CSF tau/Aβ42 ratio for increased risk of mild cognitive impairment

Background: Processes of Alzheimer disease (AD) likely begin years prior to the onset of cognitive impairment (latent AD), progress though a prodromal phase of mild cognitive impairment (MCI), and culminate in dementia. While many studies have evaluated CSF tau and Aβ42 as biomarkers of the dementia or prodromal stages of AD, we are unaware of any study to evaluate these potential CSF biomarkers of latent AD. Methods: We determined the ratio of CSF tau/Aβ42 (T/Aβ) using Luminex reagents in 129 control individuals that spanned from 21 to 100 years of age; for comparison we included patients with MCI (n = 12), probable AD (n = 21), or other neurodegenerative diseases (n = 12). Results: We identified 16% of the control group with abnormally elevated CSF T/Aβ; all were 53 years or older. Using age-matched controls with normal CSF T/Aβ we showed that the high CSF T/Aβ subgroup of controls had significantly increased frequency of the ε4 allele of the apolipoprotein E gene and significantly increased risk of conversion to MCI during follow-up of up to 42 months suggesting that they had latent AD at the time of lumbar puncture. Conclusions: These generally applicable methods establish cutoff values to identify control individuals at increased risk of conversion to mild cognitive impairment which may be useful to people weighing the risk-benefit ratio of new preventive therapeutics and to researchers striving to enrich clinical trial populations with people with latent Alzheimer disease.