Age and Ageing collection: Treatments in Dementia
This collection of 15 papers provides an update on the advances of pharmacological and non-pharmacological interventions in dementia over the last 15 years. The published studies reflect the efficacy of the current anti-dementia treatments, preventive treatments of cardio and cerebrovascular incidents known to be risk factors for dementia, alongside the use of antidepressant medication and non-pharmacological interventions for treatment of behavioural and psychopathological symptoms of dementia. We also address the future preventative steps and therapeutic strategies currently in development to combat the devastating consequences of dementia.
The last 35 years brought clinical and research innovations into age-related mental health and physical illnesses. The dementia epidemiological studies were followed by extensive correlative clinico-neuropathological and biochemical studies and expanded our knowledge about the molecular substrates of cognitive ageing and dementia. The ‘tauist’ and ‘BAPtists’ camps (BAP is beta amyloid plaques), flourishing in the 80s and 90s, divided over what comes first - tangles or plaques, and the unlikely outsider, acetylcholine, claimed the first round in the (drug) battle. Do you remember the excitement that came with the first anti-dementia drug trials? The first patients we treated with the second generation of them? The first National Institute for Health and Care Excellence (NICE) guidelines for dementia brought back hope for people with dementia and their families. We, old age physicians, psychiatrists and neurologists were named as main prescribers of these drugs. The anticipation of combating cognitive disabilities was visible: ‘We are now 10 years closer to having a cure’ was the sentence frequently repeated at that time.
Indeed we are still closer than we were some 10 and even closer than we were some 20 or 30 years ago in respect to our clinical and research knowledge and expertise about dementia. Our patients, their families/carers and our clinical services have all benefited from this – memory services co-exist within several medical disciplines, including old age psychiatry and geriatric medicine, primary care and neurology. Initially started as diagnostic memory services, they transformed into ‘Memory Protection Services’ providing support to both the worried well and those with dementia and their families. The UK Prime Minister Dementia Challenge and the Commissioning for Quality and Innovation (CQUIN) for dementia have positively contributed to changing our clinical culture, and becoming hospital and society ‘dementia friendly’. Dementia is now ‘everybody’s business’ - dementia screening is incorporated in the routine clinical assessments, anti-dementia drugs are widely available and having dementia is not a societal stigma.
However, dementia treatment options still remain rather limited. The known anti-dementia drugs appear to have some effect on cognition and behaviour for the first few years, with their efficacy slowly diminishing with the disease duration. The enthusiasm for diagnostic and therapeutic advances has now largely moved on dementia prevention and successful ageing, the arrest of known risk factors for dementia, i.e. education, smoking, diabetes mellitus. At the same time we are witnessing a rapid escalation of polypharmacy among older people – is this a result of increased health awareness and/or pharmacological advances to prevent and treat chronic diseases? What the long term effect is on overall health of older people remains to be determined.
All the above changes in dementia policies and research have influenced the research contributions published over the last few decades in Age and Ageing. The 15 papers included in the current collection represent only a handful of the research studies, reviews and research letters and cover a very wide palette of clinical and basic science studies on dementia treatments.
Lifestyle plays an important role in reducing the risk for development of dementia. Healthy diet (consisting of daily portions of fruit and vegetables), as well as maintaining longstanding lifestyle habits such as sauna bathing are among those that are associated with significantly lowering the dementia risks from middle age onwards. Whether this is due to improving people’s overall health, or via substantially reducing the risk factors for dementia, i.e. obesity, diabetes, high blood pressure and stress, needs further investigations.
The anti-dementia drugs (cholinesterase inhibitors, ChEIs) are widely prescribed in the UK health system, and their accessibility to dementia patients is incorporated in the UK National Dementia Strategy and the NICE guidelines for dementia. Their effectiveness and cost-effectiveness were reassessed following the latest NICE recommendations for the use of ChEIs in mild dementia. The new evidence (as based on <£30,000/ Quality Adjusted Life Year (QALY);) suggests both improved confidence about their beneficial effects and cost-effectiveness. Furthermore, the current anti-dementia drugs reduce the mortality in dementia patients by more than 20% and people do not die from dementia, but advanced age, heart failure and treatment with antipsychotic drugs. The ChEIs also have the anti-inflammatory properties and inhibit the release of cytokines from microglia and monocytes in the brain tissue. They may, thus, offer not only an additional neuroprotection against neurodegenerative changes but have an impact on other physiological modalities, i.e. inflammation and pathological pain.
Not all people with dementia will benefit from ChEIs treatment. Holmes and Lovestoneprovide a high figure of non-responders to anti-dementia treatments (34% for those with mild to moderate cognitive impairment and over 60% for the whole AD group after the first year after commencing ChEIs). This figure is very close to the findings of a recent larger Italian study. Although these findings confirm the modest cognitive effect ChEIs have, at the same time they do not dispute the larger body of evidence regarding slowing down the cognitive decline by several years as a result of the ChEIs treatment. The latest generation of ChEIs, octohydroaminoacridine, targeting not only acetylcholinesterase, but also butyrylcholinesterase, improves both cognitive and behavioural symptoms in mid to moderate AD dementia. The pharmacological properties of the new drug appear to bear similarities to rivastigmine, but in the lack of comparative studies it is difficult to comment how the new medication will change the management of our dementia patients. Further evaluation of the long-term effect of octohydroaminoacridine, as well as comparative head to head studies with the current anti-dementia treatments are now awaited.
It remains unclear whether and how treatment of dementia-associated risk factors, i.e. diabetes, hypertension, renal or heart failure, may modify cognitive and behavioral functioning in people with dementia. Two review papers in the current collection provide an in-depth overview of the complex nature of blood pressure changes and atrial fibrillation with ageing, and its impact on cognitive performance. In the first one, the authors highlight a number of practical steps to address hypertension in older people, including medication choice, de-prescribing, individualised treatment whenever possible, guided by patient priorities and randomised trials of targeted de-prescribing studies with patient-centered outcome measures. Similar recommendations are provided for the role of thromboprophylaxis in atrial fibrillation, suggesting for further studies to incorporate clinical cognitive measures and address the mechanism by which both atrial fibrillation and hypertension contribute to cognitive impairment in older people.
Although non-pharmacological interventions are recommended for behavioural and psychological symptoms of dementia (BPSD, they tend to be social, rather than BPSD targeted. It is thus not surprising that the prescription rate for antipsychotic, benzodiazepine and antidepressant medication is rather high in people with dementia, and in particular for those dementia patients who live in remote areas or areas serviced by large surgeries. Furthermore, the prescription of these drugs appears to be higher especially in nonagenarians with dementia. This is in sharp contrast to the evidence that most of the prescribed medication, including antidepressants, have very little or no effect upon people’s cognition and behaviour. These findings urge for regular medication revision in people with dementia to avoid redundant and/or harmful drug intake.
This overview summarises briefly the major advances in dementia therapeutics to date as followed in Age and Ageing. What will the following 35 years bring in the dementia research? Will they utilise the technological advances of the 21st century and produce a cure for dementia? Are we facing dementia-free future? And, when? Will the novel anti-dementia treatments be able to ‘dissolve’ the plaques and tangles, and completely reverse the dementia process? Will they also help with the BPSD? Will the lifestyle-based approach modify or even stop the dementia ‘bomb’? What will the personalised dementia care look like? Are we going to witness globalisation of the dementia ‘intelligent homes’ for independent living? These are just a handful of the futuristic expectations both professionals and people with dementia and their carers expect and hope for.
Prof Elizabeta Mukaetova-Ladinska
University of Leicester and Leicestershire Partnership Trust
Currently available anti-dementia treatments
- The effect of treatment with selective serotonin reuptake inhibitors in comparison to placebo in the progression of dementia: a systematic review and meta-analysis
Jones HE, Joshi A, Shenkin S, Mead GE.
Age & Ageing 2016; 45 (4): 448-456
- Long-term cognitive and functional decline in late onset Alzheimer's disease: therapeutic implications
Holmes C, Lovestone S.
Age & Ageing 2003; 32 (2): 200-4
- Evolution of the evidence on the effectiveness and cost-effectiveness of acetylcholinesterase inhibitors and memantine for Alzheimer's disease: systematic review and economic model
Hyde C, Peters J, Bond M, et al.
Age & Ageing 2013; 42 (1): 14-20
- Associations of acetylcholinesterase inhibitor treatment with reduced mortality in Alzheimer's disease: a retrospective survival analysis
Mueller C, Perera G, Hayes RD, Shetty H, Stewart R.
Age & Ageing 2018; 47 (1): 88-94
- Comparative analysis of mortality in patients with Alzheimer's disease treated with donepezil or galantamine
López-Pousa S, Olmo JG, Franch JV, et al.
Age & Ageing 2006; 35 (4): 365-71
- Acetylcholinesterase inhibitors for Alzheimer's disease: anti-inflammatories in acetylcholine clothing!
Age & Ageing 2006; 35 (4): 336-8
- Observational cohort study: deprivation and access to anti-dementia drugs in the UK
Cooper C, Lodwick R, Walters K, et al.
Age & Ageing 2016; 45 (1): 148-54
- Efficacy and safety of a novel acetylcholinesterase inhibitor octohydroaminoacridine in mild-to-moderate Alzheimer's disease: a Phase II multicenter randomised controlled trial
Xiao S, Wang T, Ma X, et al.
Age & Ageing 2017; 46 (5): 767-773
- Sauna bathing is inversely associated with dementia and Alzheimer's disease in middle-aged Finnish men
Laukkanen T, Kunutsor S, Kauhanen J, Laukkanen JA.
Age & Ageing 2017; 46 (2): 245-249
- Lower risk of incident dementia among Chinese older adults having three servings of vegetables and two servings of fruits a day
Lee ATC, Richards M, Chan WC, Chiu HFK, Lee RSY, Lam LCW
Age & Ageing 2017; 46 (5): 773-779
- The use of non-pharmacological interventions for dementia behaviours in care homes: findings from four in-depth, ethnographic case studies
Backhouse T, Killett A, Penhale B, Gray R.
Age & Ageing 2016; 45 (6): 856-863
Management of vascular risk factors for dementia
- New horizons: the management of hypertension in people with dementia
Harrison JK, Van Der Wardt V, Conroy SP, et al.
Age & Ageing 2016; 45 (6): 740-746
- Thromboprophylaxis in atrial fibrillation and association with cognitive decline: systematic review
Moffitt P, Lane DA, Park H, O'Connell J, Quinn TJ.
Age & Ageing 2016; 45 (6): 767-775
Drug use in people with dementia
- The burden of psychotropic drug prescribing in people with dementia: a population database study
Guthrie B, Clark SA, McCowan C.
Age & Ageing 2010; 39 (5): 637-42
- Drug use in persons with and without Alzheimer's disease aged 90 years or more
Taipale H, Koponen M, Tanskanen A, Tolppanen AM, Tiihonen J, Hartikainen S.
Age & Ageing 2016; 45 (6): 900-904