When does Alzheimer’s disease really start? The role of biomarkers

This paper reviews biomarkers and their usefullness at diagnosing AD. Since biomarkers can do so before traditional clinical symptoms, the authors evaluate when AD can be said to have started. They consider the disease one with a gradual progression with different stages.

AD biomarkers

In cerebrospinal fluid

• Aβ42 and tau. Aβ is diminished in the CSF of patients with AD compared to healthy patients since it forms Aβ oligomers in the brain. An increase of tau in the CSF is a good predictor, while not specific to AD.

Imaging biomarkers

• PiB-PET: a ligand of Aβ that allows analysis of Aβ load and spatial distribution when used in PET.
• FDG-PET: measures the cerebral metabolism of glucose and indicates neuronal and glial function. It correlates with decreased levels of synaptophysin that indicates a loss of synaptic activity.
• Structural and Functional MRI: cerebral atrophy can be quantified with MRI and be detected before the onset of clinical symptoms. It is considered a reliable diagnostic tool. It shows atrophy and thinning of the cerebral cortex.

When AD starts

AD is an extended disease that with a latent start that progresses gradually untli the patient’s cognition is compromised. Dementia is the final stage rather than the onset of the disease.

Increased levels of Aβ would lead to the formation of plaques and a reduction in the levels of Aβ in the CSF - all while the patient is cognitively normal. Then there would be in increase in CSF tau abnormalities. The final stage would show cortical atrophy and decreased hippocampal volume that an MRI would detect.

Risk factors in biomarker dynamics

People without APOE4 show an initial increase and then a decrease in CSF Aβ42 with a progression of CSF tau. Those with at least one APOE4 allele showed only a decrease in CSF Aβ42 associated with a progression of tau pathology and then both markers became positive with disease progression.

New classification - A/T/N system

• A: β-amyloid marker - on the Alzheimer’s continuum
• T: value of tau marker - have AD
• N: neurodegeneration or neuronal injury markers - have AD