LongeCityNews Last Updated: 17 January 2026 - 06:41 PM

The proteasome is a specialized protein complex that breaks down unwanted proteins into short peptide molecules for reuse in further protein synthesis. Any protein designated as unwanted by the addition of a ubiquitin tag can be broken down in this way. This activity is important, a form of cellular maintenance. When impaired, loss of proteasomal function allows damaged and damaging proteins to build up in the cell, degrading the function of other cellular components and activities. Unfortunately, aging causes loss of proteasomal function just as it degrades the function of all complex systems in the cell.

In today's open access paper, researchers discuss the link between the age-related impairment of proteasomal function and the chronic inflammation that is characteristic of aging. This is a part of the increased attention given to the cGAS-STING pathway and its relevance in aged tissues. The sensor cGAS evolved to detect nucleic acids characteristic of invading pathogens, but is unfortunately also triggered by mislocalized DNA from the cell nucleus or mitochondria that escapes into the cytoplasm of the cell. cGAS in turn activates STING, a central inflammatory regulatory. Diminished proteasomal activity allows the build up of misfolded and other harmful proteins that can disrupt mitochondrial function and structure sufficiently to allow mitochondrial DNA into the cell cytosol.

This sort of connection is why interventions that improve forms of cell maintenance such as proteasomal activity and autophagy tend to reduce age-related inflammation. These forms of intervention range from exercise to sophisticated genetic upregulation or downregulation of specific protein machinery used in cell maintenance processes. Some are more practical than others, and effect sizes vary. What they all have in common is that they help to reduce the level of damage in the form of broken proteins inside cells, thereby improving mitochondrial function, and reducing cGAS-STING activity and consequent inflammatory signaling.

Impaired Proteasome as a Catalyst for cGAS-STING Activation in Alzheimer's Disease

Misfolded proteins and protein degradation systems have contributed significantly to the understanding of Alzheimer's disease (AD). The ubiquitin-proteasome system (UPS), is vital for clearing abnormal proteins that could trigger inflammation if accumulated. Neurons are particularly vulnerable to UPS impairment due to their high reliance on precise protein homeostasis for function and survival. Findings from the studies of the 5×FAD and tau-P301S mice revealed that the synaptic proteasome function is impaired even in the early stages, a phase before overt plaque formation, correlating with early memory deficits. Blocking proteasome function in healthy neurons causes AD-like effects, such as oxidative stress, synaptic loss, and cognitive decline.

Conversely, boosting UPS activity can reverse these effects. Deletion of a 26S proteasome subunit causes neurodegeneration and Lewy-like inclusions, accompanied by abnormal mitochondria, linking proteasome failure to mitochondrial dysfunction and neuronal damage that extends beyond protein aggregation. Increased production of reactive oxygen species (ROS) can damage mitochondrial lipids and proteins, compromise membrane integrity, and ultimately cause membrane rupture. This occurs due to abnormal protein aggregation caused by proteasomal failure, which disrupts redox balance. Although UPS is involved in mitochondrial quality control, its impairment weakens the removal of damaged mitochondrial proteins, leading to oxidative stress that eventually causes mitochondrial membrane collapse. This collapse can then leak mitochondrial DNA into the cytosol. This leaked mtDNA acts as a damage-associated molecular pattern, thereby activating the cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) DNA-sensing pathway, to cause neuroinflammation.

It has been shown in a neuron-specific proteasome knockout mouse that the cGAS-STING pathway was activated, as evidenced by increased protein levels of cGAS and STING, and pro-inflammatory factors, such as STAT1, NF-κB, IL-1β, TNF-α, and IL-6, as well as signs of neurodegeneration, including decreased brain weight and necroptosis markers. These results link proteasomal dysfunction to immune responses and cell death in the brain

According to a new study, as many as 90% of Alzheimer’s cases can be attributed to “suboptimal” variants of the APOE gene. These results highlight the gene’s importance for Alzheimer’s prevention [1].

Three alleles of APOE

A growing amount of research links Alzheimer’s disease to the gene APOE, which codes for apolipoprotein E [2]. This protein helps move cholesterol and other fats around the body and brain, facilitating, among other things, membrane repair and post-injury cleanup.

APOE has three common alleles: ε2, ε3, and ε4 (often written APOE2/3/4). APOE3 is the most widespread and is usually considered the “normal” one – that is, neither protective nor risk-associated. Having APOE4 substantially increases the risk of eventually getting Alzheimer’s, especially in homozygous (ε4/ε4) individuals. Conversely, APOE2 confers significant protection, but it’s also the rarest of the three. A new study from University College London, published in the journal npj Dementia, purports to show how much of Alzheimer’s burden can be directly attributed to APOE genetics.

Genetics explain the majority of cases

The study analyzes data from approximately 470,000 participants across four large cohorts: UK Biobank (UKB), FinnGen, the A4 Study, and the Alzheimer’s Disease Genetics Consortium (ADGC). It included participants aged 60 and older, focusing on those with genetic data and confirmed diagnoses.

Outcomes were assessed through clinical diagnoses, neuropathology, and amyloid-β positivity, with population attributable fractions (PAFs) calculated to quantify the burden of Alzheimer’s and dementia linked to APOE genotypes. PAF is the proportion of cases that would not occur in a population if the causal effect of the exposure were removed, assuming everything else stayed the same.

The PAF for Alzheimer’s cases attributable to APOE3 and APOE4 ranged from 71.5% in FinnGen to 92.7% in ADGC, linking a vast majority of Alzheimer’s cases to these alleles. For all-cause dementia, PAFs were 44.4% in UKB and 45.6% in FinnGen. In the A4 Study, where the outcome was amyloid-β positivity on PET scans at baseline, 85.4% of cerebral amyloidosis cases were attributable to APOE3 and APOE4.

These striking results were mostly due to choosing the most protective ε2/ε2 variant as baseline, despite it also being the rarest (0.3% to 0.6% in the study’s cohorts). This constitutes a significant departure from most previous studies, which treated APOE3 as the baseline “neutral” allele and only considered the additional risk from APOE4.

Lead author Dr. Dylan Williams said: “We have long underestimated how much the APOE gene contributes to the burden of Alzheimer’s disease. The ε4 variant of APOE is well recognized as harmful by dementia researchers, but much disease would not occur without the additional impact of the common ε3 allele, which has been typically misperceived as neutral in terms of Alzheimer’s risk.”

Some experts push back

Not all Alzheimer’s researchers appreciated this approach. “The claim that ‘most cases’ are linked to a single gene is simply an artefact of the authors’ choice to use the rare, protective ε2/ ε2 genotype as their baseline, effectively labelling approximately 95% of the population (who have ε3 or ε4 alleles) as being ‘at genetic risk’,” said Anneke Lucassen, Professor of Genomic Medicine at the University of Oxford.

Some scientists also highlighted the fact that Alzheimer’s is a multifactorial disease, where “nothing is guaranteed” and where risk can be substantially reduced by lifestyle interventions such as diet, exercise, and sleep [3].

“While these findings offer a better understanding of the role of genetics, it is important to remember that having a high-risk form of the gene is not a certain diagnosis,” said Dr. Richard Oakley, Associate Director of Research and Innovation at Alzheimer’s Society: “Alzheimer’s remains a complex condition influenced by a mix of people’s backgrounds, genetics, and lifestyle. As we continue to further our understanding of risks and causes, we must not lose sight of the risk factors that remain within our control.”

A paradigm shift

The authors’ choice to treat the most protective genetic variant as baseline is a sign of a paradigm shift worth dwelling on. Conventional medicine tends to equate “normal” with “good enough” – something that does not warrant investigation or intervention. This study, on the other hand, considers the entire range of effects of various APOE genotypes on Alzheimer’s risk, demonstrating an approach that can be described as “suboptimal is pathological” as opposed to “abnormal is pathological.”

This echoes the geroscience postulate that aging is a pathological process in its entirety. Armed with the latest tech, including rapidly advancing gene editing techniques, medicine should aim at the biggest possible prize rather than confine itself to treating deviations from the norm.

“There has been major progress in recent years in gene editing and other forms of gene therapy to target genetic risk factors directly,” said Williams, “Moreover, genetic risk also points us towards parts of our physiology that we could target with more conventional drugs. Intervening on the APOE gene specifically, or the molecular pathway between the gene and the disease, could have great, and probably under-appreciated, potential for preventing or treating a large majority of Alzheimer’s disease.”

That said, the study had several noteworthy limitations. The PAF estimates may be imprecise due to the rarity of ε2 homozygotes, which served as the reference group, potentially affecting confidence intervals. Additionally, most participants were of European ancestry, limiting the generalizability of findings to other ethnic groups.

Literature

[1] Williams, D. M., Heikkinen, S., Hiltunen, M., FinnGen, Davies, N. M., & Anderson, E. L. (2026). The proportion of Alzheimer’s disease attributable to apolipoprotein E. npj Dementia, 2(1), 1.

[2] Troutwine, B. R., Hamid, L., Lysaker, C. R., Strope, T. A., & Wilkins, H. M. (2022). Apolipoprotein E and Alzheimer’s disease. Acta Pharmaceutica Sinica B, 12(2), 496-510.

[3] Livingston, G., Huntley, J., Liu, K. Y., Costafreda, S. G., Selbæk, G., Alladi, S., … & Mukadam, N. (2024). Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. The lancet, 404(10452), 572-628.

Researchers here conduct a meta-analysis of clinical trial results for the effects of resistance exercise on cognitive function. As might be expected given what is known of the effects of exercise on health, the amassed data strongly indicates that programs of resistance exercise improve cognitive function in older people. Mechanistically, it is known that exercise reduces inflammation, increases blood flow to the brain, improves immune function, improves mitochondrial function, increases autophagy, and touches on a range of downstream effects of those changes that may positively impact the state of the aging brain.

Resistance exercise has recently gained attention as a promising strategy to promote neuroplasticity and mitigate cognitive deterioration; however, evidence from randomized controlled trials (RCTs) remains inconsistent. This systematic review and meta-analysis aimed to evaluate the effects of resistance exercise on cognitive function in older adults.

17 RCTs (n=739) met the inclusion criteria. Pooled analyses showed that resistance training significantly improved overall cognitive function (standardized mean difference, SMD = 0.40), working memory (SMD = 0.44), verbal learning and memory (mean difference, MD = 3.01), and spatial memory span (SMD = 0.63), whereas effects on processing speed, executive function, and attention were not significant. Heterogeneity and publication bias analyses indicated stable and unbiased results. The magnitude of improvement appears to depend on age and exercise parameters, suggesting a potential dose-response relationship.

Link: https://doi.org/10.3389/fpsyt.2025.1708244

Researchers here provide data to support the claim that if everyone had the most favorable ε2 variant of the APOE gene, Alzheimer's disease incidence would be a tenth of what it is now. APOE is involved in cholesterol trafficking and metabolism, and in recent years it has been suggested that the APOE variants connected with higher risk of Alzheimer's cause dysfunction in microglia in the brain. Independently, that microglia become more inflammatory and dysfunctional with age has become an important line of research in the study of neurodegenerative conditions. Evidence strongly supports an important role for dysfunctional microglia in provoking the pathology associated with these conditions. Therapies focused on microglia have yet to emerge, but a number of approaches demonstrated in the laboratory and animal studies could lead to clinical trials given sufficient motivation and funding.

Variation in the APOE gene strongly affects Alzheimer's disease (AD) risk. However, the proportion of AD burden attributable to this variation requires clarification, which would help to elucidate the scope of strategies targeting apolipoprotein E (APOE) for AD prevention and treatment. We estimated the extents to which clinically diagnosed AD, AD neuropathology and all-cause dementia are attributable to the common APOE alleles in four large studies.

First, we used data on 171,105 and 289,150 participants aged ≥60 years from UK Biobank (UKB) and FinnGen, respectively. AD and all-cause dementia were ascertained from linked electronic health records in these cohorts. Second, we examined amyloid-β positivity from amyloid positron emission tomography scans of 4,415 participants of the A4 Study. Third, we analysed data from the Alzheimer's Disease Genetics Consortium (ADGC), where neuropathologically confirmed AD cases were compared to pathology-negative, cognitively intact controls (N = 5,007).

In each analysis, we estimated outcome risk among carriers of APOE risk alleles ε3 and ε4, relative to individuals with an ε2/ε2 genotype, and calculated attributable fractions to show the proportions of the outcomes due to ε3 and ε4. For AD, fractions ranged from 71.5% in FinnGen to 92.7% in the ADGC. In A4, 85.4% of cerebral amyloidosis was attributable to ε3 and ε4. The proportions of all-cause dementia attributable to ε3 and ε4 in UKB and FinnGen were 44.4% and 45.6%, respectively. Without strong underlying risks from APOE ε3 and ε4, almost all AD and half of all dementia would not occur. Intervening on APOE should be prioritised to facilitate dementia prevention.

Link: https://doi.org/10.1038/s44400-025-00045-9