Claire Sweeney and Ian Murray, PhD

Introduction. Alzheimer’s disease (AD) is a neurodegenerative disease in which tau and amyloid proteins misfold to form pathological neurofibrillary tangles and amyloid plaques.⁶ There are an estimated 50 million AD patients worldwide and this number is expected to triple by 2050 as the increasing population ages.^6,7 Features of AD patients include loss of episodic memory and brain atrophy.⁷ By the time a clinical diagnoses is made, much of the irreversible brain damage has already occurred. Biomarkers used to study Alzheimer’s include those for plaque deposition (CSF Aβ₄₂ and PET amyloid imaging), and those for neurodegeneration (CSF tau, and FDG-PET).⁶ Appearance of CSF amyloid beta (Aβ) early in AD presentation suggests that it may have the highest efficacy in predicting AD.⁷ Methods. In this review several publications were analyzed. In the first, linear mixed models were used to compare within‐person rates of change over 7 years across diagnostic groups and to evaluate the association of CSF biomarkers as predictors of magnetic resonance imaging (MRI) biomarkers.¹ The second study analyzed cortical and subcortical gray matter pathological loss at two years in 12 early onset AD patients and 19 controls.² In the third study, CSF Aβ₄₂ and Aβ₄₀ were measured in 211 subjects with rapidly progressive dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies, and mixed pathologies.³ Finally, 118 participants with a range of cognitive impairments, including AD, underwent 158 resting state functional MRI sessions (rsfMRI), Aβ-PET and Mental State Examination measurements.⁴ Results. Baseline concentrations of CSF Aβ₄₂ decrease and continue to decrease following cognitive impairment and correlate with aggregated brain amyloid deposits.¹ In early onset AD patients, CSF Aβ₄₂ was found to be predictive of cortical thinning while t-tau/NfL was predictive of subcortical atrophy in both early and late onset AD patients.² The ratio CSF Aβ₄₂/Aβ₄₀ has shown better correlation with amyloid-PET than Aβ₄₂ alone and can better distinguish between cases with versus without AD pathology better than CSF Aβ₄₂.³ Mechanistically, sleep is related to an elevated blood oxygen level-dependent (BOLD) signal, and BOLD signal changes related to changes in CSF Aβ₄₂, suggesting a coupling between the two measures. In AD disease conditions, the BOLD signal and CSF become uncoupled.⁴ Conclusions. CSF Aβ₄₂ correlates with cognitive impairment, Aβ plaque, and gross pathology generally more effectively in AD patients compared to other biomarkers. Better knowledge of AD biomarkers is an important part of being able to study future disease reversal and preventions. Ultimately lack of sufficient sleep is an important risk factor that correlates with AD biomarkers.

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3. Baiardi S, Abu-Rmeileh S, et al. Antemortem CSF Aβ42/40 ratio predicts Alzheimer’s disease pathology better than Aβ42 in rapidly progressive dementias. Annals of Clinical and Translational Neurology 2018;6(2): 263-273.
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