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Review
. 2023 Jul:150:105192.
doi: 10.1016/j.neubiorev.2023.105192. Epub 2023 Apr 20.

New perspectives on the basal forebrain cholinergic system in Alzheimer's disease

Anne S Berry  1 , Theresa M Harrison  2
Affiliations
Review

New perspectives on the basal forebrain cholinergic system in Alzheimer's disease

Anne S Berry et al. Neurosci Biobehav Rev. 2023 Jul.

Abstract

The basal forebrain cholinergic system (BFCS) has long been implicated in age-related cognitive changes and the pathophysiology of Alzheimer's disease (AD). Limitations of cholinergic interventions helped to inspire a shift away from BFCS in AD research. A resurgence in interest in the BFCS following methodological and analytical advances has resulted in a call for the BFCS to be examined in novel frameworks. We outline the basic structure and function of the BFCS, its role in supporting cognitive and affective function, and its vulnerability to aging and AD. We consider the BFCS in the context of the amyloid hypothesis and evolving concepts in AD research: resilience and resistance to pathology, selective neuronal vulnerability, trans-synaptic pathology spread and sleep health. We highlight 1) the potential role of the BFCS in cognitive resilience, 2) recent work refining understanding about the selective vulnerability of BFCS to AD, 3) BFCS connectivity that suggests it is related to tau spreading and neurodegeneration and 4) the gap between BFCS involvement in AD and sleep-wake cycles.

Keywords: Acetylcholine; Amyloid; Attention; Basal forebrain; Learning; Memory; Reserve; Resilience; Tau.

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Conflict of interest statement

Competing Interests The authors have no competing interests to declare.

Figures

Figure 1.
Figure 1.
History of cholinergic and amyloid hypotheses of Alzheimer’s disease. We present a timeline illustrating the factors contributing to the evolution of the cholinergic hypothesis and the amyloid hypothesis. We highlight their strengths and limitations, and suggest areas ripe for further theoretical development. AD = Alzheimer’s disease; ChAT = choline acetyltransferase; BF = basal forebrain; A/T/N = amyloid/tau/neurodegeneration; MTL = medial temporal lobe; BFCS = basal forebrain cholinergic system
Figure 2.
Figure 2.
Role of the cholinergic basal forebrain system in Alzheimer’s disease. We highlight the central role of the basal forebrain cholinergic system in supporting optimal cognitive performance and brain health, and highlight its selective vulnerability and contribution to resistance and resilience to Alzheimer’s disease (AD). ACh = acetylcholine; TrkA = tropomyosin receptor kinase A; NGF = nerve growth factor; REM = rapid eye movement; APP = amyloid-beta precursor protein
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