Table 3.

Summary of recommendations from 15 guidelines published in 2018–2022

Recommendation	Guidelines including recommendation	Rationale for recommendation
Screening
Assess MCI relating to AD in patients who are concerned, not assume normal aging	AAN 2018 [20]	MCI is associated with increased risk of progression to dementia and indicates a pathologic disease state rather than normal cognitive aging [20]
Administer Mini-Mental State Examination (MMSE) in individuals with neurocognitive disorders to screen dementia	Korean dementia [22]	Not clearly reported (a results summary of individual studies in the supplementary report indicating the sensitivity and specificity of MMSE and Montreal Cognitive Assessment (MoCA) [22]
Take genetic tests early for those with family history and regular screening for people aged > 65 years	TCM Chinese guidelines [18]	Not clearly reported. The recommendation was suggested in the prevention section (supported by at least 1 result of level III-nonrandomized, period-specific, contrast study and expert consensus) [18]
Do not screen asymptomatic community-dwelling adults	MOHM [27]	Balance of benefits and harms from screening asymptomatic community-dwelling adults has not been determined [27]
Testing and diagnosis
Rule out reversible causes, other diseases or conditions (e.g., metabolic, vascular, systemic or psychiatric disorders) or Parkinson disease–MCI or vascular cognitive impairment)	AAN 2018 [20]; Indian dementia [21], Danish MCI [30], NICE dementia [23];	To investigate clinical features that show a high suspicion of reversible or condition-related dementia [21], to avoid premature dementia diagnosis [20] and to establish subtypes [23, 30]
Brief cognitive tests (some example tests are listed), in consideration of other test results and the overall clinical context	AAN 2018 [20]; Danish MCI [30]; Irish dementia [28]; Korean dementia [22]; NICE dementia[23]; Indian dementia [21]	Various instruments have acceptable diagnostic accuracy for detecting MCI, with no instrument being superior to another [20]. A brief cognitive test should be interpreted in the context of other test findings and the overall clinical setting. Despite some methodologic flaws in terms of the evidence base, the findings show that cognitive tests contribute useful information in the evaluation of dementia and MCI [30]. Cognitive function testing provides further information for the clinical assessment [28] and supports clinicians in diagnosing dementia subtypes. A patient’s performance may be affected by education, language, hearing and culture [28]. Administering MMSE may be considered to determine whether overall cognitive function of patients has reached the level of dementia [21, 22]. NICE suggested using validated cognitive testing in initial assessment or if dementia is still suspected [23]
Do not advocate the use of biomarker tests for routine diagnosis	AAN 2018 [20]; Danish MCI [30]; NICE dementia [23]; EANM [16]	There are currently no biomarkers that have been conclusively demonstrated to predict progression [20]; the specificity of these biomarkers is relatively low, entailing many false-positive cases. Biomarkers may be used in situations where in consultation with a person with MCI it is considered crucial to identify the underlying cause of the cognitive problems [30], and to minimize test burden for patients, physicians may consider the use of biomarkers or more specialized imaging for people with suspected AD where diagnostic uncertainty remains. Providers should consider the age of a patient before referring them for biomarker tests due to lack of reliability of some tests in older people [23]. EANM guidelines suggested the use of [18F] FDG-PET could be complementary to other biomarkers to differentiate AD with other subtypes [16]
Consider offering an examination of biomarkers for AD on basis of cerebrospinal fluid analysis or amyloid imaging to increase the certainty of AD	Danish MCI [30]; Korean dementia [22]; NICE dementia [23]	CSF Aβ, total tau, phosphorylated tau test can increase the accuracy of the diagnosis of AD in patients with MCI or dementia [22], investigate diagnostic uncertainty [23, 30]
Clinicians may discuss the option of biomarker research or refer patients, or both, if feasible	AAN 2018 [20]	Identifying biomarkers that can stratify risk is expected to be particularly important for prognosis. There are no biomarkers clearly shown to predict progression in patients with MCI [20]
Assessment of activities of daily living (ADL)	Danish MCI [30]; Indian dementia [21]	A systematic ADL evaluation should be considered as part of a basic clinical assessment of MCI or dementia [30]. Assessment of ADL is crucial since ADL information may support the creation of individualized treatment approaches [21]
Use APOE gene	Korean dementia [22]; NICE dementia [23]	The NICE committee made the decision to issue a “do not use” recommendation for APOE genetic testing because APOE status is more of a risk factor for dementia than a biomarker for the development of dementia [23]. Korean dementia guidelines recommended APOE genotyping can be helpful in the diagnosis and prognostic evaluation of AD dementia in adults with MCI or dementia [22]
CSF testing can be used to confirm/differentiate AD diagnosis	Korean dementia [22]; NICE dementia [23]	Evidence from meta-analysis studies [22]
Imaging of AD focuses on amyloid and FDG uptake and structural atrophy to increase the diagnosis accuracy	Danish MCI [30]; Korean dementia [22]; NICE dementia[23]; EANM [16]	Offering functional imaging ([18F] FDG-PET) could clarify presence or absence of AD [30]; offering structural imaging can exclude other causes of cognitive impairment, establish the subtype dementia [30] and increase the sensitivity and accuracy of AD diagnosis by evaluating the MTL atrophy as well as by excluding other causative disease [22] The use of FDG-PET may be considered by the treating physician based on the varying quality of the evidence, which ranged from very low to moderate. Despite the fact that licensed products are now available for amyloid imaging, little research exists on its accuracy and affordability [23] (18F) FDG-PET is considered to be a maker of neurodegeneration and progression. Clinical studies suggest that (18F) FDG-PET is an independent biomarker for predicting AD conversion in persons with MCI along with amyloid-β and tau, independently of hippocampal volume and of amyloid PET status [16]
Treatment
AchE inhibitors and memantine for AD cognitive symptoms still play the main role	Taiwan dementia [17]; NICE dementia [23]; Australian Deprescribing 1 [24]; Indian dementia [21]	AchE inhibitors and memantine are the approved pharmacologic treatment options for the cognitive impairment in AD. The effectiveness of AchE inhibitors for the cognitive domains and global functioning is clearly demonstrated in short-term 3- to 6-month RCTs. Few studies have shown that AchE inhibitors continue to be beneficial over the long term (up to 1 year). But the quality of this evidence is limited [21]. The NICE committee expressed concerns about the paucity of evidence regarding the initiation of AchE inhibitors and memantine but concurred that initiation is implicitly linked to diagnosis [23]. Based on data from short-term studies, AchE inhibitors and memantine have been found to be cost-effective in treating approved indications in some populations and settings [24]. Studies show that the early and long-term use of donepezil is beneficial for cognitive function. The oral administration of 6–12 mg/day of rivastigmine showed positive effect on cognitive function, daily living and overall assessment for adults with mild and moderate AD. Memantine can improve overall performance, cognitive function, daily function and behavior in adults with moderate to severe AD. Treatment with memantine for 6–7 months is not effective in those with mild AD [17]
No medication is recommended in the treatment of MCI due to AD	AAN 2018 [20]; Taiwan dementia [17]; Indian dementia [21]	No FDA-approved medications for the treatment of MCI. No high-quality or long-term studies supporting pharmacologic or dietary interventions [20]; galantamine can increase mortality risk in adults with MCI. No valid evidence supporting the use of rivastigmine in adults with MCI exists [17]. AchE inhibitors and memantine have not shown beneficial effect in delaying the progression of MCI to dementia. No medication is identified for MCI. It is anticipated that disease-modifying medications for dementia will work better in MCI than in dementia stage [21]
Nonpharmacologic interventions for MCI (e.g., regular exercise, cognitive interventions, resistance training)	AAN 2018 [20]; Taiwan dementia [17]; WHO 2019 [29]	For MCI, treatment with exercise training for 6 months is likely to improve cognitive measures, and cognitive interventions may be beneficial in improving measures of cognitive function [20]. Aerobic exercise and resistance training were more effective in improving executive function than stretching and balance training in adults with MCI [17]. Physical activity may be recommended to adults with MCI to reduce the risk of cognitive decline [29]
Other nonpharmacologic approaches, including acupuncture, diet therapy, smoking cessation, may reduce the risk of cognitive impairment and BPSD and delay the progression of AD	Danish dementia [25]; Irish dementia [28]; Taiwan dementia [17], MOHM [27], WHO 2019 [29], DOHD [26]; TCM Chinese [18]	Nonpharmacologal interventions should be used initially to treat noncognitive symptoms [26], first line for BPSD [28], and combined with antipsychotic medication [25]. Nonpharmacologic interventions attempt to promote positive effects on cognition, quality of life, mood and other BPSD [27]. Mediterranean diet and an antihypertensive diet together were significantly positively correlated with postponing cognitive aging and may lower the risk of AD [17]. For mild to moderate AD patients, acupuncture for 12 weeks 3 times per week enhanced the ADAS-cog score [17]. Interventions for tobacco cessation should be offered to adults who use tobacco since they may reduce the risk of cognitive decline and dementia in addition to other health benefits [29]
Monitoring
Cognitive status of patients with MCI should be monitored over time	AAN 2018 [20]	Patients with MCI can improve, remain stable or progress cognitively over time [20]
Frequent reviews of medications and cognitive status were recommended. Regular physical examination for persons aged ≥ 65 years	Irish dementia [28]	It is important to support needs of patients and carers after diagnosis [28]
Evaluate the clinical progress of elderly people with subjective cognitive decline (SCD) through periodic follow-ups every 1 or 2 years	Korean dementia [22]	Older people with SCD show higher risk of progression to AD dementia than those without SCD [22]
Do not stop AchE inhibitors in AD patients because of the severity alone	NICE dementia [23]	Evidence suggested that using a set cut-off for disease severity to determine when to stop treatment is not possible (as no effective cut-off to use was found) [23]
Deprescribing an AchE inhibitor or memantine should be a trial discontinuation, with close periodic monitoring (e.g., every 4 weeks) and re-initiation of the medication if the individual shows clear worsening of condition after withdrawal	Australian Deprescribing 1 [24]; Australian Deprescribing 2 [19]	Practice points are not a direct result of SR [19, 24]

(18F) FDG-PET = 18F-fluorodeoxyglucose-positron emission tomography; AAN = American Academy of Neurology; Aβ = amyloid beta; AChE = acetylcholinesterase; AD = Alzheimer’s disease; ADAS-cog = Alzheimer’s Disease Assessment Scale–cognitive; ADL = activities of daily living; APOE = apolipoprotein E; BPSD = behavioral and psychologic symptoms of dementia; CSF = cerebrospinal fluid; DOHD = Department of Health Dublin; EANM = European Association of Nuclear Medicine; FDA = US Food and Drug Administration; FDG = fluorodeoxyglucose; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; MoCA = Montreal Cognitive Assessment; MOHM = Ministry of Health Malaysia; MTL = medial temporal lobe; NA = not applicable; NIA-AA = National Institute on Aging and Alzheimer's Association; NICE = National Institute for Health and Care Excellence; PET = positron emission tomography; RCT = randomized controlled trial; SCD = subjective cognitive decline; SR = systematic review; TCM = traditional Chinese medicine