In the hunt for the elusive origins of Alzheimer’s disease, researchers may have to dig deeper than ever before. Deeper into the brain, that is. According to a November 4 report in Nature Communications, the basal forebrain, a subcortical structure that houses cholinergic neurons, falls prey to neurodegeneration before the entorhinal cortex—the region commonly considered the disease’s first victim. Researchers led by Nathan Spreng of Cornell University in Ithaca, New York, tapped into longitudinal imaging, biomarker, and cognitive data from the Alzheimer’s Disease Neuroimaging Initiative to track the pathological chain of events leading to AD. They report that the forebrain had already started shriveling in people who had abnormal levels of Aβ42 in their cerebrospinal fluid but were still cognitively normal. In contrast, the entorhinal cortex only began to shrink once a person started having memory problems as well.
The prevailing view in the field is that the entorhinal cortex—a region nestled next to the hippocampus—degenerates first (see Braak et al., 2006). Previous studies have suggested that following diffuse Aβ deposition broadly in the neocortex, incipient tau tangles in the EC somehow transform into neuronal killers there and in the hippocampus, and then ultimately move out into the neocortex as well (see Mar 2016 news; Aug 2016 news).
However, a different line of research has for many years focused on early degeneration in the basal forebrain, specifically in a hub of cholinergic neurons called the nucleus basalis of Meynert (NbM) (see Mesulam et al., 2004; Sassin et al., 2000; Grothe et al., 2010; and Kilimann et al., 2014).
Axons from these NbM-dwelling cholinergic neurons spread far and wide to form myriad connections with neurons throughout the cortex. These neurons are the main source of acetylcholine (ACh) in the brain. NbM neurons receive input from the nearby EC, and researchers think the bond between these two regions allows people to focus on and remember new or important events, while relegating familiar or irrelevant events to the background (see Egorov et al., 2002).
A previous study using cross-sectional ADNI data had linked NbM degeneration to Aβ accumulation (as assessed by amyloid PET) in preclinical AD (see Grothe et al., 2014), but the longitudinal data necessary to pin down when this degeneration occurs was lacking. Along with Spreng, first author Taylor Schmitz of the University of Cambridge in England now took advantage of a larger body of ADNI data to time basal forebrain degeneration in the span of AD progression.
The cohort analyzed consisted of 434 older adults who underwent brain imaging and cognitive tests at baseline, and again after one and two years. Of these participants, 150 were healthy, 103 had mild cognitive impairment but never progressed to AD, 84 had MCI and did progress to AD, and 97 had AD throughout the two-year time course.
Using voxel-based morphometry analysis of MRI data to measure the size of brain regions, the researchers first determined that both the NbM and the EC shrank with clinical progression of AD. But which region took the first hit? To find out, the researchers tracked how the size of each affected the other over time. They found that a small NbM at baseline—indicative of prior degeneration—correlated strongly with a shrinking EC one and two years later. The opposite was not true: Smaller baseline EC volumes did not portend a shrinking NbM at later time points. Furthermore, small baseline NbM volumes did not correlate with degeneration in other regions of the brain, indicating that the relationship between NbM and EC degeneration was unique.
To place this neurodegenerative relationship within the context of AD pathology, the researchers incorporated CSF Aβ42 measurements that were available for 216 participants. Based on CSF, they designated each participant as Aβ-positive or -negative. Among cognitively normal people, who were categorized as “controls” at enrollment, the researchers found significantly more NbM degeneration in people who were Aβ-positive than in those who were Aβ-negative, but they had no degeneration in the EC. This implied that in the presymptomatic stage of AD, degeneration already occurs in the NbM but not yet in the EC. EC degeneration became apparent once cognitive symptoms surfaced: People with MCI and low CSF Aβ who had not progressed to AD had modest EC degeneration, while people with progressive MCI or with AD lost as much EC tissue.
To define the relationship between degeneration in the NbM and EC, the researchers did mediation analyses, which uses multiple regression to test how one variable depends on another. A temporal cascade emerged: In the presence of Aβ pathology, NbM degeneration led to EC degeneration, which triggered memory problems.
Marsel Mesulam of Northwestern University in Chicago thought the study may reinvigorate the field’s interest in the cholinergic system, which has faded from view in recent years. As with any study that leans on statistics to infer causality from correlation, Mesulam urged caution in interpreting the results. He said future studies will need to more carefully tie this NbM degeneration to cholinergic neurons, because structural MRI makes it difficult to exclude the involvement of nearby noncholinergic neurons. This task could be accomplished by PET to single out cholinergic neurons, along with tau PET as a proxy for their neurodegeneration, he wrote.
Where does Aβ fit into the picture? After all, the researchers only observed NbM degeneration in people with abnormal CSF Aβ levels. Michel Grothe of the German Center for Neurodegenerative Diseases in Rostock pointed out that NbM cholinergic neurons—dubbed the “drain of the brain”—may take on Aβ from their numerous cortical contacts and that could be toxic for the cells (see Ovsepian and Herms, 2013).
However, Grothe noted another, albeit controversial, chain of events, namely that cholinergic degeneration sets off Aβ pathology in cortical neurons. Previous reports indicated that cholinergic lesions in rodents triggered Aβ accumulation in connected cortical regions (see Roher et al., 2000). In people with AD, researchers uncovered more amyloid plaques in regions with cholinergic connections, and observed cholinergic dysfunction in preclinical AD (see Arendt et al., 1985; and Potter et al., 2011). In theory, degeneration in the NbM could initiate Aβ pathology in the neocortex, Grothe speculated.
Researchers proposed that the NbM could be responsible for the spread of tau pathology as well. Years ago, Mesulam reported that tau tangles arose in these neurons prior to memory problems, and accumulated there as AD progressed (see Mesulam et al., 2004). Schmitz and others acknowledged the possibility that tau aggregates might spread transynaptically from the NbM to the EC, just as previous studies have indicated they can spread from the EC into the hippocampus and beyond (see Nov 2010 news; Feb 2012 news). Elliott Mufson of the Barrow Neurological Institute in Phoenix added that one possible trigger of tauopathy in cholinergic neurons could be misregulation of nerve growth factor signaling, which reportedly causes tangles to form there.
While “tau-first” theories are enticing, Grothe acknowledged that unlike a cholinergic lesion in a rodent, the process of AD in humans is a complex chain of interwoven events. Once Aβ pathology begins, for example, it could amplify degeneration in the NbM and subsequently, the EC.
Still other groups have proposed that degeneration starts even deeper in the brain—in the locus coeruleus of the brain stem, which has extensive connections with the NbM (see Dec 2010 webinar). Carefully tracking cholinergic degeneration and amyloid accumulation via PET imaging would be a way to unravel this relationship in future studies, Grothe said.—Jessica Shugart
- Tau PET Aligns Spread of Pathology with Alzheimer’s Staging
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