Progression to dementia in memory clinic patients with mild cognitive impairment and normal β-amyloid

Abstract

BackgroundDetermination of β-amyloid (Aβ) positivity and likelihood of underlying Alzheimer’s disease (AD) relies on dichotomous biomarker cut-off values. Individuals with mild cognitive impairment (MCI) and Aβ within the normal range may still have a substantial risk of developing dementia, primarily of Alzheimer type. Their prognosis, as well as predictors of clinical progression, are not fully understood. The aim of this study was to explore the associations of cerebrospinal fluid (CSF) biomarkers (Aβ42, total tau, phosphorylated tau) and other characteristics, including modifiable vascular factors, with the risk of progression to dementia among patients with MCI and normal CSF Aβ42.MethodsThree hundred eighteen memory clinic patients with CSF and clinical data, and at least 1-year follow-up, were included. Patients had normal CSF Aβ42 levels based on clinical cut-offs. Cox proportional hazard models with age as time scale and adjusted for sex, education, and cognition (Mini-Mental State Examination) were used to investigate predictors of progression to dementia and Alzheimer-type dementia. Potential predictors included CSF biomarkers, cognitive performance (verbal learning and memory), apolipoprotein E (APOE) ε4 genotype, medial temporal lobe atrophy, family history of dementia, depressive symptoms, and vascular factors, including the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score. Predictive performance of patient characteristics was further explored with Harrell C statistic.ResultsLower normal Aβ42 and higher total tau and phosphorylated tau were associated with higher dementia risk, and the association was not driven by Aβ42 values close to cut-off. Additional predictors included poorer cognition, APOE ε4 genotype, higher systolic blood pressure, and lower body mass index, but not the CAIDE dementia risk score. Aβ42 individually and in combination with other CSF biomarkers improved the risk prediction compared to age and cognition alone. Medial temporal lobe atrophy or vascular factors did not increase the predictive performance.ConclusionsPossibility of underlying AD pathology and increased dementia risk should not be ruled out among MCI patients with CSF Aβ42 within the normal range. While cut-offs may be useful in clinical practice to identify high-risk individuals, personalized risk prediction tools incorporating continuous biomarkers may be preferable among individuals with intermediate risk. The role of modifiable vascular factors could be explored in this context.

2020 update on the clinical validity of cerebrospinal fluid amyloid, tau, and phospho-tau as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework

“…Similar findings were also reported by Jang et al [ 147 ]. Other studies have reported improved predictive performance for identifying incipient AD by combining CSF AD biomarkers with neuropsychological measures [ 148 , 149 ].…”

Use of Biomarkers in Ongoing Research Protocols on Alzheimer’s Disease

“…In fact, among cognitively intact individuals, the detection of isolated amyloid positivity (or “Alzheimer’s pathological change” [ 3 ]) is associated with a more considerable heterogeneity of clinical outcomes, thus complicating the assessment of clinical endpoints. Moreover, most of the subjects testing positive for A biomarkers will likely not exhibit a significant cognitive and functional worsening over time [ 9 , 17 , 18 ]. For instance, it has been calculated that the lifetime risks of developing AD dementia of a 60-year-old man and a 60-year-old woman with amyloidosis are only 23% and 31%, respectively [ 9 ].…”

Serum Thioredoxin-80 is associated with age, ApoE4, and neuropathological biomarkers in Alzheimer’s disease: a potential early sign of AD

“…Diagnosis for MCI was done using the consensus criteria for MCI which require the presence of both subjective and objective cognitive impairment including one or several cognitive domains, but no dementia or impairment of daily living activities [ 20 ]. Dementia diagnoses were carried out following the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), as previously described [ 21 ].…”