and Kelly Del Tredici1
Zentrum f. Biomed. Forschung AG Klinische Neuroanatomie/Abteilung Neurologie, Universität Ulm, Ulm, Germany
The present exposition of the AD-related pathological process rests upon some basic assumptions:
The AD process is a uniquely human condition involving specific nerve cell types of the CNS and it progresses along a biological continuum.
Tau pathology with or without Aβ deposition in cognitively intact individuals are not ‘normal age changes’ but represents a premorbid state.
AD-associated pathology causes a functional decline of vulnerable nerve cells rather than global neuronal loss.
Physical (i.e., synaptic) contacts between susceptible projection cells of involved regions play a key role in the pathogenesis of sporadic AD.
The AD process is not Aβ-dependent.
Because AD is a disorder of the human CNS for which no truly suitable animal model exists (Reid and Evans 2013), the ongoing trend away from autopsy-controlled diagnosis is irresponsible, unwarranted, and even detrimental to the AD field. Many of the unsolved questions and issues related to the neuropathology of AD can be addressed effectively in tissue from autopsy-controlled prospective studies performed on cohorts that include individuals from normal aging populations (Morrison and Hof 1997; Nelson et al. 2011). Among those requiring answers, several mentioned in this monograph are summarized here as follows:
Why does the AD-related pathological process develop almost exclusively within vulnerable nerve cell types of the CNS, although neurons in the PNS and ENS have normal tau and the amyloid precursor protein (APP)?
Do molecular and conformational changes make oligomeric tau toxic to crucial cellular functions?
Does the induction of the pathological protein misfolding process entail mechanisms and pathways that are different from those regulating its propagation?
Can conformational variants influence the degree of tau pathogenicity as well as the rate of the pathological process?
Why does non-argyrophilic abnormal tau material develop in both the axon and somatodendritic compartment of vulnerable nerve cell types?
Why does argyrophilic abnormal tau material only develop in the cell soma (NFTs) and dendrites (NTs) but not in the axon of involved neurons?
Which neuronal types in the human CNS produce and secrete Aβ?
At which specific cellular sites is Aβ released into the ISF?
How do Aβ deposits develop from expansive (i.e., cloud-like) and unsharply defined structures into compact primitive or cored plaques?
Why do Aβ plaques not develop in the pallidum, lateral tuberal nuclei, and lateral mamillary nucleus?
Why does the spinal cord develop tau pathology and CAA without Aβ plaques?
Can differences in the individual ‘reserve capacity’ influence the rate of the pathological process?
The AD-related pathological process can begin in childhood or in young adulthood but it exists in nearly every individual and continues into old age. The topographic distribution of the pathology reveals that the process follows a stereotypic pattern. The rate of progression, however, shows considerable inter-individual differences, and this explains why only a relatively small number of persons become demented. Most individuals do not develop a sufficient degree of AD-associated pathology during the course of a lifetime to manifest a clinically recognizable symptomatology of MCI or AD.
In addition to neuroimaging and biomarker improvement, more refined diagnostic instruments developed to acquire data pertaining to dysfunctions of the diffusely projecting nuclei would help to identify the presence of the pathological process closer to the time of its inception. At present, the clinical diagnosis of AD is usually made only when the pathological process has reached NFT stage V or VI, which is much too late.
Initiation of therapeutic interventions during the end-stages of the AD pathological process is futile because available anti-dementia drugs do not arrest, reverse, or even modify the tau and Aβ pathologies (Molnar et al. 2009; Maarouf et al. 2010). Most efforts at developing effective strategies aimed at preventing abnormal protein aggregation, reducing Aβ/tau levels, or removing the protein accumulations have been unsuccessful (Bulic et al. 2010; Gong et al. 2010; Iqbal and Grundke-Iqbal 2011; Wagner et al. 2013; Lou et al. 2014). Mechanisms still to be elucidated are, for example, not only those of variant tau conformers (Sanders et al. 2014) but also those influencing the degree of myelination of vulnerable projection neurons (Ullén 2009; Fields 2011). Nerve cell activity provides the physiological stimulus for oligodendroglia cells to produce and sustain the myelin sheath (Ullén 2009). The more active the nerve cell, the thicker the myelin sheath becomes during the differentiation process and, presumably, the better protected the neuron is against the AD process. As such, it makes sense to seek means of slowing the rate at which the pathological process progresses, including augmentation of the individually variable ‘cognitive reserve’ (Savica and Petersen 2011; Erickson et al. 2012; Meng and D’Arcy 2012; Barulli and Stern 2013; Serrano-Pozo et al. 2013; Xu et al. 2014) because even a slight delay in the rate of progression would mean a sharp decrease in the number of patients crossing the clinical threshold to MCI and AD. The aim would be to alter the postnatally ongoing myelination process to such an extent that quantifiable increases in the degree of myelination would correspond to greater resistance on the part of vulnerable nerve cells (Stern 2002, 2009; Bengtsson et al. 2005; Schlaug et al. 2003; Draganski and May 2008; Craik et al. 2010; Gärtner et al. 2013; Freedman et al. 2014).