. Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer's pathology. Nat Commun. 2016 Nov 4;7:13249. PubMed.


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  1. The cholinergic hypothesis of AD has been a staple of the field for many years. This hypothesis was the result of the classic studies showing a loss of cholinergic neurons in the basal forebrain and a decrease of cortical cholinergic activity in AD (see review in Mufson et al., 2016). These findings lead to investigations of the connectivity of the basal forebrain cholinergic neurons, which were demonstrated to provide the major cholinergic innervation to the entire cortical mantle (Mesulam et al., 1983). By contrast, most cortical regions do not display reciprocal connections with the cholinergic basal forebrain (Ch4), with a few exceptions including the entorhinal cortex (Mesulam et al., 1984), a component of the tri-synaptic medial temporal lobe memory circuit that degenerates early during the onset of AD. Since cholinergic pharmacotherapy has not yet resulted in consistent improvements in cognition, the cholinergic hypothesis has fallen out of favor in the AD community. Recent findings in molecular biology suggest that AD pathology spreads via a trans-synaptic mechanism between anatomically and functionally interconnected neuron populations (Clavaguera et al., 2009; de Calignon et al., 2012). However, how the interactive temporal sequence of disease pathology associates with well-defined afferent and efferent connectional pathways during initial stages of the disease remains unclear. Although this concept has been studied in rodent models of AD, the field is just beginning to apply imaging techniques to evaluate related phenomena during the onset of AD in humans. The subcortical Ch4 to entorhinal cortex (EC) projection system provides a human-based model to test such hypotheses. In their elegant article, Schmitz and colleagues demonstrate in a large cohort of age-matched older adults with a clinical diagnosis ranging from cognitively normal to MCI to AD, that Ch4 basal forebrain volume predicted longitudinal decreases in EC cortex degeneration but not vice versa. Data also provide evidence linking the Ch4 to EC degenerative sequence to memory dysfunction and showing that this process is dependent upon increased CSF amyloid neuropathology late in the disease process. The authors argue that Ch4 degeneration occurs early in non-demented elder people but it is not until EC volume reduction accompanies basal forebrain pathology that cognitive impairment appears.

    Of interest is the observation that abnormal Ch4 degeneration is clinically silent or not being detected by current neuropsychological tests in the early stages of AD. Together the data suggest that loss of basal forebrain afferent innervation to the EC induces pathology in this paralimbic cortical region. The factors that drive this Ch4 to EC putative trans-synaptic degenerative sequence during the progression of human AD remains unknown. Since Ch4 neurons display tau-positive neurofibrillary tangles (NFTs), it is possible that a toxic form of tau is transported to the EC, which activates a disease process resulting in cellular dysfunction as the disease progresses. Such a temporal course would require an extended preclinical period.

    Since basal forebrain cellular degeneration occurs prior to EC dysfunction, it is imperative to determine what triggers basal forebrain degeneration early in the disease. Given that the survival of Ch4 neurons depends upon the neurotrophin nerve growth factor (NGF) and its high (trkA) and low affinity (p75NTR) receptors, and that NGF dysregulation induces NFTs, impaired trophic factor support may initiate NFT formation in Ch4 neurons (Mufson et al., 2016). Once tau aggregation occurs in Ch4 neurons, it can then be transported via anterograde transport to anatomically connected brain regions such as the EC. The transport of aggregated tau allows this putative toxic moiety to be incorporated into EC neurons and then be transported to the hippocampus and onward over years of disease, resulting in more severe cognitive decline. On the other hand, Ch4 and EC neurons may be selectively vulnerable to a degenerative intraneuronal process(es), which is activated at different stages of the disease process and is not trans-synaptic dependent. Since CFS amyloid levels seem to play a role late in AD, amyloid may not be necessary or sufficient for the initiation of cellular dysfunction during the early phases of the disease. Neuropathological evidence suggests that other subcortical pathways (e.g., the brainstem locus coeruleus noradrenergic forebrain projection system) are affected either before or after Ch4 degeneration. Whether subcortical pathological spread is a common feature in AD remains an intriguing question. The work of Schmitz and co-workers adds more fuel to the fire that the trans-synaptic transport of a toxic prion-like protein plays a pivotal role in the spread of AD pathology across a wide range of subcortical anatomically and functionally linked brain regions. Finally, these data will reinvigorate interest in the cholinergic hypothesis of AD and suggest a polypharmaceutical approach for the treatment of the disease, which follows a temporal time course.


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    . Molecular and cellular pathophysiology of preclinical Alzheimer's disease. Behav Brain Res. 2016 Sep 15;311:54-69. Epub 2016 May 13 PubMed.

    View all comments by Elliott Mufson
  2. The exact temporal sequence of events underlying sporadic AD is still hotly contested. This is an important question because it holds the key to understanding the mechanism of pathogenesis and for identifying critical intervention targets. It is generally accepted that amyloid deposition precedes neurofibrillary tangle (NFT) formation, that cortical NFTs initially emerge in the entorhino-hippocampal complex, and that the resultant neurodegeneration of the medial temporal lobe is responsible for the memory loss. It is also accepted that the Ch4 (i.e., cholinergic) neurons of the nucleus basalis become subjected to early NFT formation. The resultant neurodegeneration of Ch4 causes the cortical cholinergic denervation that has become the target of the first effective pharmacologic intervention in AD. However, the causal and temporal relationship between the cholinergic lesion and the other two ingredients of AD pathology remain unclear. Many interactions have been proposed but none have been convincing.

    In their elegant paper based on ADNI data, Schmitz and Spreng use longitudinal structural MRI, amyloid imaging, and cognitive assessment to construct a model of sequential interactions among molecular markers of AD, sites of atrophy, and the onset of memory impairment. They conclude that atrophy of the nucleus basalis precedes and presumably drives the atrophy of the entorhinal cortex. They also conclude that the memory loss does not emerge until neurodegeneration encompasses both the nucleus basalis and entorhinal cortex (EC). To quote the authors, “…our findings strongly suggest that a subcortical-cortical pathologic spread from Ch4 to EC defines the earliest link in the predictive pathological staging of AD.”

    As in all other attempts to map the temporal sequence of events in AD, these results need to be interpreted cautiously. For one, although the region of the nucleus basalis shown in Figure 1a was rigorously defined according to existing probabilistic maps of Ch4, it is likely to include not only cholinergic cell bodies (i.e., the Ch4) but also components of the ansa peduncularis, the ansa lenticularis and several non-cholinergic cell populations. Is the Schmitz and Spreng temporal (and presumably causal) sequence specifically mediated by a cholinergic mechanism? This question can be addressed through the use of cholinergic ligands and tau PET imaging. The former would determine whether the atrophy in the region of the nucleus basalis is also associated with cortical cholinergic denervation whereas the latter would help to determine whether the atrophy is associated with NFT within Ch4 neurons. The second caveat relates to the obvious limitation of using correlation to infer causality, even when the statistical analyses are rigorous and innovative. This is where animal models would be essential. Does a lesion of Ch4 lead to entorhinal neurodegeneration?

    Once considered the prime mover of the pathologic cascade, the cholinergic component of AD has gradually moved away from the limelight. The Schmitz and Spreng paper may reverse this trend and increase the enthusiasm for developing newer and more effective cholinomimetic treatments.

    View all comments by Marsel Mesulam

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