Breakthrough Alzheimer’s drug slows down cognitive decline in dementia patients

Lewy body disease (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson’s disease with or without dementia, is an insidious neurodegenerative disorder. It’s second only to Alzheimer’s disease (AD) in prevalence.

Characterized by abnormal protein deposits called Lewy bodies in the brain, LBD affects cognitive function, movement, and autonomic processes, often leading to severe disability and reduced life expectancy.

DLB alone accounts for 10-15% of all dementia cases. With the global prevalence projected to increase from 5.5 million in 2020 to 14 million by 2050, the societal and economic impact is significant.

DLB patients experience a faster rate of cognitive and functional decline compared to those with AD, contributing to a diminished quality of life and increased caregiver burden. Economically, the cost of managing DLB is about twice that of AD, underscoring the urgent need for effective treatments.

Despite its widespread impact, DLB remains a therapeutic challenge. Currently, no disease-modifying treatments are approved outside Japan. Physicians often resort to off-label use of medications approved for AD, such as cholinesterase inhibitors (ChEIs) and memantine. These drugs target symptoms but do not halt disease progression.

ChEIs, including donepezil, galantamine, and rivastigmine, work by inhibiting the breakdown of acetylcholine, a neurotransmitter vital for memory and learning. Studies suggest these inhibitors offer some cognitive benefits.

A meta-analysis of ten trials found that rivastigmine and donepezil improved Mini-Mental State Examination (MMSE) scores by 1 to 2.5 points annually. In contrast, memantine, which targets the brain's glutamatergic system, has shown limited to no cognitive benefit in DLB patients.

Yet, recent comprehensive reviews reveal inconsistencies. A network meta-analysis involving eight randomized controlled trials found no significant difference in cognitive outcomes between patients treated with ChEIs or memantine and those given placebos. Furthermore, most clinical trials have short durations—typically less than a year—leaving long-term efficacy largely unexplored.

Emerging observational studies offer new hope. Research from Karolinska Institutet, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, examined 1,095 DLB patients over a decade.

The findings suggest ChEIs may not only slow cognitive decline but also improve survival. Patients treated with ChEIs showed slower cognitive deterioration over five years compared to those receiving memantine or no treatment. Additionally, ChEIs were associated with a reduced risk of death within the first year post-diagnosis.

Hong Xu, assistant professor at Karolinska Institutet and the study's first author, highlighted the critical nature of these findings. “There are currently no approved treatments for DLB, so doctors often use drugs for Alzheimer’s disease, such as cholinesterase inhibitors and memantine, for symptom relief. However, the effectiveness of these treatments remains uncertain due to inconsistent trial results and limited long-term data,” Xu said.

Maria Eriksdotter, senior author of the study, added, “Our results highlight the potential benefits of ChEIs for patients with DLB and support updating treatment guidelines.”

ChEIs’ potential benefits may extend beyond cognitive preservation. By increasing acetylcholine levels, these drugs enhance communication between neurons. More intriguingly, acetylcholine plays a role in the cholinergic anti-inflammatory pathway (CAP), a critical defense mechanism that modulates systemic inflammation. Chronic inflammation is increasingly recognized as a contributor to neurodegenerative diseases, including DLB.

Activation of CAP by ChEIs could help reduce neuroinflammation, which exacerbates neuronal damage in DLB. This anti-inflammatory effect might explain the association between ChEI use and reduced risks of severe cardiovascular events like myocardial infarction and stroke.

Furthermore, a study from the Cambridgeshire and Peterborough NHS Foundation Trust showed that ChEI users with DLB had lower all-cause mortality rates, suggesting potential systemic benefits.

While the Karolinska study presents promising data, it is important to note its observational nature. Causality cannot be firmly established, and confounding factors, such as patients’ lifestyle habits, frailty, and coexisting Alzheimer’s pathology, could influence the results. Additionally, diagnosing DLB remains challenging due to overlapping symptoms with AD and Parkinson’s disease.

Despite these limitations, the findings provide a strong case for further exploration of ChEIs in DLB management. Long-term, randomized controlled trials are necessary to confirm their benefits and elucidate their mechanisms of action. As DLB cases rise globally, advancing our understanding of effective treatments becomes increasingly urgent.

DLB’s complex pathology underscores the need for multifaceted therapeutic approaches. Current research is exploring disease-modifying therapies targeting alpha-synuclein, the main component of Lewy bodies. Immunotherapies and incretin mimetics are also under investigation, though none have shown definitive success in clinical trials so far.

In the interim, optimizing the use of ChEIs could provide critical symptom relief and improve survival for millions living with DLB. As research progresses, integrating these insights into clinical practice will be vital for enhancing patient care and quality of life.

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.

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