Is sporadic Alzheimer′s disease a developmental disorder?

Abstract

Alzheimer 0 s disease (AD) is a neurodegenerative disorder of higher age that specifically occurs in human. Its clinical phase, characterized by a decline in physiological, psychological, and social functioning, is preceded by a long clinically silent phase of at least several decades that might perhaps even start very early in life. Overall, key functional abilities in AD patients decline in reverse order of the development of these abilities during normal childhood and adolescence. Early symptoms of AD, thus, typically affect mental functions that have been acquired only during very recent hominid evolution and as such are specific to human. Neurofibrillar degeneration, a typical neuropathological lesion of the disease and one of the most robust pathological correlates of cognitive impairment, is rarely seen in non-primate mammals and even non-human primates hardly develop a pathology comparable to those seen in AD patients. Neurofibrillar degeneration is not randomly distributed throughout the AD brain. It preferentially affects brain areas that become increasingly predominant during the evolutionary process of encephalization. During progression of the disease, it affects cortical areas in a stereotypic sequence that inversely recapitulates ontogenetic brain development. The specific distribution of cortical pathology in AD, moreover, appears to be determined by the modular organization of the cerebral cortex which basically is a structural reflection of its ontogeny. Here, we summarize recent evidence that phylogenetic and ontogenetic dimensions of brain structure and function provide the key to our understanding of AD. More recent molecular biological studies of the potential pathogenetic role of a genomic mosaic in the brains of patients with AD might even provide arguments for a developmental origin of AD.

Loss-of-Huntingtin in Medial and Lateral Ganglionic Lineages Differentially Disrupts Regional Interneuron and Projection Neuron Subtypes and Promotes Huntington's Disease-Associated Behavioral, Cellular, and Pathological Hallmarks

“…Therefore, brain regions displaying the earliest and greatest vulnerabilities to cell death in HD are likely the consequence of synergy between selective developmental insults within discrete brain regions (first hit) and additional postdevelopmental insults (second hit). Overall, our findings add to an emerging number of studies also implicating regional-and neuronal-specific maturational deficits in the pathogenesis of adult-onset neurological disorders, including dystonia, spinocerebellar ataxia type 1, and Alzheimer's disease (Pappas et al, 2015;Arendt et al, 2017;Edamakanti et al, 2018).…”

Rationale for the development of an Alzheimer’s disease vaccine

“…The Aβ passive immunotherapy clinical trials may have failed because they were too late in the disease process, but another possible reason for failure is that the entire approach of reducing Aβ might be wrong. There is evidence for many potentially causative pathways in AD, and many facts contradicting a central etiological role of Aβ, [82][83][84][85] including the following:…”

Developmental suppression of forebrain trkA receptors and attentional capacities in aging rats: A longitudinal study

“…During the progression of sporadic AD, cortical areas are affected in a stereotypic sequence that recapitulates ontogenetic brain development (Arendt et al, 2017). Although the available evidence supports the idea that perhaps reduced trophic support during ontogenetic development and maturation of the cortical cholinergic input system may escalate into MCI and AD (Sanchez-Ortiz et al, 2012; Sarter and Bruno, 2004), the premise that developmental abrogation of BF trkA signaling would accelerate age-related decline in the cholinergic system and cognitive capacities has never been tested.…”