Emerging Biomarkers in Cognition

Emerging Biomarkers in Cognition Fifteen–Twenty High-Yield Points Rationale

Cognitive impairment in the elderly is usually the result of mixed pathology. More than 230 combinations of neuropathology have been described, and altered proteins occur even in cognitively normal older people.

Emerging biomarkers therefore aim to move beyond amyloid and tau to capture the full range of contributing processes — synucleinopathy, TDP-43, vascular injury, inflammation, and synaptic loss.

The four properties sought are: early positivity, high specificity, minimal invasiveness, and low cost enough for population use.

Hyperphosphorylated tau, amyloid-β, α-synuclein and TDP-43 are the four principal aggregating proteins; all four are found in the brains of cognitively normal older people, which limits the specificity of any one marker.

α-Synuclein seed amplification assay (SAA) in CSF detects Lewy body pathology with high accuracy and is the key emerging marker for DLB and Parkinson's disease dementia; skin biopsy assays are in development.

TDP-43-related pathology (LATE — limbic-predominant age-related TDP-43 encephalopathy) is a common mimic of AD in the very old; no validated fluid biomarker yet exists, which is an important knowledge gap.

Neurofilament light (NfL) in CSF and plasma is a sensitive but disease-non-specific marker of axonal injury; it is most useful for tracking progression and treatment response rather than diagnosis.

Glial fibrillary acidic protein (GFAP) in plasma reflects reactive astrocytosis and rises very early — often before p-tau217 — making it a candidate marker of the earliest amyloid-associated response.

Inflammatory markers under study include soluble TREM2, YKL-40, and IL-6, reflecting the microglial and astrocytic activation that is a hallmark of brain ageing.

Neurogranin (post-synaptic) and SNAP-25 and synaptotagmin-1 (pre-synaptic) in CSF index synaptic loss, which correlates with cognition better than plaque burden.

SV2A PET imaging quantifies synaptic density in vivo and is emerging as a sensitive measure of early degeneration.

Loss of aerobic glycolysis and altered brain energy metabolism are described hallmarks of brain ageing and can be imaged with FDG-PET.

Diffusion tensor imaging demonstrates loss of white matter integrity following an anterior-to-posterior gradient — frontal lobes first, occipital last — consistent with the "last in, first out" model of myelination.

Small vessel disease markers (white matter hyperintensities on FLAIR, lacunes, microinfarcts, microbleeds on T2*GRE, dilated perivascular spaces) are increasingly recognised as major determinants of cognitive decline and disability in the older person.

Retinal biomarkers — optical coherence tomography measurement of retinal nerve fibre layer thinning — are an accessible surrogate of neuroaxonal loss already validated in demyelinating disease and under study in dementia.

Electrophysiology: impaired LTP-like plasticity on 5-Hz repetitive TMS distinguishes amnestic MCI that converts to AD; quantitative EEG connectivity measures are also being studied.

Accelerated long-term forgetting — normal learning with abnormally rapid loss over days to weeks — may be a clinical marker of presymptomatic disease.

Gait speed and dual-task gait are practical physical biomarkers: slowing of walking speed under a concurrent cognitive task predicts cognitive decline and is measurable with a stopwatch over 10 metres.

Digital biomarkers — passive smartphone and wearable data on typing, speech, sleep and mobility — are the most rapidly growing category and are attractive for community screening.

Interpretation caveat: no emerging biomarker should be used in isolation. Each must be interpreted against the clinical syndrome, education level, and the high probability of mixed pathology in old age.