Biomarkers for Alzheimer's Dementia

Biomarkers for Alzheimer's Dementia Fifteen–Twenty High-Yield Points Concept

A biomarker is an objectively measured indicator of a normal or pathological process. In AD they are needed because clinical diagnosis alone is unreliable and pathology begins years to decades before symptoms.

Current diagnostic criteria require biomarkers reflecting the three core features of the disease: β-amyloid, phosphorylated tau, and neurodegeneration — the basis of the ATN classification.

Biomarkers serve four purposes: diagnosis, staging, prognosis, and monitoring treatment response (including patient selection for anti-amyloid therapy).

CSF Aβ1-42 is reduced in AD because amyloid is sequestered into plaques. The Aβ42/40 ratio is preferred because it corrects for individual differences in total amyloid production.

CSF phosphorylated tau (p-tau181) and total tau are raised, reflecting tangle formation and neuronal injury respectively. The combination of low Aβ42 with high p-tau is the classical AD signature.

A useful discriminator: in normal pressure hydrocephalus CSF Aβ42 is reduced as in AD, but a rise in phospho-tau is seen only in AD — a high-yield point for the NPH-versus-AD viva question.

CSF neurofilament light (NfL) is a marker of axonal degeneration; it is elevated but non-specific, rising in many neurodegenerative and inflammatory conditions.

Amyloid PET using fibrillar Aβ ligands demonstrates plaque burden in vivo. A significant plaque burden may be present in cognitively normal people, so a positive scan alone does not equal dementia.

Tau PET tracks tangle deposition, which follows Braak staging and correlates far better with cognitive decline than amyloid does.

Structural MRI shows hippocampal and medial temporal lobe atrophy, ventricular enlargement, and cortical thinning. Longitudinal studies show cognitively normal people with low CSF Aβ1-42 have faster whole-brain and hippocampal volume loss.

MRI also identifies co-pathology that alters the clinical threshold: white matter hyperintensities, lacunes, microinfarcts, microbleeds and dilated perivascular spaces. Microbleeds require T2*-gradient echo sequences; white matter lesions are best seen on FLAIR.

Functional/molecular imaging for differential diagnosis: dopamine transporter (loflurane) SPECT is normal in AD but abnormal in Lewy body dementia; FDG-PET shows temporoparietal and posterior cingulate hypometabolism in AD.

Advances in assay sensitivity have made blood-based biomarkers increasingly viable — specifically plasma Aβ42/40, phosphorylated tau, and neurofilament light — with significant implications for facilitating early diagnosis.

Their attraction is practical: low cost, minimally invasive, repeatable, and scalable to primary care and to population screening in high-burden low-resource settings.

APOE ε4 is a susceptibility (risk) marker, not a diagnostic marker. It is neither sensitive nor specific and is not recommended for screening.

Deterministic mutations (APP, PSEN1, PSEN2) are diagnostic only in early-onset familial disease and mandate genetic counselling.

Electrophysiological markers: impaired LTP-like cortical plasticity on 5-Hz repetitive TMS has been described in amnestic MCI that converts to AD.

Caveats for the viva: biomarker positivity in a cognitively normal person indicates preclinical disease, not dementia; mixed pathology is common in the very old; and cut-offs vary between assays and platforms.