brain, leading to functional impairment. Over time there has been a shift in AD diagnostics, from a clinical to a biological understanding and definition, as established in the National Institute of Aging (NIA) – Alzheimer Association (AA) criteria in 2018 (Jack et al., 2018). These criteria defined two core criteria: amyloidosis (A+) and tau tangles (T+). Additionally, neurodegeneration (N+) was included as a supporting criterion, defined as either pathological total tau (T-tau) in cerebrospinal fluid (CSF) or neurodegeneration seen on magnetic resonance imaging (MRI). In the 2024 AA criteria, a notable departure from the 2018 criteria is the replacement of CSF T-tau with neurofilament light chain (NfL) as a recommended marker for neurodegeneration, based on the notation that T-tau is directly linked to AD pathology(Jack et al., 2024).

Impairment of synaptic homeostasis (Heneka et al., 2015, Milà-Alomà et al., 2020, Nilsson et al., 2021, Shankar et al., 2008, Tönnies and Trushina, 2017, Wilson et al., 2023) is believed to be early and critical events in AD cognitive decline (Wilcox et al., 2021). Given the crucial role that synapses play in cognitive function and as very early indicators of neurodegeneration, it is essential to investigate the relationship between neurodegeneration markers and synaptic health. Well-described presynaptic and postsynaptic markers are beta-site amyloid precursor protein cleaving enzyme (BACE1) and neurogranin in the CSF (Kandalepas et al., 2013, Represa et al., 1990, Zhao et al., 2007), which are shown to be early markers of neurodegeneration (Portelius et al., 2015) and cognitive decline (Kester et al., 2015) in both AD (Wellington et al., 2016) and non-AD neurodegeneration (Hall et al., 2020, Jack et al., 2024, Wang et al., 2022, Willemse et al., 2021, Zuliani et al., 2020). Full-length neurogranin is reduced in post-mortem AD brains (Kvartsberg et al., 2019), accompanied by elevated levels of its cleavage products in CSF (Kvartsberg et al., 2015, Liu et al., 2020, Tarawneh et al., 2016, Thorsell et al., 2010).

NfL and T-tau signify distinct neurodegenerative processes (Ebenau et al., 2021, Milà-Alomà et al., 2020), and might not be equally correlated to synaptic dysfunction(Mattsson et al., 2016). NfL is a subunit of neurofilaments and a neuron-specific marker linked to white matter (WM) integrity (Mielke et al., 2021, Yuan et al., 2017) and axonal damage. In contrast, T-tau shows a stronger relation to grey matter (GM) degeneration and aligns with the progression of AD-specific brain atrophy (Gispert et al., 2015, Mielke et al., 2021, Seidu et al., 2024). Initial AD pathology affects GM (DeTure and Dickson, 2019, Hampel et al., 2008), with loss of synapses and dendritic branching(Dicks et al., 2020), progressing to the WM tissue, affecting axons and loss of WM tract integrity(Schumacher et al., 2022). Eventually, the cerebral atrophy in AD involves both GM and WM brain tissue(Jack et al., 1999; Veale et al., 2021). CSF NfL and CSF T-tau are elevated in other neurodegenerative disorders in addition to AD, but are both valuable biomarkers in AD, each with its advantages and limitations(Dhiman et al., 2020; Ebenau et al., 2021; Gaetani et al., 2019; Hampel & Blennow, 2004; Khalil et al., 2018; Mattsson et al., 2019; Parnetti et al., 2019). CSF T-tau is relatively more specific to AD (Kern et al., 2019, Mattsson et al., 2016), while NfL seems to reflect a more general ongoing axonal neurodegenerative processes (Kern et al., 2019, Mattsson et al., 2016). Cognitive decline is the ultimate consequence of neurodegeneration. Variations in cognitive test profiles may point towards the etiology and topography of neural damage and help in understanding the progression of neurodegenerative diseases(Fladby et al., 2017; Jessen et al., 2014). Kern(Kern et al., 2019) and colleagues have earlier found CSF NfL to be indicative for progression to later mild cognitive impairment (MCI), without finding the same association for CSF T-tau or CSF neurogranin. In that study, CSF biomarkers were categorized into quartiles, not cut-off values, and was compared to progression in clinical staging alone, not to synaptic health or cognitive scores directly.

The objective of this study is to explore how CSF T-tau-mediated neurodegeneration ('N' marker 2018 criteria) as opposed to axonal degradation reflected in CSF NfL ('N' marker 2024 criteria) correlate with the synaptic markers (CSF neurogranin and BACE1) and cognition. By using cut-off values, we classify participants into subgroups based on biomarker pathology, allowing us to elucidate the individual contribution of NfL and T-tau pathology, as well as their combined effects, in relation to synaptic dysfunction among predementia AD patients.