Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis

Abstract

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.

Machine learning identified an Alzheimer’s disease-related FDG-PET pattern which is also expressed in Lewy body dementia and Parkinson’s disease dementia

“…This is in line with the recent observation that vascular changes precede metabolic changes 44 . However, it should be noted that there were also more false positives in perfusion SPECT, i.e., 40% of stable MCI were designated as AD in perfusion SPECT while only 24% were designated as AD in FDG-PET.…”

Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers

“…Indeed, the high cost and low practical routine administration of disease modifiers will make these drugs indicated in a portion of all AD patients even lower than the 20% currently treated with anticholinesterase inhibitors. Finally, the new diagnostic or theranostic biomarkers that the very active research in the field is likely to bring out in the next years 94 will also need to undergo the same 5-phase process described in this paper. The availability of the virtuous example of the core biomarkers will represent a significant facilitator.…”

A clinicopathological approach to the diagnosis of dementia

“…In fact, emerging data-driven models suggest that vascular disease and dysregulated inflammation are early risk factors in the pathophysiological cascade leading to AD 55 . The mechanisms of vascular disease — especially small vessel disease (SVD) — and AD-related neurodegeneration might be intricately interrelated 56 .…”