Aging is a prerequisite for late-onset AD, but how does the aging process lead to AD in some people, but not others? Wielding gene expression data from multiple datasets to address this question, researchers led by Zhidong Tu at the Icahn School of Medicine at Mount Sinai, New York, report similarities and differences between gene expression signatures in healthy aging brains versus those wracked with AD.
In the hippocampus, energy metabolism and synaptic function wane with normal aging and in AD, while neuroinflammation rages more in the latter. The researchers found that not all brain transcriptomes age equally. An AD-like gene expression signature emerged in a subset of cognitively normal people who died between the ages of 45 and 70. The findings suggest that, in some, the brain aging process veers toward AD many years prior to the typical onset of the disease. They also raise the possibility that by middle age, biomarkers of aging might predict future disease in time to prevent it.
- Postmortem transcriptomics of aging and AD compared.
- Both suggest loss of synaptic and metabolic dysfunction.
- Immune and inflammatory genes rev up more in AD.
- Transcriptomes of some healthy people under 70 resembled that of AD.
Past studies have compared gene expression changes that occur with age to those that crop up in people with AD (Berchtold et al., 2013; Lanke et al., 2018). However, it has long been unclear whether the pattern of brain aging in those destined to develop AD differs from those who will remain sharp into old age. Definitively answering that question with postmortem data is technically not feasible. Still, first author Shouneng Peng and colleagues integrated multiple postmortem datasets, and clever computational analyses, to get at the question in a cross-sectional study.
First, the authors identified gene expression signatures associated with age. To do this, Peng compared expression patterns in different brain regions from the Genotype-Tissue Expression (GTEx) and UK Brain Expression Consortium (UKBEC) datasets. Collectively, samples from these two datasets came from donors between the ages of 20 and 70 who were free of any sign of neurological disorders at death, including amyloid and tau pathology. Aging signatures emerged from 11 of 13 brain regions sampled in GTEx, and from eight of 10 brain regions sampled in UKBEC. Next, Peng compared these aging signatures with AD gene expression signatures derived from multiple other cohorts, including Mount Sinai School of Medicine, the Mayo Clinic Brain Bank, and the Religious Orders Study and Memory and Aging Project (ROSMAP) (Wang et al., 2016; Jun 2018 news; Annese et al., 2018; van Rooij et al., 2019).
Aging Versus AD. Gene expression signatures of aging were derived from brain samples in the GTEx and UKBEC datasets, while AD signatures came from previously published finds from the Mayo Clinic, Mount Sinai, ROSMAP, and others. [Courtesy of Peng et al., bioRxiv, 2021.]
In all, the scientists pulled out 91 aging genes—27 upregulated and 64 downregulated with age—and 86 AD genes, among which 51 were dialed up and 35 turned down in people with AD across several of the cohorts. In short, both the aging and AD signatures suggested an uptick in immune response genes, and a dialing down of synaptic function. For example, expression of the gene encoding synaptic vesicle 2 related protein (SVOP), a protein involved in synaptic vesicle transport, was consistently dialed down in both aging and AD signatures, as was expression of somatostatin (SST), a neuropeptide hormone that maintains the blood-brain barrier.
The scientists next broke down the aging and AD signatures by brain region. Interestingly, they identified distinct signatures of aging in different areas of the brain, with the hypothalamus, hippocampus, and cortex affected the most by aging, at least at the transcriptome level. AD signatures in each region largely overlapped with the age-related changes specific to that region.
Moving forward, Peng and colleagues focused in on the hippocampus, an area of the brain highly affected by both aging and AD. Here again they found that while erosion of fundamental processes such as transcriptional regulation, energy metabolism, membrane remodeling, and synaptic function were implied by both aging and AD signatures, other functions, particularly inflammation and immune responses, changed more markedly in people with AD.
Given the similarities between aging and AD gene expression profiles, why do only some people develop AD? The researchers hypothesized that this could be explained by different types of aging—some of which may align more tightly with the disease. To test this, they took a closer look at the hippocampal aging signatures in the cognitively normal people between the ages of 45 and 70 in the GTEx and UK cohorts. They identified three transcriptional subgroups, each with a different aging signature. Strikingly, two subgroups—defined as “AD-similar”—were more closely aligned with the AD signature than the other subgroup, dubbed “healthy aging.”
Aging Toward AD? Three age-related gene expression signatures emerged in the hippocampus among cognitively normal people who died between 45 and 70 years of age. The researchers compared each aging signature to the AD signature in an older cohort (right). Two aging signatures, B and C, resembled the AD signature. [Courtesy of Peng et al., bioRXiv, 2021.]
Had they lived into their 70s, would people with an “AD similar” gene profile in their hippocampus have been more likely to develop AD? There is no direct way to answer that question, so the researchers took an indirect approach. They compared the AD-similar and healthy aging gene signatures gleaned from the GTEx and UKBEC cohorts to gene expression profiles in another cohort of people older than 70. Derived from Mount Sinai, this separate cohort comprised parahippocampal gyrus brain samples from 19 people who were deemed cognitively normal and free of amyloid or tau pathology at death, and 59 others who had had both clinical and neuropathological evidence of AD. Donors ranged from 70 to 104 years old. Lo and behold, the gene expression of the cognitively normal people in the older Mount Sinai cohort “aligned with that of the healthy aging” subgroup from the younger GTEx/UKBEC cohort, while the gene expression profile of the people with AD in the older Mount Sinai cohort aligned with the “AD similar” subgroup in the GTEx/UKBEC samples. Together, this suggested that sometime in middle age, the brain starts to age in a way that charts the course to either AD or cognitive resilience in older age.
Tu believes that collectively, the data suggest that with aging comes deterioration of basic biological functions critical to maintaining cellular health, which may occur earlier in people who are on the path to AD. This cellular distress provokes inflammatory responses, which exacerbate destruction and ultimately lead to neurodegeneration.
To Jeroen van Rooij of Erasmus University in Rotterdam, studies like this could help distinguish between nonspecific changes and insults that occur with normal aging, and those that occur in specific disease states, including AD.
Tu plans to use the data to find aging biomarkers that could predict, in middle age, if a person is on the path to AD. “I hope this work can send a message that we really should spend more time looking at relatively early stage changes in aging that could potentially lead to development of AD,” he said.
Andrea Tenner of the University of California, Irvine, commented that the identification of different aging signatures, some of which appear to be AD-like, is useful. “Additional steps are needed to determine if those expression signatures are deterministic of the development of AD or the age of onset of AD, and/or what environmental factors synergize to induce the neuronal dysfunction that results in cognitive loss,” Tenner wrote. She wondered how these gene expression profiles correlate with the AD subtypes reported by several of the authors earlier this year (Jan 2021 news).
Commentators both praised and lamented the study’s integration of multiple datasets in its analysis, which makes the data challenging to interpret. Karl Herrup of the University of Pittsburgh in Pennsylvania noted that many of the genes that the authors included in the aging and AD signatures only changed expression in a minority of the datasets. “One of the things that I take away from the entire exercise is that both AD and aging, even in this fairly homogeneous cohort, are incredibly variable,” Herrup wrote.—Jessica Shugart
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No Available Further Reading
- Peng S, Zeng L, Haure-Mirande JV, Wang M, Huffman DM, Haroutunian V, Erlich M, Zhang B, Tu Z. Transcriptomic changes highly similar to Alzheimer’s disease are observed in a subpopulation of individuals during normal brain aging. bioRxiv, July 13, 2021