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Metformin Linked to Reduced Cognitive Decline, Dementia Risk

Older people taking metformin, the first-line treatment for type 2 diabetes, show significantly lower rates of dementia and cognitive decline compared to those with diabetes not receiving the drug, with the former having dementia rates that are, in fact, similar to people without diabetes, new research shows.

“After controlling for dementia risk factors that might promote cognitive aging, metformin appeared to mitigate the effect of diabetes on cognitive decline in older people,” first author Katherine Samaras, MBBS, PhD, told Medscape Medical News.

The findings are notable considering the increased risk of cognitive decline that is associated with diabetes, said Samaras, leader of the Healthy Ageing Research Theme at the Garvan Institute and an endocrinologist at St Vincent’s Hospital, Sydney, Australia.

“As they age, people living with type 2 diabetes have a staggering 60% risk of developing dementia, a devastating condition that impacts thinking, behavior, the ability to perform everyday tasks, and the ability to maintain independence,” she said in a press release issued by her institute.

And the results are particularly remarkable in that “few prior studies have controlled for multiple dementia risk factors, including the dementia susceptibility gene APOE4,” Samaras emphasized. 

As the front-line drug treatment for type 2 diabetes, metformin has been extensively studied and, with some other research also showing cognitive benefits, “these results are not surprising,” Mark E. Molitch, MD, told Medscape Medical News.

Nevertheless, “this reinforces the idea that metformin should be the first drug used to treat diabetes, and it should be continued if other drugs are added for blood glucose control,” said Molitch, of the Division of Endocrinology, Metabolism & Molecular Medicine, at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

Significant Differences in Global Cognition, Executive Function 

In the observational, prospective study, published online in Diabetes Care, Samaras and colleagues identified 1037 community-dwelling people without dementia between the ages of 70 and 90 who were enrolled in the Sydney Memory and Ageing Study in Australia.

Among the participants, 123 (12%) had type 2 diabetes, including 67 who were treated with metformin; 34 as a single medication and 33 in combination with other medications, most commonly sulfonylureas (70%).

Of the 56 patients with diabetes who did not receive metformin, 34 were treated with diet alone, while the remainder were treated with other glucose-lowering medications.

There were no significant baseline differences between the groups in cognitive performance at baseline, after a multivariate adjustment. Their mean age was about 79.

All participants received neuropsychological testing for cognitive function every 2 years, including memory, executive function, attention, speed, and language tests.

In terms of cognitive decline over the 6 years, those treated with metformin had a significantly lower decline in global cognition compared to those with diabetes not taking metformin (P = .032), and the rate of decline of metformin-treated participants was not different compared to those without diabetes.

There was also a slower decline in executive function in those treated versus not treated with metformin (P =

Penn Medicine researchers discover a rare genetic form of dementia

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IMAGE: Abnormal neurofibrillary tangles (NFTs) — a buildup of tau protein in parts of the brain — helped Edward Lee, MD, PhD, an assistant professor of Pathology and Laboratory Medicine, and…
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Credit: Edward Lee

PHILADELPHIA — A new, rare genetic form of dementia has been discovered by a team of Penn Medicine researchers. This discovery also sheds light on a new pathway that leads to protein build up in the brain — which causes this newly discovered disease, as well as related neurodegenerative diseases like Alzheimer’s Disease — that could be targeted for new therapies. The study was published today in Science.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by a buildup of proteins, called tau proteins, in certain parts of the brain. Following an examination of human brain tissue samples from a deceased donor with an unknown neurodegenerative disease, researchers discovered a novel mutation in the Valosin-containing protein (VCP) gene in the brain, a buildup of tau proteins in areas that were degenerating, and neurons with empty holes in them, called vacuoles. The team named the newly discovered disease Vacuolar Tauopathy (VT)–a neurodegenerative disease now characterized by the accumulation of neuronal vacuoles and tau protein aggregates.

“Within a cell, you have proteins coming together, and you need a process to also be able to pull them apart, because otherwise everything kind of gets gummed up and doesn’t work. VCP is often involved in those cases where it finds proteins in an aggregate and pulls them apart,” Edward Lee, MD, PhD, an assistant professor of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania. “We think that the mutation impairs the proteins’ normal ability to break aggregates apart.”

The researchers noted that the tau protein they observed building up looked very similar to the tau protein aggregates seen in Alzheimer’s disease. With these similarities, they aimed to uncover how this VCP mutation is causing this new disease — to aid in finding treatments for this disease and others. Rare genetic causes of diseases can very often offer insight into more prevalent ones.

The researchers first examined the proteins themselves, in addition to studying cells and an animal model, and found that the tau protein buildup is, in fact, due to the VCP mutation.

“What we found in this study is a pattern we’ve never seen before, together with a mutation that’s never been described before,” Lee said. “Given that this mutation inhibits VCP activity, that suggest the converse might be true — that if you’re able to boost VCP activity, that could help break up the protein aggregates. And if that’s true, we may be able to break up tau aggregates not only for this extremely rare disease, but for Alzheimer’s disease and other diseases associated with tau protein aggregation.”

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Lee led this work with first author, Nabil Darwich, MD/PhD student in the Neuroscience Graduate Group at Penn.

These findings describe a new biologic function of VCP, define a