Atrophy of hippocampal subfields relates to memory decline during the pathological progression of Alzheimer’s disease

The etiopathogenesis of late-onset Alzheimer’s disease (AD) is increasingly recognized as the result of the combination of the aging process, toxic proteins, brain dysmetabolism, and genetic risks. Although the role of mitochondrial dysfunction in the pathogenesis of AD has been well-appreciated, the interaction between mitochondrial function and genetic variability in promoting dementia is still poorly understood. In this study, by tissue-specific transcriptome-wide association study (TWAS) and further meta-analysis, we examined the genetic association between mitochondrial solute carrier family (SLC25) genes and AD in three independent cohorts and identified three AD-susceptibility genes, including SLC25A10, SLC25A17, and SLC25A22. Integrative analysis using neuroimaging data and hippocampal TWAS-predicted gene expression of the three susceptibility genes showed an inverse correlation of SLC25A22 with hippocampal atrophy rate in AD patients, which outweighed the impacts of sex, age, and apolipoprotein E4 (ApoE4). Furthermore, SLC25A22 downregulation demonstrated an association with AD onset, as compared with the other two transcriptome-wide significant genes. Pathway and network analysis related hippocampal SLC25A22 downregulation to defects in neuronal function and development, echoing the enrichment of SLC25A22 expression in human glutamatergic neurons. The most parsimonious interpretation of the results is that we have identified AD-susceptibility genes in the SLC25 family through the prediction of hippocampal gene expression. Moreover, our findings mechanistically yield insight into the mitochondrial cascade hypothesis of AD and pave the way for the future development of diagnostic tools for the early prevention of AD from a perspective of precision medicine by targeting the mitochondria-related genes.

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Adult lifespan effects on functional specialization along the hippocampal long axis

Bowman,

Charles,

Birr

2024

Preprint

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There has been increasing attention to differences in function along the hippocampal long axis, with posterior regions proposed to have properties that are well suited to representing fine-grained details and coarser representations in anterior regions. Whether long axis functional specialization persists into older age is not known, despite well documented memory changes in older age. In this study, we used a large database of fMRI data (n =323 humans of both sexes included) from across the adult lifespan (ages 18-88) to determine the degree of functional differentiation across the hippocampal posterior-anterior axis. Our first approach was to measure the similarity among signals within each hippocampal subregion. We found that intra-region signals within the most posterior hippocampal subregion became more similar in older age, but did not relate to episodic memory performance. As a second approach, we measured functional connectivity between hippocampal subregions and the rest of the brain. The functional connectivity profiles of the posterior and anterior hippocampal subregions became more distinct from one another with increasing age, and age-related reductions in connectivity were strongest for the intermediate portion of the hippocampus. In contrast, anterior hippocampal functional connectivity remained relatively stable across the adult lifespan, and stronger anterior hippocampus connectivity with the anterior cingulate was associated with better episodic memory in older adults, suggesting that the anterior hippocampus may help some older adults compensate for age-related changes to more posterior hippocampal regions to preserve episodic memory.

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Atrophy of hippocampal subfields relates to memory decline during the pathological progression of Alzheimer’s disease

Cited by 5 publications

References 42 publications

Bayesian Tensor Modeling for Image-based Classification of Alzheimer’s Disease

Bayesian Tensor Modeling for Image-based Classification of Alzheimer’s Disease

Hippocampal transcriptome-wide association study and pathway analysis of mitochondrial solute carriers in Alzheimer’s disease

Adult lifespan effects on functional specialization along the hippocampal long axis

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