Alzheimer’s pathology lies silent for decades

By Eleanor McDermid

The pathologic process of Alzheimer's disease (AD) begins more than 20 years before clinical symptoms become apparent, say researchers.

Their conclusions are drawn from analysis of the Dominantly Inherited Alzheimer Network (DIAN) ‑ a worldwide network of centers treating patients with autosomal dominant AD. This yielded 128 patients with a known mutation for AD.

The earliest change in these patients was a decline in levels of amyloid-beta (Aβ)₄₂ in the cerebrospinal fluid (CSF), relative to those in control participants without AD mutations. This occurred at about 25 years before the expected age of symptom onset, defined as the age at which participants' parents had first developed clinical symptoms (45.7 years on average). The participants developed mild dementia an average of 3.3 years after the age of parental onset.

However, significant differences in Mini-Mental State Examination scores between patients and controls appeared from 5 years before the patients were diagnosed with dementia.

"These findings suggest that the diagnosis of clinical dementia is made late in the course of the biologic cascade of autosomal dominant Alzheimer's disease," Randall Bateman (Washington University School of Medicine, St Louis, USA) and colleagues write in The New England Journal of Medicine.

The decline in Aβ in the CSF was followed by Aβ deposition in the brain on positron-emission tomography, which occurred from about 15 years before expected symptom onset, along with increased levels of tau in the CSF and evidence of atrophy of bilateral hippocampi.

Ten years before expected symptom onset, the patients exhibited significant declines in cerebral glucose metabolism.

Bateman et al comment that their findings do not directly apply to patients with sporadic AD, but say that cross-sectional studies in such patients have also suggested the presence of a series of pathologic changes leading to dementia.

"Our results support the hypothesis of a pathophysiological cascade and suggest the possibility of a common pathophysiology between autosomal dominant Alzheimer's disease and the much more common 'sporadic' form," they write.

If the two forms of AD do follow a similar pattern, then the researchers' results suggest that any person with a positive scan for amyloid deposition will eventually develop AD.

"These findings suggest that the targeting of Aβ earlier in the course of the disease may provide better clinical outcomes than the treatment of mild to moderate dementia after substantial neuronal and synaptic loss has occurred," they conclude.

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