Alzheimer Biomarkers Indicate Very Early Disease Process
The process of Alzheimer disease begins years, if not decades, before the onset of clinical dementia, according to a newly published study in the New England Journal of Medicine. In the Dominantly Inherited Alzheimer Network, or DIAN, trial, patients who are genetically destined to acquire AD (a small minority of AD cases) showed physiologic signs of the underlying disease process well before the onset of any cognitive dysfunction.
According to the prospective, longitudinal study, which included 88 people who carry a deterministic gene for AD and 40 controls:
- CSF levels of amyloid beta (Aβ) 42, an indirect marker of Aβ deposition in the brain, began declining 25 years before the expected onset of clinical dementia.*
- Evidence of Aβ on PET scans, increasing levels of CSF tau, and hippocampal atrophy (via MRI) were seen 15 years before the expected expected onset of clinical dementia.
- Ten years before expected overt dementia, evidence of cerebral hypometabolism (per FDG-PET) and mild clinical symptoms in the form of episodic memory loss were observed.
- Dementia, on the basis of diagnostic criteria, was seen 3 years before its expected onset (suggesting that the recognition of dementia in practice—outside of a longitudinal study—is typically delayed by at least a few years).
While the DIAN study authors caution that confirmation of their data is needed and that these results shouldn’t necessarily be applied to the subclinical progression of sporadic AD (the overwhelmingly most common form of AD), a generalization of their findings does not seem unreasonable and is, moreover, highly likely.
If valid and generalizable, the DIAN biomarker data suggest that abnormalities in the CNS production and/or deposition of Aβ42 are the very earliest signs of AD (notably years before evidence of tau abnormalities). Consequently the use of anti-Aβ42 compounds, despite their relative disappointment in established AD (on the basis of phase 2 studies), remains at least theoretically viable in nascent disease—like in MCI. But even so, effective interventions in AD may need to be applied long before there is any clinical hint of illness.
CNS = central nervous system; CSF = cerebrospinal fluid; FDG = fluorodeoxyglucose; MCI = mild cognitive impairment; MRI = magnetic resonance imaging; PET = positron emission tomography.
* Estimated on the basis of the age of onset of clinical dementia in the affected parent.