Stable readout of visual representations mediates flexible generalization.

Dementia is one of the world’s most pressing health challenges. Disease cases are projected to surge from 55 million in 2019 to over 153 million by 2050 []. This places an unprecedented burden on already overstretched healthcare systems. Globally, dementia costs are estimated to exceed $9.2 trillion (USD) [] within the next twenty years, becoming one of the costliest healthcare conditions. Unlike other leading causes of death, such as cardiovascular disease and cancer, dementia remains without an effective treatment or prevention strategy. Once diagnosed, Alzheimer’s Disease (AD), accounting for 60–80% of dementia cases, and other related dementias (e.g., frontotemporal or vascular dementia) [], are irreversible and progressive, causing debilitating memory loss and thinking problems, mood and behavioural symptoms, impaired function and quality of life, and ultimately death [, ]. Even before symptoms appear, a marked decline in brain glucose and lipid metabolism, especially in astrocytes and microglia cells, starts to occur [, ]. This metabolic disruption can start 10–20 years before clinical symptoms appear and often coincides with nerve cell loss, changes in brain structure (e.g., white matter atrophy) and blood vessels, cerebral insulin resistance and mitochondrial dysfunction, and oxidative stress [–]. Classic Alzheimer’s Disease and related dementias (ADRD) neuropathology includes buildup of beta-amyloid (Aβ) plaques and tau tangles in nerve cells, interfering with synaptic function and eventually leading to neuronal cell death [, ]. Neuroinflammation, a central mechanism driving disease progression, releases harmful inflammatory cytokines (e.g., interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), and C-reactive protein (CRP)) that further exacerbate disease progression by damaging synapses and compromising blood–brain barrier integrity [–]. Co-pathologies are typically present in later-stage dementias (e.g., vascular disease, Lewy bodies, and TAR DNA-binding protein 43 (TDP-43) accumulation) and rapidly accelerate the disease [, ]. While there is no cure for dementia, novel amyloid clearance therapies (e.g., Lecanemab) for ADRD are being introduced imminently, but these monoclonal antibody therapies act on a single upstream target (Aβ). Systematic reviews of phase III monoclonal antibody clinical trials show only modest cognitive benefits, and present concerns around contradictory results, long-term efficacy, safety concerns, and inhibitory costs [, ]. These challenges highlight the need for complementary approaches that identify earlier, modifiable pathways contributing to cognitive decline. Understanding blood-based biomarkers of neurodegenerative pathology offers a less expensive, non-invasive way to examine how lifestyle and other MRFs may influence cognitive and functional outcomes.