The dynamics of biomarkers across the clinical spectrum of Alzheimer’s disease

Abstract

Background: Quantifying changes in the levels of biological and cognitive markers prior to the clinical presentation of Alzheimer's disease (AD) will provide a template for understanding the underlying aetiology of the clinical syndrome and, concomitantly, for improving early diagnosis, clinical trial recruitment and treatment assessment. This study aims to characterise continuous changes of such markers and determine their rate of change and temporal order throughout the AD continuum. Methods: The methodology is founded on the development of stochastic models to estimate the expected time to reach different clinical disease states, for different risk groups, and synchronise short-term individual biomarker data onto a disease progression timeline. Twenty-seven markers are considered, including a range of cognitive scores, cerebrospinal (CSF) and plasma fluid proteins, and brain structural and molecular imaging measures. Data from 2014 participants in the Alzheimer's Disease Neuroimaging Initiative database is utilised. Results: The model suggests that detectable memory dysfunction could occur up to three decades prior to the onset of dementia due to AD (ADem). This is closely followed by changes in amyloid-β CSF levels and the first cognitive decline, as assessed by sensitive measures. Hippocampal atrophy could be observed as early as the initial amyloid-β accumulation. Brain hypometabolism starts later, about 14 years before onset, along with changes in the levels of total and phosphorylated tau proteins. Loss of functional abilities occurs rapidly around ADem onset. Neurofilament light is the only protein with notable early changes in plasma levels. The rate of change varies, with CSF, memory, amyloid PET and brain structural measures exhibiting the highest rate before the onset of ADem, followed by a decline. The probability of progressing to a more severe clinical state increases almost exponentially with age. In accordance with previous studies, the presence of apolipoprotein E4 alleles and amyloid-β accumulation can be associated with an increased risk of developing the disease, but their influence depends on age and clinical state. Conclusions: Despite the limited longitudinal data at the individual level and the high variability observed in such data, the study elucidates the link between the long asynchronous pathophysiological processes and the preclinical and clinical stages of AD.

Detection of cognitive decline using a single-channel EEG with an interactive assessment tool

“…Theta also showed separation between low cognitive load and resting state. This is in line with previous reports of frontal Theta and Delta increase during cognitively demanding tasks [36]–[38]. This difference was not present in the senior population, supporting the notion that Theta and Delta may be indicative to cognitive decline and serve as a predictor of deterioration status, consistent with previous findings [10], [11].…”

Detection of Cognitive Decline using a Single-Channel EEG with an Interactive Assessment Tool

“…It was shown that cognitive decline is associated with high-risk for developing dementia, and Alzheimer's disease in particular [2], and that cognitive decline may be detected several years before dementia onset with known validated tools [39]. Dementia is gradually recognized as one of the most signi cant medical challenges of the future.…”

“…Absolute power values were converted to logarithm base 10 to produce values in dB. The following frequency bands were included: Delta (0.5-4 Hz), Theta (4-7 Hz), Alpha (8-15 Hz), Beta (16-31 Hz), and lower Gamma (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45). The BAFs analysis included the activity of the three selected biomarkers: ST4, A0, and VC9 normalized to a scale of 0-100.…”

Nanotechnology Therapy for Alzheimer′s Disease Memory Impairment Attenuation

“…These early signs of cognitive decline are followed by abnormal changes in Aβ1-42 cerebrospinal fluid (CSF) levels and concurrent hippocampal atrophy. More than a decade after the first signs of memory dys- function, brain hypometabolism develops, accompanied by abnormal changes in total and phosphorylated tau proteins levels [ 62 ]. These conclusions are consistent with the study of predicting time to dementia in AD patients participating in the Neuroimaging Initiative that reported early changes in verbal memory, CSF Aβ1–42, and hippocampal volume [ 63 ].…”