Near-Lifespan Tracking of Cerebral Microvascular Degeneration in Aging to Alzheimer’s Continuum

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting millions of people worldwide and is currently incurable. As the population ages, AD and related dementia are becoming the biggest epidemic in medical history: the number of people aged 65 and older with AD is projected to increase between two- and three-fold by 2050. Imaging and biomarker studies suggest that the pathophysiological processes of AD begin more than a decade before the diagnosis of dementia, opening the possibility of early, preemptive prediction. For accurate prediction, it is important although challenging to fully understand how multiple etiologies and age-related prodromal processes contribute to the onset of Alzheimer’s continuum, across a long period comparable to the lifespan. Addressing this challenge was one of the overarching transformative concepts at the 2015 AD Research Summit, “to develop new programs on systems biology and integrative physiology to gain a deeper understanding of the complex biology of the disease.” Among other factors, cerebral microvascular degeneration (CMD) may play a key role in the onset and development of Alzheimer’s continuum, potentially prior to, along with, or independently of the beta-amyloid (Aβ) accumulation. Despite its importance for early detection and as a therapeutic target for early intervention, it is unknown whether CMD is a causal factor for AD pathogenesis or an early consequence of multifactorial conditions that lead to AD at a later stage. Here, this Viewpoint suggests that we should fill two critical knowledge gaps: (1) Temporal relationships between various CMDs and other key factors before/during/after the onset of Alzheimer’s continuum have not been established; (2) Little integrative study down to the capillary vessel level has been conducted on how individual defects in various microvascular structural and flow properties distinctly correlate with and/or contribute to neuronal degeneration. As the first step toward filling these gaps, I propose utilizing recent advances in microscopic imaging and image analysis techniques to longitudinally track a comprehensive set of CMDs over the lifespan in model animals, along with Aβ, tau, neuronal degeneration, and cognitive impairment when possible.