Aβ42/Aβ40 and Aβ42/Aβ38 Ratios Are Associated with Measures of Gait Variability and Activities of Daily Living in Mild Alzheimer’s Disease: A Pilot Study

Abstract

Gait disturbances are some of the earliest changes in dementia and their monitoring presents an opportunity for early diagnosis. The exact relationship between gait and well-established biomarkers of Alzheimer’s disease (AD) remains to be clarified. In this study we compared gait-related measures with cerebrospinal fluid (CSF) markers of AD pathology. We recruited seventeen participants with mild AD in a multi-site study and performed gait assessment as well as lumbar punctures to obtain CSF. CSF Aβ42/Aβ40 and Aβ42/Aβ38 correlated positively with measures of variability (step time and step length) in the clinic-based assessments. This was driven by a negative relationship between gait variability and Aβ40 and Aβ38 but not Aβ42.The amyloid ratios and gait variability measures were also associated with more severe functional impairment. We interpret these data as an indication that increasing amyloid production (i.e., increasing Aβ40 and Aβ38) is associated with diminishing cognitive-motor control of gait. These preliminary results suggest that the two amyloid ratios may be a marker of the earliest disturbances in the interplay between cognitive and motor control which characterize dementia.

Diagnosis of Alzheimer’s disease utilizing amyloid and tau as fluid biomarkers

“…Another derivative of Aβ that can act as a potential AD biomarker is Aβ40, which is the most abundant isoform present in the CSF. Although there are no substantial changes in the levels of CSF Aβ40 in AD patients and the CSF concentration of Aβ40 does not correlate with amyloid deposits in the brain, a significant decrease can be seen when amyloidogenic peptide levels are compared by the CSF Aβ42/Aβ40 ratio [15][16][17][18][19][20][21][22] . This ratiometric analysis is more reliable than solely observing Aβ42 concentrations because it compensates for intraindividual fluctuations within AD patients.…”

“…Of these fragmented peptides, Aβ38 tends to exhibit increased concentrations in patients' CSF. Thus, the ratio of Aβ42/Aβ38 has been shown to positively correlate with imaging biomarkers and provide a stronger association with AD pathogenesis than CSF Aβ42 alone 15,[22][23][24][25][26] . A recent study involving three different cohorts, established the efficacy of these ratiometric analyses in accurately diagnosing and distinguishing AD from other forms of dementia 15 .…”

“…Aβ aggregates have also been discovered in the ocular region of AD patients, namely, the lens [76][77][78] and retina 22,[79][80][81][82] . The human eye, which permits the noninvasive observation of disease pathology mechanisms that may be similarly reflected in the afflicted brain, is an extension of the central nervous system and shares structural similarities with the brain.…”

“…Commercial ELISA CSF Aβ42 has an inverse correlation with amyloid burden, as measured by PIB-PET [10][11][12][13][14] Commercial immunoassays Ratios of CSF Aβ42 to other Aβ isoforms (Aβ40 or Aβ38) are strongly correlated with accurate AD diagnosis [15][16][17][18][19][20][21][22][23][24][25][26]…”

Flexible nanopillar-based immunoelectrochemical biosensor for noninvasive detection of Amyloid beta

“…The human eye is anatomically closer to the brain than other human organs; Aβ can be relatively easily obtained there without any surgical procedure. To date, few methods including enzyme-linked immunosorbent assay, mass spectrometry, surface plasmon resonance, surface-enhanced Raman spectroscopy, and nanomaterial-based imaging techniques have been developed and proposed to detect Aβ species [17][18][19][20][21][22][23]. Based on the affinity sensing principle with aptamer and antibody, the researches for Aβ analysis based on the minimized detection principle on biosensing chip as a point-of-care testing (POCT) device were demonstrated [24][25][26].…”