Progression to dementia in memory clinic patients with mild cognitive impairment and normal β-amyloid.
Alzheimers Res Ther. 2019 12 05; 11(1):99.AR

Abstract

BACKGROUND

Determination 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.

METHODS

Three 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.

RESULTS

Lower 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.

CONCLUSIONS

Possibility 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.

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Authors+Show Affiliations

Rosenberg A

Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland. anna.rosenberg@uef.fi.

Solomon A

Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland. Division of Clinical Geriatrics, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

Division of Clinical Geriatrics, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden. Clinic for Cognitive Disorders, Theme Aging, Karolinska University Hospital-Huddinge, Stockholm, Sweden. Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland. The Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, UK.

MeSH

AgedAmyloid beta-PeptidesApolipoprotein E4BiomarkersCognitive DysfunctionDementiaDisease ProgressionFemaleHumansLongitudinal StudiesMagnetic Resonance ImagingMaleMiddle AgedNeuropsychological TestsPeptide FragmentsPhosphorylationPrognosisTemporal Lobetau Proteins

Pub Type(s)

Journal Article

Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31805990

Citation

Rosenberg, Anna, et al. "Progression to Dementia in Memory Clinic Patients With Mild Cognitive Impairment and Normal Β-amyloid." Alzheimer's Research & Therapy, vol. 11, no. 1, 2019, p. 99.

Rosenberg A, Solomon A, Jelic V, et al. Progression to dementia in memory clinic patients with mild cognitive impairment and normal β-amyloid. Alzheimers Res Ther. 2019;11(1):99.

Rosenberg, A., Solomon, A., Jelic, V., Hagman, G., Bogdanovic, N., & Kivipelto, M. (2019). Progression to dementia in memory clinic patients with mild cognitive impairment and normal β-amyloid. Alzheimer's Research & Therapy, 11(1), 99. https://doi.org/10.1186/s13195-019-0557-1

Rosenberg A, et al. Progression to Dementia in Memory Clinic Patients With Mild Cognitive Impairment and Normal Β-amyloid. Alzheimers Res Ther. 2019 12 5;11(1):99. PubMed PMID: 31805990.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Progression to dementia in memory clinic patients with mild cognitive impairment and normal β-amyloid. AU - Rosenberg,Anna, AU - Solomon,Alina, AU - Jelic,Vesna, AU - Hagman,Göran, AU - Bogdanovic,Nenad, AU - Kivipelto,Miia, Y1 - 2019/12/05/ PY - 2019/08/23/received PY - 2019/11/13/accepted PY - 2019/12/7/entrez PY - 2019/12/7/pubmed PY - 2020/8/7/medline KW - Alzheimer’s disease KW - Biomarkers KW - Cerebrospinal fluid KW - Dementia KW - Disease progression KW - Mild cognitive impairment KW - Prognosis SP - 99 EP - 99 JF - Alzheimer's research & therapy JO - Alzheimers Res Ther VL - 11 IS - 1 N2 - BACKGROUND: Determination 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. METHODS: Three 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. RESULTS: Lower 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. CONCLUSIONS: Possibility 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. SN - 1758-9193 UR - https://www.unboundmedicine.com/medline/citation/31805990/Progression_to_dementia_in_memory_clinic_patients_with_mild_cognitive_impairment_and_normal_β_amyloid_ DB - PRIME DP - Unbound Medicine ER -

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Progression to dementia in memory clinic patients with mild cognitive impairment and normal β-amyloid.Alzheimers Res Ther. 2019 12 05; 11(1):99.AR