04 Oct 2022

The 9th Kuopio Alzheimer Symposium and 3rd Nordic Memory Clinic Conference took place jointly on August 23-25 at the Kuopio Music Center, a modern performing arts and conference center in this Finnish city just short of the Arctic Circle. Co-organized by Mikko Hiltunen, University of Eastern Finland, Kuopio, this northernmost dementia conference drew about 300 people from Scandinavia, elsewhere in Europe, and some from Asia and the Americas, too. On the agenda were diverse topics ranging from genetics and biomarkers to prevention and therapies. One take-home message from the meeting: People who live past 100 may enjoy built-in resilience to brain disorders such as dementia.

That’s one conclusion from the 100-plus Study, an observational cohort being followed by Henne Holstege and her colleagues at Amsterdam University Medical Center in the Netherlands. Holstege reported that while some centenarians do accumulate pathologies associated with aging and neurodegeneration—think cardiovascular damage and proteopathies—these don’t necessarily lead to cognitive decline. The reason? The very old are protected by their genetics.

For example, cognitively healthy centenarians have a much lower genetic risk for Alzheimer’s disease, Holstege said, attributing some of that to a variant in the gene for phospholipase C-γ2. An analysis of nine families who carry the PLC2G P522R variant suggests that it boosts the immune system. “While the effects are small, the data point to PLCG2 as a potential therapeutic target,” said Holstege.

“This work on centenarians is super important,” said Henrik Zetterberg, University of Gothenburg, Sweden, who attended the Kuopio meeting. “It’s almost like their amyloid pathology is inert, or surrounded by something that shields it,” he speculated.

Holstege began the study in 2013, inspired by Hendrikje van Andel-Schipper, who, at 115, was the oldest woman alive when she died in 2005. Van Andel-Schipper had shown no signs of dementia. “She demonstrated that cognitive decline is not inevitable in people who live to very old age,” said Holstege. Van Andel-Schipper’s mother had lived to 100 and she, too, had her full faculties. Does the van Andel-Schipper genome—and that of other cognitively healthy centenarians—hold clues to dementia prevention or treatment? Holstege started the 100-plus Study to find out.

In Kuopio, Holstege reviewed some of the latest data from the project. She initially aimed to recruit 500 cognitively healthy centenarians. As of June 2021, 406 had signed up. Their average age when they joined was 101; the oldest is now 107. Seventy percent are women; 43 percent still live independently. About 30 percent have agreed to donate their brains after death and, to date, 95 of them have passed away. Holstege showed neuropathology findings from 85 of those.

100-Plus Study. The project scours the blood and tissues of healthy centenarians for clues to dementia prevention and treatment. [Courtesy Holstege lab, www.holstegelab.eu.]

At autopsy, some of these centenarians were found to have had pathologies typical of people with AD. Ph.D student Andrea Ganz from Holstege’s lab and Meng Zhang, from Marcel Reinder’s lab at Technical University Delft, The Netherlands, saw that many had been in stage 2 or 3 amyloidosis when they died, as judged by NIA criteria, and had accumulated stage 2 or even stage 3 neuritic plaques per CERAD scores. All were in at least Braak stage I for neurofibrillary tangles, though the majority were at stage III or higher. The brains weighed about as much as those from people who had had AD dementia, but neither plaques nor tangles correlated with MMSE score.

The same was true for a host of other age-related pathologies, including cerebral amyloid angiopathy, TDP-43 proteinopathy, Lewy bodies, hippocampal sclerosis, granulovacuolar degeneration, atherosclerosis, and vascular infarcts. Many centenarians had at least one of these. Across all of these pathologies, increased levels in the postmortem brain generally came with lower cognitive scores before death, but the associations were weak. Of all neuropathological substrates tested, tangles correlated most robustly with lower performance, but these healthy centenarians seemed surprisingly resistant even to the effects of high levels of tangles, Holstege said. A manuscript on this data was uploaded to medRXiv on August 30 (Zhang et al., 2022).

So what is going on in these brains? To investigate this question at a systems biology level, Holstege collaborated with Guus Smit in Amsterdam UMC, who studies bulk brain proteomes. The scientists compared the centenarians' proteomes to those from 50- to 95-year-old people with AD and to 50- to 90-year-old healthy controls. They found that, while concentrations of about two dozen proteins fall with age, in centenarians, these protein levels were higher than expected for their age. For four other proteins that normally tick up with age, levels remained steady in the centenarians. The proteins that bucked these trends included those involved in microtubule and intermediate filament biology, myelination, the immune system, basic metabolism, and protein transport. “In a nutshell, these centenarians have younger-looking brains,” said Holstege.

What bestows the vim and vigor? Holstege believes genetics holds the key. Based on 83 known genetic risk variants for AD, Niccoló Tesi, also at Amsterdam UMC, found that centenarians have a much lower polygenic risk score for this disease than do people with AD. Indeed, in a previous, smaller analysis of about two dozen AD gene variants, people with AD were likelier than cognitively healthy centenarians to have risk variants in APOE and TREM2, but less likely to have protective variants in other genes, including PLCG2 (Tesi et al., 2019). “There is a depletion of risk variants and an enrichment of protective variants versus age-matched controls,” said Holstege.

Scientists had previously found the P522R protective variant in PLCG2, and that it may boost immune function and indeed longevity (Aug 2017 conference news; Sep 2020 news). Holstege learned that it also protects against frontotemporal dementia and dementia with Lewy bodies, and that people who live past 90 are much likelier to carry this variant (May 2019 news).

To explore more deeply how the P522R protective variant in PLCG2 might function, Holstege and colleagues identified nine families—beyond the centenarian cohort—who carry it. Annieck Diks works with Holstege’s collaborator Jacques van Dongen in Leiden University Medical Center. She found that 33 carriers of the variant seemed to have blood cells counts that resembled those of younger people. Their B cells seemed more sensitive to stimuli, more ready to phosphorylate PLCG2 and release intracellular calcium. Their myeloid cells made more reactive oxygen species and phagocytosed more avidly than did cells from siblings who did not carry this particular variant. Diks uploaded a paper on this data on the Research Square preprint server (Diks et al., 2022). 

Researchers in Kuopio called findings outstanding. Holstege said these outcomes were expected given similar findings in mouse studies. To her knowledge, this was the first data on freshly isolated human peripheral immune cells. “Admittedly, these are peripheral cells, but for now we think this is a good model for what might go on in the brain,” she said.

The Hiltunen lab at UEF studies how the PLCG2 variant affects brain cells as part of a personalized medicine project for newly discovered microglia-associated genetic variants in AD. For this project, called PMG-AD, Hiltunen collaborates with four other investigators: Christian Haas, Ludwig-Maximilians University, Munich; Jari Koistinaho, University of Helsinki; Jean-Charles Lambert, Institut Pasteur de Lille, France; and Stefan Lichtenthaler, Technical University of Munich.

PMG-AD identifies carriers of the PLCG2 P522R variant, among others, in several cohorts, including the Alzheimer Disease European Sequencing consortium, the European Alzheimer’s Data Bank, Alzheimer's Disease Genetics Research Unit, and FINGER—the Finnish multimodal intervention trial. The researchers will probe microglia derived from blood monocytes and iPSCs for functional effects of the variants. The goal is to correlate those with transcriptomic, proteomic, and amyloid and microglial PET data in search of protective or disease markers or drug targets.

Hiltunen also collaborates with Holstege to characterize the molecular and cellular mechanisms that protect her study's centenarians. “I strongly believe that the pool of protective genetic variants dictates a lot in these individuals,” he told Alzforum. “The PLCG2 variant may even override the adverse effects of APOE4.”

“All in all, studies done in this 100+ cohort provide seminal information on key determinants of resilience and longevity, including genetic variants. This may provide specific targets to tackle in Alzheimer's and other neurodegenerative diseases,” he said.—Tom Fagan

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References

News Citations

1. Searching for New AD Risk Variants? Move Beyond GWAS 4 Aug 2017
2. Protective AD Variant Pinpoints Sweet Spot for Microglial Activation 24 Sep 2020
3. The Mutation You Want: It Protects the Brain, Extends Life 31 May 2019

Paper Citations

1. Zhang M, Ganz AB, Rohde S, Rozemuller AJ, Netherlands Brain Bank, Reinders MJ, Scheltens P, Hulsman M, Hoozemans JJ, Holstege H. Resilience and resistance to Alzheimer’s disease-associated neuropathological substrates in centenarians: an age-continuous perspective. medRxiv August 30, 2022. medRxiv
2. Tesi N, van der Lee SJ, Hulsman M, Jansen IE, Stringa N, van Schoor N, Meijers-Heijboer H, Huisman M, Scheltens P, Reinders MJ, van der Flier WM, Holstege H. Centenarian controls increase variant effect sizes by an average twofold in an extreme case-extreme control analysis of Alzheimer's disease. Eur J Hum Genet. 2019 Feb;27(2):244-253. Epub 2018 Sep 26 PubMed.
3. Diks AM, Teodosio C, de Mooij B, Groenland RJ, Naber BA, de Laat IF, Vloemans SA, Rohde S, de Jonge MI, Lorenz L, Horsten D, van Dongen JJ, Berkowska MA, Holstege H. PLCG2 variant p.P522R - associated with healthy aging- may reduce the aging of the human immune system. This preprint is Under Review at Molecular Neurodegeneration. Research Square

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