Alzheimer’s Disease is the seventh leading cause of death in humans, with over fifty million cases being reported globally1. Sufferers experience a gradual loss of brain function, with feelings of confusion, frustration, and anger frequently disclosed. Understandably, the implications can be profound for caregivers, too – reduction in productivity, social isolation and stress as an increased financial burden are all too common.
Asymptomatic Alzheimer’s Disease
But do all patients experience the same cognitive decline? Could some patients with the disease escape having any symptoms at all? Some doctors report that a subset of patients appear to be resilient to the disease2. These people develop all the physical brain changes we expect to see in Alzheimer’s disease, but they don’t seem to have symptoms. When physicians investigated how often this happens, they found it to be rare, but less rare than one might expect.
Studies reported that around 3-5% of otherwise healthy trial participants had signs of amyloid build up in the brain that would usually cause cognitive decline3. This means, as many as one in twenty people could have a stronger natural defence against Alzheimer’s. Alzheimer’s experts hope to study these individuals to discover how they differ from those with symptoms. This could tell us a lot about what causes dementia. More importantly, this could this help scientists to develop drugs to give others the same benefit enjoyed by the select few.
Dutch Dementia Detectives
A recent paper by Dutch investigators examined brain specimens donated to the Netherlands Brain Bank4. The researchers were looking for identifiable differences at the biochemical level between people with symptomatic Alzheimer’s Disease and those with the asymptomatic resilient form. They used a combination of high-throughput screening and statistical analyses to explore differences between the two groups and compared them to healthy subjects. The symptomatic and resilient groups had similar levels of the classic diagnostic risk markers – β amyloid and pTau proteins. Both groups included individuals carrying the APOE4 gene variant – this is the version of the gene that increases a person’s risk of developing the illness5.
The study identified six differences between the symptomatic and resilient groups. They found significantly higher levels of the antioxidant metallothionein in a subset of brain cells of the resilient group. Increased antioxidant activity in these regulatory cells, known as astrocytes, might ‘mop up’ toxic free oxygen species and reduce cell damage. Both resilient men and women benefited from these antioxidants, with women having more significant gains.
Researchers also observed fewer defective microglia. Microglia are a type of brain cell that assist the immune system in the brain6. As humans age, these cells can degenerate into a toxic pro-inflammatory state and contribute to the progression of Alzheimer’s disease.
The brains of the symptomatic group were working overtime to remove and recycle proteins. The researchers speculate that in symptomatic Alzheimer’s Disease, healthy proteins might be heading prematurely to the recycling bin.
They noted far greater numbers of mitochondria in the resilient group’s glial cells. More mitochondria, the proverbial ‘powerhouse of the cell’, would provide extra energy to these nerve cells, allowing them to supply nutrients effectively and remove waste from the brain.
The authors acknowledge that it is impossible to tell which of these six differences, if any, might be responsible for the resilient type.
Medical Mystery
This is a fascinating area of Alzheimer’s disease research. Received wisdom tells us that the build-up of β amyloid and pTau proteins is responsible for much of the damage to our brains that causes this form of dementia. Most research into treatments for Alzheimer’s focus on preventing build up of these proteins, but these resilient patients are not injured in an obvious way6. Could this work suggest that researchers need to approach the problem from another angle? Are β amyloid and pTau proteins as important as we think they are in cognitive decline? It’s too soon to draw firm conclusions, as the Dutch researchers point out, far more investigation is needed before we can pinpoint the crucial differences.
What’s more, very few samples were tested in each group, and the donors all came from a single country with limited genetic variability. Future studies with more participants from more diverse populations are needed to help bring the picture into clearer focus. The authors speculated that future genetic experiments could recreate the resilient form of the disease in mice. Resilient and symptomatic mice would allow them to test potential drugs to help ameliorate the disease in humans.
Resilience Could Be the Key
People who are resilient to this devastating disease may hold the key to eliminating it. Further genetic studies could pave the way for testing potential new drugs with the ability to delay the onset of Alzheimer’s Disease symptoms in humans. Considering the profound impact this would have on our ageing population, let’s hope they succeed.
References
1.Gustavsson A, Norton N, Fast T, et al. Global estimates on the number of persons across the Alzheimer’s disease continuum. Alzheimers Dement. 2023;19(2):658-670. doi:10.1002/alz.12694
2.Aiello Bowles EJ, Crane PK, Walker RL, et al. Cognitive Resilience to Alzheimer’s Disease Pathology in the Human Brain. J. Alzheimers Dis. 2019;68(3):1071-1083. doi:10.3233/JAD-180942
3.Sin MK, Cheng Y, Roseman JM, Latimer C, Ahmed A, Zamrini E. Characteristics and Predictors of Alzheimer’s Disease Resilience Phenotype. J Clin Med. 2023;12(7):2463. Published 2023 Mar 23. doi:10.3390/jcm12072463
4.de Vries LE, Jongejan A, Monteiro Fortes J, et al. Gene-expression profiling of individuals resilient to Alzheimer’s disease reveals higher expression of genes related to metallothionein and mitochondrial processes and no changes in the unfolded protein response. Acta Neuropathol Commun. 2024;12(1):68. Published 2024 Apr 25. doi:10.1186/s40478-024-01760-9
5. Steele OG, Stuart AC, Minkley L, et al. A multi-hit hypothesis for an APOE4-dependent pathophysiological state. Eur J Neurosci. 2022;56(9):5476-5515. doi:10.1111/ejn.15685
Augusto-Oliveira M, Arrifano GP, Lopes-Araújo A, et al. What Do Microglia Really Do in Healthy Adult Brain?. Cells. 2019;8(10):1293. Published 2019 Oct 22. doi:10.3390/cells8101293
6.Breijyeh Z, Karaman R. Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules. 2020;25(24):5789. Published 2020 Dec 8. doi:10.3390/molecules25245789
Very interesting reading. A year or so back my mom has a bad fall and ended up in hospital. They did all kinds of tests and were convinced she had dementia, to the point that they would not release her without her having a full time carer . No matter how much my brother and I argued that she was sharp as a pin and that what they thought they were seeing in hospital was ICU syndrome and frustration (they put her in nappies and so she’d say “get away from me, I don’t know you” and things that really did t help me) they would not budge and kept saying we were in denial. Apparently all her blood tests and scans indicated late stage dementia. Anyway, we relented just to get her discharged and the carers lasted just over a year. A year that she hated. It’s puzzled me for a long time how all the blood and brain tests could point towards late stage dementia but she doesn’t have the memory loss and other symptoms. She’s even under a geriatrician oh says that she has cognitive impairment expected at 81 but no physicals signs of dementia “yet”.