Re: 알츠하이머 예방과 치매 치료의 전략 2024년 JAMA review

[문형철]

Abstract

Importance Dementia affects 10% of those 65 years or older and 35% of those 90 years or older, often with profound cognitive, behavioral, and functional consequences. As the baby boomers and subsequent generations age, effective preventive and treatment strategies will assume increasing importance.

Observations Preventive measures are aimed at modifiable risk factors, many of which have been identified. To date, no randomized clinical trial data conclusively confirm‎ that interventions of any kind can prevent dementia. Nevertheless, addressing risk factors may have other health benefits and should be considered. Alzheimer disease can be treated with cholinesterase inhibitors, memantine, and antiamyloid immunomodulators, with the last modestly slowing cognitive and functional decline in people with mild cognitive impairment or mild dementia due to Alzheimer disease. Cholinesterase inhibitors and memantine may benefit persons with other types of dementia, including dementia with Lewy bodies, Parkinson disease dementia, vascular dementia, and dementia due to traumatic brain injury. Behavioral and psychological symptoms of dementia are best treated with nonpharmacologic management, including identifying and mitigating the underlying causes and individually tailored behavioral approaches. Psychotropic medications have minimal evidence of efficacy for treating these symptoms and are associated with increased mortality and clinically meaningful risks of falls and cognitive decline. Several emerging prevention and treatment strategies hold promise to improve dementia care in the future.

Conclusions and Relevance Although current prevention and treatment approaches to dementia have been less than optimally successful, substantial investments in dementia research will undoubtedly provide new answers to reducing the burden of dementia worldwide.

초록

중요성

치매는 65세 이상 인구의 10%,

90세 이상 인구의 35%에게 영향을 미치며,

심각한 인지, 행동, 기능적 장애를 동반하는 경우가 많습니다.

베이비붐 세대와 그 이후 세대가 노령화됨에 따라

효과적인 예방 및 치료 전략의 중요성이 점점 더 커질 것입니다.

관찰 결과

예방 조치는 수정 가능한 위험 요인을 대상으로 하며,

많은 요인이 이미 식별되었습니다.

현재까지 어떤 종류의 개입이 치매를 예방한다는 것을 결론적으로 확인한 무작위 임상 시험 데이터는 없습니다. 그럼에도 불구하고 위험 요인을 해결하는 것은 다른 건강상의 이점을 가질 수 있으며 고려되어야 합니다.

알츠하이머 병은

콜린에스테라제 억제제, 메만틴, 항아밀로이드 면역조절제로 치료할 수 있으며,

후자는 알츠하이머 병으로 인한 경도 인지 장애 또는 경도 치매 환자의 인지 및 기능 저하를 약간 늦추는 효과가 있습니다.

콜린에스테라제 억제제와 메만틴은

루이체 치매, 파킨슨병 치매, 혈관성 치매, 외상성 뇌손상으로 인한 치매 등

다른 유형의 치매 환자에게도 도움이 될 수 있습니다.

치매의 행동 및 심리적 증상은 근본 원인을 식별하고 완화하며

개인별 맞춤형 행동 접근법을 포함한 비약물적 관리로 가장 효과적으로 치료됩니다.

정신과적 약물은

이러한 증상 치료에 대한 효과 증거가 미미하며,

사망률 증가 및 낙상 및 인지 기능 저하의 임상적으로 의미 있는 위험과 연관되어 있습니다.

여러 신흥 예방 및 치료 전략은 미래 치매 관리 개선에 희망을 제시합니다.

결론 및 관련성

현재 치매 예방 및 치료 접근법은 최적의 성과를 내지 못했지만,

치매 연구에 대한 상당한 투자는 전 세계적으로 치매 부담을 줄이는 새로운 해법을 제공할 것입니다.

Dementia, which has both cognitive deficits and functional consequences,1 is a disorder of aging with preval‎ence ranging from 3% among those 65 to 70 years old to 35% among those 90 years and older.2 As the baby boomers (born between 1946 and 1964) age over the next 3 decades, the effect of dementia will be monumental, with the number of individuals in the US with Alzheimer disease (AD) expected to double above the current estimate of 6.7 million.3 From a global perspective, more than 55 million people have dementia worldwide— more than 60% of whom live in low- and middle-income countries—with nearly 10 million new cases each year.4 The most common cause of dementia is AD, which accounts for an estimated 60% to 80% of cases. Other causes of dementia include vascular (approximately 5%-10%), frontotemporal degeneration (3% of those with onset 65 years or older and 10% of those with onset younger than 65 years), and Lewy body disease (approximately 5%), although Lewy body disease may be underdiagnosed in clinical practice. Moreover, more than 50% of those diagnosed with AD have mixed dementia with more than 1 identifiable cause.3 Beyond its effects on patients, dementia affects caregivers, with at least 11 million providing care in the US in 2022.3 The toll of dementia caregiving can be enormous—up to 40% report depressive symptoms,5 and 30% regularly feel completely overwhelmed6 ; their role and needs must also be considered in the care of the patient. Despite the promise of amyloid immunomodulators for AD, it is likely thatmost persons with dementia will not be eligible for these at the time of diagnosis;moreover, the clinical effectiveness and duration of effect of these drugs remain uncertain. In this review, we summarize the current evidence and explore emerging science on the preventionand treatment of dementia to inform clinical decisionmaking (Figure).

치매는 

인지 기능 장애와 기능적 장애를 모두 동반하는 질환으로,1 

노화 관련 질환으로 65세에서 70세 사이의 인구에서 3%, 

90세 이상 인구에서 35%의 유병률을 보입니다. 2 

베이비붐 세대(1946년부터 1964년 사이에 태어난 사람들)가 

향후 30년간 노령화됨에 따라 치매의 영향은 엄청날 것으로 예상되며, 

미국에서 알츠하이머병(AD)을 앓는 사람의 수는 현재 추산치인 670만 명을 넘어 두 배로 증가할 것으로 예상됩니다. 3 

전 세계적으로 5500만 명 이상이 치매를 앓고 있으며, 

이 중 60% 이상은 저소득 및 중소득 국가에 거주하며 매년 약 1000만 명의 신규 환자가 발생합니다.4 

치매의 가장 흔한 원인은 AD로, 

전체 사례의 약 60%에서 80%를 차지합니다. 

치매의 다른 원인에는 혈관성 치매(약 5~10%), 

전두측두엽 퇴행성 치매(65세 이상에서 발병한 경우 3%, 65세 미만에서 발병한 경우 10%), 

루이체 치매(약 5%)가 있으며, 

임상实践에서 루이체 치매는 진단이 미흡할 수 있습니다. 

또한 AD로 진단받은 환자의 50% 이상은 

1개 이상의 원인이 확인되는 혼합형 치매를 동반합니다. 3 

치매는 환자에게 미치는 영향 외에도 돌봄 제공자에게도 영향을 미치며, 

2022년 미국에서만 1,100만 명 이상이 돌봄을 제공하고 있습니다.3 

치매 돌봄의 부담은 엄청날 수 있으며, 

40%가 우울증 증상을 보고하며,5 

30%는 정기적으로 완전히 압도된 느낌을 받습니다.6 

환자의 돌봄 과정에서 그들의 역할과 필요도 반드시 고려되어야 합니다. 

알츠하이머병에 대한 아밀로이드 면역조절제의 잠재적 효과에도 불구하고, 

대부분의 치매 환자는 진단 시점에 이러한 치료제에 적합하지 않을 가능성이 높습니다. 

또한 이러한 약물의 임상적 효과와 효과 지속 기간은 여전히 불확실합니다. 

이 리뷰에서는 

치매 예방 및 치료에 대한 현재의 증거를 요약하고, 

임상적 의사결정을 지원하기 위해 새롭게 떠오르는 과학적 연구를 탐구합니다(그림).

Methods

This Narrative Review draws from several systematic reviews published between 2018 and 2023, including the 2020 Lancet Commission review7 and the Alzheimer’s Association’s Alzheimer’s Disease Facts and Figures, 3 which is updated annually. We augmented these reviews by searching PubMed for each topic heading of the Lancet review plus other topics we were aware of, adding new studies published from January 2020 to August 2023. We excluded validation studies, opinion pieces, and editorials. When drawing conclusions, emphasis was placed on meta-analyses of clinical trials (eg, Cochrane reviews), individual clinical trials, and, when clinical trial data were unavailable, metaanalyses of observational studies.

방법
이 서술적 검토는 2018년부터 2023년까지 발표된 여러 체계적 검토를 바탕으로 합니다. 

이 중에는 2020년 Lancet Commission 검토7와 알츠하이머 협회의 '알츠하이머 병 사실과 통계' 3(매년 업데이트됨)가 포함됩니다. 

우리는 Lancet 검토의 각 주제 헤더와 우리가 알고 있는 다른 주제를 대상으로 PubMed를 검색하여 2020년 1월부터 2023년 8월까지 발표된 새로운 연구를 추가했습니다. 검증 연구, 의견 기사, 편집 칼럼은 제외했습니다. 결론을 도출할 때 임상 시험의 메타분석(예: Cochrane 리뷰), 개별 임상 시험에 중점을 두었으며, 임상 시험 데이터가 없는 경우 관찰 연구의 메타분석을 참고했습니다.

Prevention

Most of the evidence supporting strategies to prevent dementia is based on observational studies, and the few randomized clinical trials (RCTs) have important limitations. Preventive measures are aimed at reduction of modifiable risk factors, including social determinants of health. In 2019, the World Health Organization published guidelines on risk reduction of cognitive declineand dementia,8 and in 2020, the Lancet Commission identified 12 modifiable risk factors that account for an estimated 40% of dementia risk worldwide (Table 1).7None of these risk factors has a relative risk that exceeds 1.9. Moreover, conclusive RCTevidence is lacking thatmodification of any risk factor can prevent dementia. Nevertheless, several potentially valuable interventions can be initiated in midlife or later life that may have beneficial effects for individual patients (Table 2).9-39

예방 

치매 예방 전략을 뒷받침하는 대부분의 증거는 관찰 연구에 기반을 두고 있으며, 소수의 무작위 대조 시험(RCT)은 중요한 한계를 가지고 있습니다. 예방 조치는 수정 가능한 위험 요인의 감소를 목표로 하며, 이는 건강의 사회적 결정 요인을 포함합니다. 2019년 세계보건기구(WHO)는 인지 기능 저하 및 치매 위험 감소에 대한 지침을 발표했으며,8 2020년 랜싯 위원회는 전 세계 치매 위험의 약 40%를 차지하는 12개의 수정 가능한 위험 요인을 식별했습니다(표 1).7 이 중 어느 위험 요인도 상대 위험도가 1.9를 초과하지 않습니다. 또한, 어떤 위험 요인의 수정으로도 치매를 예방할 수 있다는 결론적인 무작위 대조 시험(RCT) 증거는 부족합니다. 그럼에도 불구하고, 중년기나 노년기에 시작할 수 있는 몇 가지 잠재적으로 유용한 개입 방법이 개인 환자에게 유익한 효과를 가져올 수 있습니다(표 2).9-39

Education/Cognitive Stimulation

Higher levels of education in childhood and late adolescence appear to be most important for late-life cognition.40 The effects of education and cognitive stimulation in later life are more difficult to ascertain because of the possibility of reverse causation (ie, people do not participate in these activities because they already have cognitive impairment). Systematic reviews of interventions, such as computerized cognitive training, have failed to find convincing evidence of improvement of cognition,41 though some have demonstrated improvement on the specific tasks trained.9

Hearing Aids

Evidence on treating hearing loss as a means of preventing dementia is mixed. A meta-analysis of mostly observational studies concluded that hearing aids and cochlear implants led to a 19% reduction in cognitive decline,10 but a recent clinical trial of a hearing intervention failed to demonstrate a benefit on cognition at 3 years.11

Treatment of Cardiovascular Risk Factors

Observational studies13 and a Cochrane review of clinical trials14 examining the association of blood pressure control with prevention of dementia had conflicting results. In the SPRINT MIND trial,12 intensive treatment of blood pressure to a target of less than 120 mm Hg vs 140 mm Hg reduced incident probable dementia by 17%, but this was not a statistically significant finding. However, secondary outcomes of mild cognitive impairment (MCI) or MCI or dementia demonstrated similar reductions in risk and were statistically significant. The use of statins to reduce cognitive decline or dementia was not supported in a Cochrane review,15 nor was aspirin protective in a large clinical trial.16

Diet

Observational studies support the protective effect of a Mediterranean diet, the DASH (Dietary Approaches to Stop Hypertension) diet, and a hybrid of the 2 called the MIND diet.21 However, a recent clinical trial comparing 3 years of a MIND diet with a control diet with mild caloric restriction did not demonstrate differences in global cognition or magnetic resonance imaging (MRI) findings of dementia.22 Among mostly middle-aged persons with overweight and obesity, weight loss was associated with improved attention and memory.23

Alcohol Consumption and Smoking 
The evidence on alcohol use and subsequent dementia is mixed. Many studies suggest that light to moderate drinking has a protective effect compared with abstinence.17,18 Some,19,20 but not all,17 studies suggest that heavy drinking or alcohol use disorders increase dementia risk. In a longitudinal study, tobacco smoking cessation was associated with reduced risk of dementia over the subsequent 8 years.24

알코올 섭취와 흡연
알코올 섭취와 치매 발병 간의 관계에 대한 증거는 혼합되어 있습니다. 많은 연구는 경도에서 중등도의 알코올 섭취가 금주에 비해 보호 효과를 보인다고 제안합니다.17,18 일부 연구19,20는 과도한 알코올 섭취나 알코올 사용 장애가 치매 위험을 증가시킨다고 제안하지만, 모든 연구가 이를 확인하지는 않았습니다.17 장기 추적 연구에서 흡연 중단은 이후 8년간 치매 위험 감소와 연관되었습니다.24

Depression

The relationship between depression and dementia is complicated. Depression can be a predictor of future dementia, a prodrome or presenting symptom of dementia, or a concurrent illness. Moreover, observational studies generally have not distinguished between treated and untreated depression. Although treatment of major depression with antidepressants can improve psychomotor speed and delayed recall,25 to our knowledge, no RCT has demonstrated that treatment of depression prevents dementia. Sleep In longitudinal studies, sleep disturbances have been associatedwith increased risk for all-cause dementia, AD, and vascular dementia.42 Specific sleep disorders were associated with different types of dementia, including insomnia (AD) and sleep-disordered breathing (allcause, AD, and vascular). Retrospective observational data suggest that treatment of obstructive sleep apnea with positive airway pressure can reduce the incidence of dementia and AD specifically.26 Although obstructive sleep apnea is associated with increased AD cerebrospinal fluid biomarkers, clinical trial evidence is lacking that treatment with continuous positive airway pressure can reverse these changes.43 Delirium Prevention Delirium, an acute confusional state that affects up to 50% of hospitalized adults and up to 80% in the intensive care unit, is a potentially modifiable independent risk factor for the subsequent development of dementia.44 Delirium is independently associated with cognitive decline and dementia in older adults45 and accelerates the trajectory of cognitive decline in those with dementia.46 Moreover, delirium may be preventable in about 50% of cases through multicomponent targeted intervention strategies.47,48 A simulation estimated that 6 new cases of dementia could be prevented per 1000 patients receiving a nonpharmacologic delirium prevention approach.27 Social Isolation Longitudinal studies have shown that frequent social contact in middle and early old age was associated with decreased dementia risk, but dementia may cause social isolation rather than the reverse.28A systematic review of interventions to increase social activity that included 3 RCTs with a total of 586 participants demonstrated small improvements on some cognitive tests.29 Physical Activity/Exercise Meta-analyses of observational studies of exercise indicated benefit of exercise on prevention of AD and dementia.30,31 The timing of physical activity may be important. Midlife physical activity has not been shown to be associated with cognitive performance,49,50 whereas later life physical activity has,30 although reverse causation is a possible explanation. A multicomponent exercise intervention that included strength training improved cognition in a RCT, especially for those with MCI.32 Diabetes A Cochrane review found no benefit of intensive control compared with standard diabetes management on cognitive decline at 5 years.35Meta-analyses of the association ofmetformin use with cognitive impairment have been mixed.33,34 Multifactorial Interventions Various multifactorial interventions have demonstrated benefits on cognition.36,37 The 2-year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)38 reported that a combination of diet, exercise, cognitive training, and management of cardiovascular risk factors improved cognition in healthy older adults who were at increased risk of cognitive decline; participants were not followed up long enough to determine the effect on dementia prevention.In theSystematicMulti-DomainAlzheimerRisk Reduction Trial (SMARRT), a personalized multifactorial intervention led to modest improvements in cognitive composite score, risk factors, and quality of life compared with a health education control group.39

What to Watch For

Ongoing RCTs will likely provide more clarity on the role of combined lifestyle interventions (US POINTER),51 statin therapy (PREVENTABLE),52 and the provision of hearing aids (HearCog)53 on preventing dementia.

Disease Treatment

Appropriate treatment of dementia is guided by the cause of dementia and the stage. In 2011, the National Institute on Aging and Alzheimer’s Association classified AD into 3 stages: (1) preclinical, in which cognition is normal and AD is defined by abnormal biomarkers; (2) MCI, in which cognition is impaired but function is intact and biomarkersmayhelpinformprognosis;and (3)ADdementia,inwhichcognition and function are impaired and biomarkersmay be helpful in excluding AD as cause.54,55 In 2018, the National Institute on Aging and Alzheimer’s Association proposed the AT(N) schema for AD, a clinically agnostic, biologically based classification of AD anchored by key biomarkers:amyloid (A), tau (T),and neurodegeneration (N).56A new framework for diagnosis and staging of AD is currently under consideration and includes incorporation of plasma biomarkers and classification criteria to accommodate nonequivalence between fluid and imagingbiomarkers.57Similarly, researchandclinicaldefinitionsofMCI and dementia stages have been outlined for dementia with Lewy bodies,58 Parkinson disease,59 frontotemporal degeneration,60 and vascular cognitive impairment.61The recent approval of newmedications forADand the growingexpansionofdevelopmentpipelineswith potentially more effective drug treatments across all dementiarelatedconditionswill requirespecialistsandprimarycarecliniciansalike to beable to identifyand start treatmentsearlier in the diseasecourse. AD is treated with cholinesterase inhibitors (CIs) donepezil, rivastigmine, and galantamine and N-methyl-D-aspartate receptor antagonistmemantine.CIsincreaseacetylcholineavailability,whichisimportant for memory function, and memantine reduces excitotoxic damage to neurons and resulting agitation and irritability.62Donepeziland rivastigmineareapproved to treatmild to severe dementia due to AD, whereas galantamine is approved for mild to moderate AD dementia.Memantine isapproved formoderate to severeAD dementia (Table 3). When they were first approved, the efficacy of CIs was challenged formultiple reasons, including use of cognitive scales during the trials thatwerenotusedinclinicalpractice, thevariabilityofcognitive benefit across patients, and that despite a statistically significantdifferencebetweendrugandplacebo groupsin theirchange from baseline scores, the effect size was still small and the clinical importance not clear.63 Itwasalso notknownwhether long-term usewould accompany desired outcomes, such as delay in institutionalization. It isnowestablished that response toCIsiscomplexandaffectedbymany factors, including but not limited to signs of cholinergic deficit, stage of disease, rate of disease progression, presence of apathy, concomitant diseases, and education level.64 CIs are associated with modest but persistent cognitive benefits over several years and reduced mortality,65,66 and both CIs and memantine have demonstrated prolonged time to institutionalizationand reduced caregiver burden.66,67 New immunomodulators targeting β-amyloid plaques and protofibrils, hallmark neuropathological features of AD, are now approvedby theUSFoodandDrugAdministration (FDA) forpersonswith MCI or early AD. Aducanumab, lecanemab, and donanemab indisputably reduce brain amyloid levels below the threshold level considered to beabnormal onamyloid positronemission tomography.However, evidence of clinical efficacy has been inconsistent and has prompted reconsideration of the amyloid hypothesis.68 Many questions about amyloid remain unanswered, including its biological functionand the reasonbehinditsaccumulation, theevidenceofpresymptomatic brainamyloid burdenwithout universal cognitive decline, the discordance between location of deposition and cognitive deficits on clinicalexamination,andamoreconsistent relationshipbetweenphosphorylated tau accumulation and cognitive decline.69-71 Lecanemab and donanemabare the firstamyloid-targeting drugs to showameaningfully slower rate of decline (27%-40%) in multiple cognitive and functional measures compared with placebo, as well as beneficial downstream effects on phosphorylated tau.72,73 It is estimated that these medications (Table 3) may slow disease progression by about 5 months, but it is difficult to know whether they will produce a clinicallyimportantandsustainedbenefitinanyparticularindividual.74Aducanumab’s effect on reduction of cognitive and functional decline is inconclusive, leading to its provisional FDA approval designation in 2021. As of November 2024, aducanumab will no longer be available in the US.

Themost noteworthy adverse effects of amyloid immunomodulatory drugsarevasogenic brainedemaand brain bleeding in the form of microhemorrhages or macrohemorrhages or superficial siderosis (amyloid-relatedimagingabnormalities [ARIA],namelyARIA-E [edema] or ARIA-H [hemorrhagic]).75 Risk of ARIA greatly increases with apolipoprotein Eε4 genotype, particularly homozygotes.Symptomsmay include confusion, headache, seizure, or focal neurological signs.ARIA is asymptomatic in about 70% of people and requires close MRI and clinical monitoring, particularly in the first 5 months of treatment, though ARIA can occur at any time throughout the treatment period. The frequency of surveillance MRIs to check for ARIA during treat ment is before the 5th, 7th, and 12th (aducanumab) or 14th (lecanemab) doses. There are no standard protocols as to how often surveillance of a patient’s clinical examination or routine laboratory tests should be carried out while receiving this therapy. If ARIA is suspected based on an abrupt change in neurological status, a brain MRI should be obtained as part of an emergent workup, and a clinical examination andMRImay need to be repeatedmonthly until neurological symptoms and changes on the MRI resolve. Appropriate use recommendationshavebeenpublished for thesemedicationsandprovide guidance onadministrationandmanagement of their routine useand commonadverseeffects.76,77Theprocess todetermineapatient’sappropriateness to receiveamyloidimmunotherapyis substantialandincludescognitive testing to ruleoutmoderateorseveredementia,proof of elevated brain amyloid, apolipoprotein E ε4 testing, and baseline brain MRI to eval‎uate for the presence of hemorrhages (1 macrohemorrhageor>4microhemorrhagesareexclusionarycriteria tostart treatment).Therapy requiresmonthly (aducanumab,donanemab)or twice monthly (lecanemab)infusions forup to 12 (donanemab) to 18months (lecanemab)and possibly beyond (aducanumab),aswellas serial surveillance MRIs for the first 4 to 5 months. In light of the high costs of thesedrugsand theiradministration,debate remains regarding theeffectiveness and value of these amyloid immunomodulators.78,79 There are no FDA-approved medications for non-AD dementias (Table 4), with the exception of rivastigmine for mild to moderate dementia in patientswith Parkinson disease and dementiawith Lewy bodies.80,81Off-label use of CIs and memantine for dementia with Lewy bodies, vascular dementia, and dementia due to traumatic brain injury is common, and though evidence is weak,82,83 there is some evidence to show a small benefit (Table 4).84 CIs and memantine are not recommended in frontotemporal dementia due to lack of efficacy.85

What to Watch For

There are currently 141 individual treatments in trials for AD across 12 Common Alzheimer Disease Research Ontology mechanisms86 as well as treatments for AD at the preclinical, asymptomatic stage. The AHEAD study87 is currently eval‎uating the use of lecanemab in asymptomatic individuals with mild to moderately elevated brain amyloid levels. Tau-directed treatments include passive immunotherapies and small molecule tau aggregation inhibitors.88 Ongoing studies are also targeting amyloid and tau simultaneously. Thirteen treatments are under investigation for dementia with Lewy bodies.89 Current investigationalmedications for frontotemporal degeneration have been focused on people with identifiable genetic variations (GRN,C9ORF72), as well as on variousmechanisms to suppress expression‎ and pathological dysregulation of tau and progranulin pathways.90

Treatment of Behavioral and Psychological Complications

Although cognitive impairment is the clinical hallmark of dementia, behavioral and psychological symptoms of dementia (BPSD), such as apathy, delusions, and agitation, are common and often are the presenting symptoms.91-93 BPSD is a fundamental aspect of the neurodegeneration that is present in all forms of dementia and may either arise fromorbeexacerbatedby stressorspresentinpatients (eg,acute infection,delirium), theircaregivers (eg,communication style),or their environment (eg,excessiveauditory stimuli).94Nearlyall patientswill exhibit thesesymptomsatsomepointduring thecourseofdementia.92 When new BPSD occurs, a differential diagnosis should be generated (eg,using theDICE [Describe,Investigate,Create,andEval‎uate] approach95) to help identify a potential underlying cause. There is a considerableevidencebase supportingnonpharmacologicalinterventions to address BPSD in persons living with dementia and associated caregiverdistress.96-98Caregiver-focusedinterventionshave themost consistent evidence base—including common elements such as skills training, psychoeducation,andactivity tailoring—and reduce both frequency and severity of BPSD as well as the caregiver distress in response to such symptoms.99Ifdistressing ordangerous symptoms remain, time-limited trials of pharmacotherapy targeting BPSD can be considered with clear, objective treatment goals in mind.100 If a patient is already prescribed psychoactive medications yet the level of BPSD is severe enough to merit a new medication trial, this suggests that the current regimen is ineffective. Therefore, prior to prescribing newmedications, consider amedication “cleanup” focused on deprescribing psychoactive medications. Following the approach outlined by Davies et al,101 cognitive medications (ie, cholinesterase inhibitors and memantine) should be continued while medications specifically started for BPSD (as opposed to an underlying, preexisting psychiatric disorder) would be considered for discontinuation prior to starting a new medication. Clinicians might prioritize medications for discontinuation based on the evidence of harms, such as where a benzodiazepine or gabapentin is coprescribed with an opioid.102,103But even a medication perceived as relatively safe (eg, a serotonin reuptake inhibitor such as sertraline) could be causing gastrointestinal distress or akathisia that is manifesting as agitation in a patient with dementia. Although evidence of efficacy is lacking, psychotropic medications suchasantidepressants,benzodiazepines,andantiepilepticsare widely prescribed.92,104 Atypical antipsychotics have modest evidenceofefficacy.105Risperidoneisapproved forshort-termuseinboth Canada (aggression or psychosis) and theUK (aggression) and is a potential first pharmacological treatment step formajor, potentially dangerous symptoms that have not responded to behavioral approaches.93 While quetiapine is the most widely prescribed antipsychotic for individuals with dementia,94 it is among those with the least evidence of efficacy for BPSD.99 Two other antipsychotics are worth noting: (1) brexpiprazole,whichwas recently FDAapproved for agitation in persons with AD but has the same classwide safety concerns related to increased mortality as other antipsychotics, and (2) pimavanserin, a serotonin-receptor modulator that acts primarily as a selective 5-hydroxytryptamine receptor subtype 2A inverse agonist and antagonist rather than binding to D2 dopamine or histamine receptors.106 Pimavanserin is FDA approved for the treatment of Parkinson disease psychosis (but not psychosis of AD) and has a potentially lower mortality risk than other atypical antipsychotics used for this indication.107

AlthoughBPSDmay resemble symptoms of psychiatric disorders in individuals without cognitive impairment, medications that are effective for thesedisordersaregenerallynoteffective for thesamesymptomsin dementia.94 Forexample,aCochranemeta-analysis ofantidepressant studies for depression in persons living with dementia concluded that there is insufficient evidence of efficacy,108 though citalopram can reduce agitation.109Antidepressants are also ineffec tive for apathy,110,111 although methylphenidate may be beneficial.112 Antiepileptic “mood stabilizers” (eg,valproicacid,carbamazepine)and trazodone are ineffective for irritability and agitation. Valproic acid merits particular mention because it is perceived as the leading alternative toantipsychotics forBPSD in long-term care settings113despite a Cochrane review recommending against its use in persons with dementia.114 Well-established safety concernsaboutmedications forBPSD includeanincreased riskof fall-relatedinjury formostpsychotropics115-117 andmortality forantipsychotics.118 Lessappreciated is theadverseeffect on cognition in persons with dementia.119,120 Clinicians should monitor for psychotropic changes during inpatient or subacute care120,121 of persons living with dementia and continually reeval‎uate the balance of risks and benefits of these treatments.

What to Watch For A trial of electroconvulsive therapy for agitation in moderate to severe dementia is underway,122 alongwithaCitAD follow-up usingescitalopram (S-CitAD)123 and studiesofcannabinoids.124On thenonpharmacological front,a trialofanonlinecaregiver-directedplatformbased on DICE is underway.125 Limitations When considering prevention, we confined this review to existing published data and did not conduct new analyses. Thus, we were unable to consider the effect of multiple contributors on risk but are able to provide some insight from several studies that address more than 1 risk factor.36-39 We were also unable to compare the relative benefits of these interventions across strata of increasing age, where the balance of risks vs benefits may become less favorable. Although not covered here, key aspects of patient-centered care and health equity must be considered, including focusing on patient- or caregiver-identified goals, caregiver support, use of communitybased services, housing and social issues, and advance directives and hospice. Conclusions Although numerous risk factors for developing dementia have been identified, convincing evidence that modification of these factors, either alone or in combination, can prevent dementia is lacking. AD can be treated with cholinesterase inhibitors, an N-methyl-Daspartate antagonist, or β-amyloid immunomodulator medications, with the last modestly slowing cognitive and functional decline in people withMCI ormild dementia due to AD.Ongoing clinical trials will help to elucidate the long-term clinical efficacy, safety, and cost-effectiveness of theseemerging treatments. Psychotropicmedications have minimal evidence of efficacy for treating BPSD and are associated with notably increased risks of falls and cognitive decline.Ongoing and future research will undoubtedly provide new insights into prevention and treatment of dementia.