The Entorhinal Cortex‐hippocampal System Is an Early Target of Clusterin‐related Neurodegeneration in Alzeimer's Disease
Year: 2014
Type: article
Abstract: Both unbiased and targeted proteomic analyses suggest that clusterin (apolipoprotein-J/apoJ) is a biologically relevant biomarker of Alzheimer's disease (AD). Independently, several recent large-scale genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in the clusterin gene (CLU) to be associated with risk for AD. Converging evidence from these distinct approaches is beginning to reveal that the entorhinal cortex (ERC)-hippocampal system is the site of early functional and structural changes reflecting the role of clusterin in AD. To compare longitudinal differences in neuronal activity during aging between risk allele carriers and non-carriers of the AD risk variant SNP in CLU, rs11136000, we studied non-demented individuals (N=88) in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging (BLSA) who underwent serial 15 O-water PET imaging (baseline and up to 8 follow up scans). We also analyzed trajectories of cognitive decline among CLU risk allele carriers and non-carriers in individuals who remained cognitively normal (n = 599), as well as in those who subsequently converted to mild cognitive impairment or AD (n = 95). Cognitively normal carriers of the CLU risk allele showed significant and dose-dependent longitudinal increases in resting state rCBF in the hippocampus bilaterally. In cognitively normal individuals who eventually converted to mild cognitive impairment or AD, CLU risk allele carriers showed faster rates of decline in memory performance relative to non-carriers in the pre-symptomatic stages of disease progression. The AD risk variant CLU influences longitudinal changes in hippocampal activity in asymptomatic individuals and is associated with faster decline in memory performance in pre-symptomatic stages of disease progression. We discuss these findings in the light of our recent proteomic studies showing an association between plasma clusterin concentration and: a) thickness of the ERC in AD and b) extent of fibrillar A β deposition in the ERC in non-demented older individuals. We also consider complementary observations from recent studies showing an interaction between the cerebrospinal fluid (CSF) concentration of clusterin and rate of ERC atrophy in non-demented individuals. Together, these emerging findings provide compelling evidence that the ERC-hippocampal system is an early target of clusterin-associated neurodegeneration in AD.
Source: Alzheimer s & Dementia
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1999201935