Detecting Early Cognitive Decline in Alzheimer's Disease with Brain Synaptic Structural and Functional Evaluation

Abstract

Early cognitive decline in patients with Alzheimer's (AD) is associated with quantifiable structural and functional connectivity changes in the brain. AD dysregulation of Aβ and tau metabolism progressively disrupt normal synaptic function, leading to loss of synapses, decreased hippocampal synaptic density and early hippocampal atrophy. Advances in brain imaging techniques in living patients have enabled the transition from clinical signs and symptoms-based AD diagnosis to biomarkers-based diagnosis, with functional brain imaging techniques, quantitative EEG, and body fluids sampling. The hippocampus has a central role in semantic and episodic memory processing. This cognitive function is critically dependent on normal intrahippocampal connections and normal hippocampal functional connectivity with many cortical regions, including the perirhinal and the entorhinal cortex, parahippocampal cortex, association regions in the temporal and parietal lobes, and prefrontal cortex. Therefore, decreased hippocampal synaptic density is reflected in the altered functional connectivity of intrinsic brain networks (aka large-scale networks), including the parietal memory, default mode, and salience networks. This narrative review discusses recent critical issues related to detecting AD-associated early cognitive decline with brain synaptic structural and functional markers in high-risk or neuropsychologically diagnosed patients with subjective cognitive impairment or mild cognitive impairment.

Keywords: ATN biomarkers; Alzheimer’s disease; cognitive decline; functional connectivity; hippocampus; large-scale networks; memory; structural connectivity; synaptic density; synaptic function.

Figure 1

Nerve cell. Abbreviation: (AP with red arrows) direction of action potential transmission.

Figure 2

The tripartite synapse. Abbreviations: AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor), NMDAR (N-methyl-D-aspartate receptor, tetrameric protein with two GluN1 subunits and two GluN2 (A-D) subunits, a type of L-glutamate receptor). The AP with red arrow represents the direction of action potential transmission.

Figure 3

Chemical synapse (left) and electrical synapse (right). The AP with red arrows represents the direction of action potential transmission.

Figure 4

Toxic soluble AβO and truncated, misfolded, and hyperphosphorylated toxic tau oligomers are the critical drivers of synapse loss and neuronal death in AD. The transformation of normal tau to its toxic oligomers is promoted by increased GSK3β activity; GSK3β inhibits Aβ42 degradation and promotes Aβ42 production by stimulating β- and γ-secretase activity. Increased TNFα and IFITM levels also promote high GSK3β activity. Ageing-associated chronic low-grade sterile inflammation and reduced reelin synthesis facilitate Aβ metabolism dysregulation. The secondary nucleation processes further accelerate the conversion of Aβ42 peptides to toxic AβOs at the AβO, protofibril and fibril nucleation sites. Abbreviations: ⇑ (increased), ⇓ (decreased), + (stimulating effect), − (inhibitory effect), - - - - (dashed lines denote internalised molecules), 99-CTF (99-amino acid membrane-bound C-terminal fragment), Aβ42 (an amyloid β peptide with 42 amino acid residues), AβO (amyloid β oligomers), AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor), APP (amyloid precursor protein), AβF (amyloid β fibril), AβPF (amyloid β protofibril), APOE (apolipoprotein E), APOER2 (reelin apolipoprotein E receptor 2), DAB1 (DAB adaptor protein 1), DAB1-P (phosphorylated DAB adaptor protein 1), GSK3β (glycogen synthase kinase 3β), IDE (insulin-degrading enzyme), IFITM (interferon-induced transmembrane protein), mGLUR5 (metabotropic glutamate receptor 5), NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells), NMDAR (N-methyl-D-aspartate receptor), NS (nucleation site), PI3K (phosphoinositide 3-kinase), PKB (protein kinase B), Tau-P (truncated, misfolded, and hyperphosphorylated tau), TNFα (tumour necrosis factor α).

Figure 5

A simplified summary of hippocampal connections in mammals. The dentate gyrus and subfields CA1 to CA3 are functionally and anatomically distinct hippocampal subunits.