Does Evidence Support Pharmacologic Treatment for Dementia?

 The enormous impact of cognitive impairments across the most diverse aspects of individual and public health emphasizes why the search for effective treatments to prevent the occurrence and slow the progression of these disorders is essential.

Recently, the US Food and Drug Administration (FDA) granted accelerated approval (ie, with no formal advisory committee meeting) for the use of lecanemab, an experimental monoclonal antibody capable of clearing the amyloid protein buildup from the brains of people living with early-stage Alzheimer's disease. As with aducanumab, the benefits associated with lecanemab were modest, and the medication caused concerning adverse events. But the outcry for treatment is so intense that the Alzheimer's Association referred to the FDA approval as a "historic moment."

This clearly highlights the lack of high‑quality evidence to support existing treatments for cognitive impairment, as we will see below.

No Robust Evidence

In 2018, the only Level A (strong) recommendation included in the American Academy of Neurology guidelines was to discuss the lack of evidence supporting the use of cholinesterase inhibitors (ChEIs) with patients and caregivers.

In 2020, "Dementia prevention, intervention, and care: 2020 report of The Lancet Commission" concluded that ChEIs have a useful, modest role in improving cognition and activities of daily living in patients with mild to moderate Alzheimer's disease. The authors wrote that memantine can be prescribed in combination, or each drug can be used separately, for moderate and severe Alzheimer's disease. However, it was felt that they offer only a small benefit.

In 2021, a thorough Cochrane review emphasized that ChEIs (donepezil, galantamine, and rivastigmine), as well as memantine, are prescribed to alleviate symptoms and delay disease progression in dementia. Given uncertainties about the benefits and adverse effects of these drugs in the long term and in severe dementia, the review sought to evaluate the effects of withdrawal or continuation of ChEIs or memantine, or both, in people with dementia — up to October 2020.

Seven trials were included in the review. All the participants had dementia due to Alzheimer's disease, but in some trials, the disease was mild to moderate, and in others it was moderate to severe or very severe. Six trials investigated the effects of stopping a ChEI, and one trial investigated stopping either a ChEI (specifically, donepezil) or memantine. The authors decided not to pool its results with the other six trials. Effects were measured over different periods of time in different trials. The authors looked separately at effects in the first 2 months (short term), between 3 and 11 months (medium term), and after a year or more (long term).

In summary, the results suggest the following conclusions about maintaining treatment with a cholinesterase inhibitor, compared with withdrawal:

• may be beneficial in the short and medium term, and probably in the long term, on memory and reasoning

• may confer little to no short-term effect, uncertain medium-term effect, and probable long-term benefit on the ability to perform activities of daily living

• may confer short- and medium-term benefits, but not long-term ones, on behavioral and mood symptoms

• showed no clear evidence in regard to physical health or risk of dying

• showed insufficient evidence in regard to quality of life or probability of nursing home placement.

The authors found no trials that only investigated stopping memantine. There was no evidence about types of dementia other than Alzheimer's disease, and the authors were unable to draw specific conclusions about continuing or stopping treatment at different stages of the illness.

The authors concluded that although there was uncertainty about the results, in light of the methodologic limitations and sources of bias inherent in the studies reporting these findings, most of the evidence pointed to benefits of continuing treatment with ChEIs.

In 2022, a systematic review of 24 studies on patients with dementia with a mean follow-up of 6-120 months indicated moderate-quality to high-quality evidence of a consistent association between long-term treatment with ChEIs and a reduction in all-cause mortality in patients with dementia. However, this study does not rule out the possibility of bias related to the absence of published trials with negative results. Moreover, the primary concern of patients and their families is quality of life and not mortality.

Practical Implications

Much like the Alzheimer's Association, patients and family members long for dementia treatments, which is only fair from an emotional point of view. Rationally, however, there is a lack of high-quality evidence on the benefits of the drugs already available.

As clinicians, in practice, we must do the following:

• Prioritize the prevention of cardiovascular risk factors

• Promote social activities, memory exercises, and treatment for depression and deafness

• Identify the causes of dementias that may be reversible

• Restrict the use of medications with anticholinergic effects

• Periodically assess basic cognition and functional capacity

• Refer patients to specialized services when needed.

If we decide to prescribe ChEIs or memantine, it is imperative that we be aware of possible adverse effects and recommended care. In addition, as has been stated, we must discuss this lack of evidence with patients and their family members and share the treatment decision.

Treatment may be discontinued due to a lack of adherence, persistent increase in the speed of cognitive decline, low life expectancy, drug intolerance, and patient or family preference.

The impact of dementias may be underestimated. A new disease, limbic-predominant age-related TDP-43 encephalopathy (LATE), a TDP-43 protein disease, has been identified in autopsies. It usually affects those over age 80 years and is a type of dementia that affects memory, thinking, and social skills, imitating Alzheimer's-type dementia. In community-based autopsy cohorts, 25% of brains presented LATE-NC burden associated with cognitive impairment. This condition may be having a growing impact among the aging population that is still relatively unknown in public health.

We need effective treatment options now more than ever!

Mauricio Wajngarten, MD, PhD

Cardiologist, Lecturer in Cardiology, Faculty of Medicine, University of São Paulo, São Paulo, Brazil

Disclosure: Mauricio Wajngarten, MD, PhD, has disclosed no relevant financial relationships.

https://www.medscape.com/viewarticle/987375