Focusing on earlier diagnosis of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is considered a continuum, progressing from preclinical disease to mild cognitive impairment (MCI) as an early stage, before reaching clinically apparent dementia. Although it is difficult to assess the potential impairments in performance of patients with MCI due to AD, this condition should be diagnosed as early as possible so that, by means of early interventions, patients can maintain their quality of life longer. Healthcare systems should support primary care physicians in their effort to identify patients with MCI due to AD and refer patients to memory clinics and specialists who can provide a reliable diagnosis and initiate appropriate disease management. This review discusses the benefits of earlier AD diagnosis, along with potential challenges and future directions.

Tweetable abstract

Healthcare systems need to support primary care physicians to identify patients with MCI due to AD to refer to specialists who can start managing the disease. Read our review on earlier diagnosis of AD.

Executive summary

• This review summarizes the benefits and challenges of earlier diagnosis of Alzheimer's disease (AD).

• Mild cognitive impairment (MCI) due to AD: risk factors and comorbidities

  	○	It is necessary to identify the underlying pathology of MCI to predict the risk of MCI progressing to dementia.
  	○	Diagnostic efforts must be expanded to further explore the causes of MCI and examine potential risk factors, such as amyloid/tau/neurodegeneration (ATN) pathologies, neuropsychological changes and comorbidities.

• Benefits of an earlier AD diagnosis

  	○	A timely diagnosis offers patients the opportunity to manage symptoms, implement coordinated care plans and seek effective support and treatment that could delay disease progression.
  	○	For care partners, an early diagnosis would offer time to adjust to and assume a care partner role.
  	○	Early diagnosis of AD would enable sufficient monitoring and effective interventions as early in the disease stage as possible to ensure that patients' level of function can be maintained for longer, delaying transition to a care facility, which in the long term, might also result in healthcare cost savings.

• Challenges for early AD diagnosis

  	○	Key guidelines on methodologies for early AD identification need to be aligned to allow for better characterization of disease stage, which would consequently help clinicians make informed decisions on disease management.
  	○	In the primary care setting, MCI is commonly underdiagnosed due to barriers such as short duration of visits, multiple comorbidities in the older population, poor integration of cognitive assessments in electronic medical record systems, insufficient reimbursement of cognitive assessment costs, high variability of MCI symptomatology, and difficulty assessing multiple domains of cognition in short tests.
  	○	Diagnostic biomarkers such as those detected from cerebrospinal fluid tests and PET are widely used in clinical research, but these are difficult to use in clinical practice and outside specialized clinics due to limited accessibility, invasiveness of the procedure, and high costs. Blood-based biomarkers could be used in primary care to identify individuals who need to be referred for further cognitive evaluation by specialists.

• Future perspectives on an earlier AD diagnosis

  	○	In the future, the recorded prevalence of the early stages of the disease may increase, as patients who may benefit from novel AD treatments will be diagnosed earlier.
  	○	The use of blood biomarkers in combination with easy-to-use cognitive assessment tools will enable physicians to promptly identify patients with early AD. Early detection of AD will facilitate prompt intervention against pathological changes that may, in turn, slow disease progression and cognitive decline.
  	○	It is necessary that primary care physicians are appropriately resourced with access to easy-to-use cognitive assessment tools and plasma biomarkers that can be implemented into the workflow of a primary care setting.
  	○	There is a need to raise awareness of the clinical value of early AD detection, and to this end, healthcare stakeholders, including patient organizations and payers, can promote broad communications and disseminate relevant materials that can help further educate primary care physicians.

• Early AD diagnosis is vital for patients to benefit from the right pharmacological and non-pharmacological interventions at the right time to maintain their quality of life. Healthcare systems should keep up with the evolving diagnostic and therapeutic landscape of AD.

Keywords: :

• AD dementia
• Alzheimer's disease
• Alzheimer disease
• amnestic
• cognitive disorders
• cognitive symptoms
• dementia
• diagnosis of MCI due to AD
• early AD diagnosis
• MCI due to AD

Current estimates show that more than 55 million people live with dementia worldwide, with approximately 10 million new cases diagnosed every year, and AD contributes to 60–70% of these cases [1]. According to the US FDA and National Institute on Aging – Alzheimer's Association (NIA-AA) staging, the AD continuum begins with preclinical AD, followed by mild cognitive impairment (MCI) due to AD [2]. The prevalence of all-cause MCI is 8.4% in people aged 65–69 years, rising to 10.1% in those aged 70–74 years, 14.8% in those aged 75–79 years and 25.2% in those aged 80–84 years [3]. As not all MCI is due to AD, identification of the underlying pathology is important for further management [4], and early intervention is essential as it may delay progress to more advanced disease stages. It is estimated that there are 69 million people living with MCI due to AD globally, ranging from 42 to 110 million, constituting 3.7% of all people aged 50 years and above [5]. Nevertheless, AD is currently underdiagnosed [6,7], and healthcare systems should implement efficient strategies for screening in at-risk populations.

Although several guidelines have indicated the need for intervention as early in the AD continuum as possible [8], in clinical trials on patients with preclinical AD, there are challenges in measuring improvements following an intervention, as these individuals have no signs of clinical impairment, and it might take several years to detect any transition from asymptomatic to symptomatic disease [9]. At present, clinical practice recommendations address identification of MCI, but the focus on the MCI stage may shift in the future to preclinical phases, especially if relevant treatment becomes available.

Early detection of AD-associated symptoms is fundamental for the management of dementia-related changes in daily life, to enable people living with AD and their care partners to make future care plans as well as seek early symptomatic and lifestyle interventions [10] or disease-modifying therapies (DMTs) that are or will soon be available for people with early AD (i.e., people with AD in the MCI or mild dementia stage) [11–14]. This review summarizes the benefits of an earlier AD diagnosis along with potential challenges and future perspectives.

MCI due to AD

MCI is a syndrome that may occur in the intermediate stage between the cognitive decline expected with physiological aging and the more severe decline observed in dementia [15]. It can be further characterized as amnestic or non-amnestic. People with amnestic MCI experience memory impairment, which is more often due to AD; hence, they have a higher risk for progression to dementia [15] as compared with those with non-amnestic MCI. The annual progression rate for amnestic versus non-amnestic MCI, where no biomarker for AD or other neurodegenerative disease has been assessed, is 18.2% versus 9.5% person-years, respectively [16]. Both amnestic and non-amnestic MCI are broad diagnostic terms that include clinical syndromes of degenerative and non-degenerative etiology and may present executive, speech, visuospatial and/or behavioral features [17]. According to the NIA-AA and FDA staging for the AD continuum, MCI due to AD is stage 3 AD, characterized by the pathological features of AD and subtly impaired performance on sensitive neuropsychological measures, as well as mild functional deficits [2]. Mild AD dementia is stage 4 AD, where patients have clinically diagnosed mild dementia; early AD encompasses patients with MCI due to AD as well as those with mild AD dementia [2,18]. In patients with clinical MCI, MCI due to AD can be diagnosed with biomarker evidence (cerebrospinal fluid, positron emission tomography [PET] and/or blood biomarkers) of AD pathology.

Risk factors for developing MCI due to AD

Identifying the underlying pathology is necessary to predict the risk of MCI progressing to dementia. MCI will not necessarily progress to dementia and may even revert to unimpaired cognition [19]; this strongly depends on the underlying etiology. In a US cohort of 18,103 individuals with varying degrees of cognitive impairment (ranging from unimpaired cognition to severe AD dementia), the annual probability of transitioning to a more severe state was 22% for individuals with MCI due to AD at the age of 65 years, with the likelihood of progression increasing with age [20]. In a study using follow-up data from AD research centers funded by the NIA, the annual probability of transitioning to more severe stages in people with MCI due to AD was 0.251 [21]. Therefore, diagnostic efforts should be expanded to identify the underlying cause of MCI and examine potential risk factors, markers for amyloid/tau/neurodegeneration (ATN) pathologies, neuropsychological changes and comorbidities.

According to studies using common measures among different data sets—including Alzheimer Disease Neuroimaging Initiative; National Alzheimer's Coordinating Center; Framingham Heart Study (FHS); BIOCARD; Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing; and AddNeuroMed—potential risk factors for developing AD include age, diagnostic state (unimpaired cognition or MCI), APOE ϵ4 carrier status and sex. Although age was the most significant risk factor, its effect on developing AD was not clear, because the effect of the interaction between age and diagnosis differed considerably among models and data sets [22]. As research in the field of AD is progressing, additional risk factors for the development of MCI due to AD will continue to emerge, underscoring the need for further research in this area.

Comorbidities in people with MCI due to AD & AD dementia

In a matched case-control study on a US claims database, the burden of comorbidities was observed to commence years prior to AD diagnosis. Such comorbidities included psychiatric disorders; cerebrovascular disease; and metabolic, cardiovascular and respiratory complaints [23]. In a recent systematic literature review on the relationship between comorbidities and AD progression, neuropsychiatric symptoms were found to become more frequent with increasing AD severity. The authors noted that there was no consistent association between cardiovascular risk factors and AD severity or progression [24]. A second systematic review conducted by Lanctôt et al. (2023) found that individuals with AD dementia were more likely to have cardiovascular disease than those without AD [25]. In a study using two large real-world US databases, people with MCI due to AD and those with AD dementia had a higher prevalence of cardiometabolic comorbidities compared with those with no diagnosis of all-cause MCI or AD dementia; more than half of those with MCI due to AD or clinically diagnosed with AD dementia had overweight or obesity [26].

With regard to modifiable risk factors, a US study that assessed the role of vascular risk factors in future risk for AD dementia in FHS participants showed that a 15 mg/dl increase in high-density lipoprotein cholesterol (‘good’ cholesterol) was linked with a lower risk for AD in early (35–50 years) (15.4%, p = 0.041) and middle (51–60 years) (17.9%, p = 0.014) adulthood. Similarly, a 15 mg/dl increase in glucose measured in middle adulthood was linked with a higher risk for AD (14.5%, p = 0.00029), suggesting that blood glucose and cholesterol management in early adulthood may decrease the risk for clinically diagnosed AD dementia [27]. Moreover, a recent study showed that ATN pathology combined with depression is also associated with an increased risk for conversion to dementia in people with MCI; in this study, 82.6% of participants had the amnestic MCI subtype [28]. Optimal management of comorbidities could be a practical approach to MCI management; therefore, it is important to identify the underlying etiology of MCI and investigate common comorbid conditions and risk factors in individuals with MCI due to AD [29].

Benefits of an earlier AD diagnosis

Impact on people living with AD & care partners

Individuals with MCI due to AD have the pathological features of AD and exhibit impaired performance on neuropsychological measures as well as impaired instrumental activities of daily living. Those with mild AD dementia have more overtly affected cognition and loss of basic daily functions [2,9]. Some people with early AD and/or their care partners may initially seek diagnostic assessment for various reasons, such as to investigate a perceived change in memory. Information on prognosis, treatment options and support programs may be sought after a diagnosis is made. A personalized approach may also need to be considered when disclosing the risk of developing AD dementia to the patient or their care partner. On receiving a diagnosis of AD, some individuals may feel anxious due to the stigma of AD and may feel vulnerable because of uncertainty around the extent and timing of deterioration. Others may focus on coming to terms with the diagnosis and try to adapt by using coping strategies and accepting support from their families, which can help them maintain personal agency and self-worth [30].

Overall, a timely diagnosis offers the opportunity to manage symptoms, implement coordinated care plans, seek effective support and symptomatic treatment that could help improve cognitive function, and even postpone moving to a care facility [31]. With early diagnosis, it may be possible to delay the development of dementia in a proportion of individuals by modifying exposure to certain risk factors. For families or care partners, an early diagnosis would allow time to adjust and facilitate transition to a care partner role [32]. A systematic review and meta-analysis showed that early-stage interventions aimed exclusively at care partners of people with MCI or mild/early-stage dementia living in the community can improve the care partners' well-being, ameliorate anxiety and caring-related distress, and improve their ability to provide care [33].

Impact on healthcare resources

Effective interventions, which require a timely diagnosis of AD, should be used as early in the disease stage as possible, as individuals' level of function can be maintained for longer, which might also result in healthcare cost savings in the long term [32]. The GERAS-J and GERAS-US cohort studies, conducted in Japan and the US, respectively, found that direct patient healthcare resource utilization was not the main driver of the overall cost of AD; particularly in people experiencing mild dementia due to AD, informal care provided by care partners accounted for the greatest proportion of overall societal cost [34,35]. However, the direct cost of formal care provided by healthcare professionals should not be underestimated, especially as this is one of the major challenges that healthcare systems could face in the near future. By diagnosing individuals early, those with MCI due to AD can be identified and monitored. A delay in disease progression by 20–30% during the earlier AD stage could allow for more time in a less impaired/more functional stage [36]. A US study examining economic burden in people transitioning to later stages of AD showed that any timely intervention that could delay AD progression could have a positive impact on the economic and health burden of the disease in the US [37].

Use of DMTs in early AD

There is a need for treatments that will interrupt the progression of AD ideally before the onset of symptoms or when symptoms are emerging. By definition, DMTs are expected to produce an enduring change in the course of AD [38]. There are three major therapeutic categories that are currently being explored for AD: agents targeting neurotransmitters/receptors, agents targeting amyloid-β production and aggregation, and approaches targeting neuroinflammation [39]. As AD is a very complex disorder affecting all brain cell types, symptomatic AD will eventually need to be approached with combination therapies that will target different underlying pathologies [40].

Earlier diagnosis can enable people with AD to receive novel DMTs earlier in the disease continuum. Amyloid-β accumulation is considered to play a key role in the pathogenesis of AD, and aducanumab and lecanemab—which are amyloid-β immunotherapies—are currently the only FDA-approved DMTs for the treatment of early AD, with evidence of reducing amyloid-β plaques [11–14]. However, despite clear evidence that aducanumab—the first FDA-approved anti-amyloid-β monoclonal antibody—reduces amyloid-β plaques in the brain, its effect on slowing cognitive decline and improving daily function remains uncertain [40], which has been a barrier to its approval by the European Medicines Agency.

Lecanemab has recently been shown to reduce brain amyloid levels in patients with early AD; based on clinical measures of cognition and function, it was found to be associated with a statistically significant reduction in cognitive decline compared with placebo at 18 months [14]. An ongoing Phase III study, AHEAD 3–45, aims to evaluate lecanemab in patients with preclinical AD and elevated amyloid levels, as well as in those with early preclinical AD and intermediate amyloid levels [41]; this study will generate important information on the relevance of early initiation of DMTs. Donanemab, another amyloid-β immunotherapy, has recently been shown to slow clinical progression in an 18-month Phase III trial in patients with early symptomatic AD and with low/medium or high tau pathology [42]. Novel DMTs under investigation in clinical trials have the potential to demonstrate further meaningful outcomes. As the treatment landscape is evolving, primary care physicians will need the right tools for early-stage biomarker-proven AD diagnosis [43].

Challenges for early AD diagnosis

AD definition

The term AD describes a continuum ranging from no cognitive impairment to severe dementia [44]. In 2018, based on the NIA-AA diagnostic framework, the presence of the two pathological hallmarks, abnormal amyloid-β and tau biomarkers, was defined as AD even in the absence of cognitive symptoms [44,45]. Based on the 2021 clinical diagnosis recommendations of the International Working Group, amyloid-β and tau biomarkers alone, without clinical input, are not sufficient to predict progression to MCI or dementia due to AD or to define an individual's place on the AD continuum [44].

In autosomal dominant AD, there are mutations in the genes encoding presenilin 1, presenilin 2 or amyloid precursor protein. On the other hand, sporadic AD is determined by the impact of several genes (such as the APOE gene), environmental exposures and other unknown factors [46]. The ATN framework proposes a purely biological definition of AD as a proteinopathy, where a patient's condition is categorized depending on abnormalities in three biomarkers (amyloid, tau and neurodegeneration) [47] on a continuum of neuropathological changes. This is based on a deterministic interpretation of the amyloid cascade hypothesis, according to which the events of amyloid and tau deposition inevitably lead to neurodegeneration and progressive cognitive impairment. Such a model would be fully congruent with observations in individuals with autosomal dominant AD but may be less applicable to those with sporadic AD. Therefore, a probabilistic model of AD has been proposed (by Frisoni et al. 2022), which suggests that amyloid deposition is a risk factor for disease progression [46]. According to this model [46], three variants of AD may be defined—autosomal dominant AD, APOE ϵ4-related sporadic AD, and APOE ϵ4-unrelated sporadic AD—accounting for the neuropathological and clinical variability seen in people with AD. Aligning methodologies for identification of early AD from key guidelines could allow for better characterization of disease stage, which would in turn help clinicians make informed decisions on disease management.

Cognitive assessment in clinical practice

A recent systematic review and meta-analysis identified several rapid (≤5 min) cognitive screening tools for MCI in different settings. Among cognitive assessment tools, including the rapid cognitive screening, six-item screener, Mini-Cog, and clock-drawing test, the rapid cognitive screening demonstrated superior sensitivity and specificity. The clock-drawing test as a stand-alone tool was found to be ineffective for MCI detection. However, the diagnostic accuracy of these rapid assessment tools remains to be further investigated [48].

Although it is vital that clinical trial end points capture information relevant to clinicians and individuals with AD, many of the measures that are designed and used for research are time-consuming and inconvenient in the context of a busy clinical setting. However, some of these assessment tools can be used in clinical practice, such as the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Functional Activities Questionnaire (FAQ) and Neuropsychiatric Inventory Questionnaire (NPI-Q). The MMSE and MoCA are used in cognitive assessment; the FAQ in functional assessment; and the NPI-Q in behavioral assessment. Tools used in clinical trials and clinical practice for assessing patient and care partner burden include the EuroQol 5-Dimension Questionnaire, Quality of Life in AD scale and the Zarit Burden Interview, although the latter's length may limit its use in clinical practice [2].

There are also several computer-based diagnostic tools that have been developed and can be used to diagnose cognitive impairment in clinical practice, such as the self-administered, verbal episodic memory test application, FACEmemory^®, which can detect memory deficits in amnestic MCI and can be used in primary care settings [49,50]; the PredictND, which can support clinicians in the differential diagnosis of dementia in memory clinics [51]; and the longitudinal cognitive test Altoida Digital Neuro Signature, which can detect longitudinal individual-level changes in people with MCI (due to AD or all-cause MCI) and AD dementia [52]. Other unobtrusive methods to detect MCI, such as passively measuring routine home computer activity or in-home sensor technology combined with wearable devices, have been studied in community-dwelling senior citizens [53,54]; however, such methods present certain ethical challenges, since private and sensitive information may be collected with some of these technologies.

In the primary care setting, MCI is commonly underdiagnosed because of barriers associated with the evaluation of an individual's cognitive performance. These barriers include the short duration of most primary care visits, high prevalence of comorbidities in older adults, poor integration of cognitive assessments in electronic medical record systems, insufficient reimbursement of costs pertinent to cognitive assessment, difficulty of assessing multiple domains of cognition in short tests, and high variability of MCI symptomatology among individuals [55]. A retrospective, observational study of older adults with incident dementia or MCI revealed that only 26% of individuals in the incident dementia cohort and 11.4% of individuals in the MCI cohort received a timely diagnosis, defined as receiving a self- or proxy-reported healthcare provider diagnosis prior to or in the same interview as the first dementia-qualifying/confirmatory MCI score. The researchers found consistent disparities in timely diagnosis across sociodemographic characteristics such as race, ethnicity and educational background [56]. Since cognitive impairment screening is not routinely performed in older adults, interventions focusing on underserved communities could enhance detection rates and reduce disparities in diagnosing dementia and MCI [56].

Role of biomarkers in early AD diagnosis

Cerebrospinal fluid and PET measures have very good diagnostic properties and are the most widely used diagnostic biomarkers for AD [57]. In a study investigating whether use of amyloid PET for a more precise diagnosis in individuals attending memory clinics would impact long-term healthcare costs, institutionalization, and mortality, the authors found that the risk for institutionalization, mortality rate, and healthcare costs were lower among those who underwent amyloid PET as part of the diagnostic work-up as compared with those who did not undergo amyloid PET [58]. However, in clinical practice and outside specialized clinics, such biomarkers may be difficult to use due to limited accessibility, the invasiveness of the procedure and high costs [59].

The Alzheimer's Association expert group (Hansson et al. 2022) recently recommended that AD-associated blood-based biomarkers with established thresholds be used as a first screening step in clinical trials, whereas at specialist memory clinics, blood-based biomarkers should be used in symptomatic patients only [59]. Blood-based biomarkers are not yet used outside research settings, although they could be used in primary care to identify individuals with cognitive impairment who may need to be referred for further cognitive evaluation by specialists. However, a particularly careful interpretation of biomarker levels may be needed in individuals presenting with conditions such as chronic kidney disease and obesity as these comorbidities may influence certain biomarker levels independently of AD [60]. Blood-based biomarkers for biological confirmation of the two AD hallmark pathologies (A/T), are phosphorylated tau (P-tau), such as p-tau181, p-tau217 and amyloid-β₄₂/β₄₀, which can specifically be used for AD diagnosis [57]. Blood-based biomarkers for detection of neurodegeneration (N) are brain-derived tau and the neurofilament light chain; brain-derived tau outperforms plasma total-tau, and unlike neurofilament light chain, is specific to AD-type neurodegeneration [61]. Further, initiatives that support the uptake of other sensitive yet accessible biomarkers need to be considered; for example, reference values for the plasma neurofilament light chain were recently investigated to estimate reliable cut-off values so that this biomarker can be used in routine clinical practice [62,63].

Considering the advancements in the field of DMTs, the appropriate use criteria for blood-based biomarkers will need regular updating. A staged approach was recently suggested, whereby negative blood-based biomarker results could rule out individuals with a low likelihood of AD pathology, followed by a confirmatory PET or cerebrospinal fluid examination for those with a positive blood-based biomarker result in a population with cognitive impairment [64].

Conclusion

Early diagnosis of AD is essential to identify people who will benefit from the right interventions to improve quality of life for themselves and their families. Healthcare policy makers need to equip primary care physicians with a diagnostic work-up and continuous targeted education for early AD, and healthcare systems should have the capacity and flexibility to keep pace with the fast-changing diagnostic and treatment environment of AD.

Future perspective on an earlier AD diagnosis

Early diagnosis of AD may increase the recorded prevalence of early stages of the disease, as individuals will be diagnosed earlier, and there will be more people with AD who may benefit from DMTs. In addition, early detection of a chronic disease like AD will enable early intervention against pathological changes, especially if novel treatments can slow disease progression and cognitive decline, resulting in people living longer with AD. This will mandate a change in our view of AD.

Primary care physicians may need to focus their efforts on identifying risk factors for AD progression and recommend lifestyle changes that may help prolong or maintain these individuals' quality of life. With the availability of easier-to-use cognitive assessment tools in combination with plasma biomarkers, primary care physicians can increase the possibility to identify people with early AD, address concerns early, and offer proactive support to them and their care partners. They can further refer these individuals to a dementia care team, memory clinic, or other relevant specialists, so that a robust diagnosis can be made and further disease management can commence. Therefore, it is necessary that primary care physicians are appropriately educated, resourced, and well equipped with access to easy-to-use cognitive assessment tools and plasma biomarkers that can be implemented into the workflow of a primary care setting. Furthermore, the uptake of new tools and resources should be accompanied by updated and unified guidelines that can help with AD diagnosis in clinical practice. There is also a need to raise awareness of the clinical value of early detection of AD, and to this end, healthcare stakeholders, including patient organizations and payers, can promote broad communications and disseminate relevant materials that can help further educate primary care physicians [65].

The Models of Patient Engagement for Alzheimer's Disease initiative, an EU-funded public-private project across five European countries, aimed to explore patient engagement strategies to identify individuals with MCI due to AD and mild AD dementia, which are not detected in memory clinics [66]. These strategies included a web-based pre-screening tool, an open house initiative (allowing access to memory clinics without the need for referral), a primary care-based protocol for early detection of cognitive decline, and a tertiary care-based pre-screening at diabetologist clinics [67]. Boada et al. (2022) [67] concluded that such engagement strategies can be considered in order to identify individuals at high risk of having MCI due to AD or mild AD dementia.

A recent analysis of major national dementia policies and healthcare system preparedness showed that even advanced economies, like those of Sweden and Germany, lack a focus on early action despite having national plans for services and support following diagnosis. National policies should evolve to reflect the latest scientific advancements in AD management and have a specific focus on early action [68]. Patient databases should be enriched with information on age, sex, race and education, so that population databases and registries can be made more granular, enabling identification of risk factors and underlying conditions that will facilitate further research on earlier detection of AD [65]. The Davos Alzheimer's Collaborative System Preparedness (DAC-SP) working group recently published a framework consisting of 10 actionable and measurable ‘nodes’ for health system transformation throughout the care pathway, from awareness to diagnosis and access to support and care. This included example projects for a node focused on screening and early detection of cognitive impairment, as well as one focused on a timely and accurate diagnosis. For instance, for screening and early detection of cognitive impairment, one concept in healthcare system patient flow is to maintain a medical record of a target population with standardized baseline cognitive test scores, which will be reviewed annually, while another concept for timely and accurate diagnosis is to ensure the use of appropriate biomarker components [69].

With regard to genetic testing for predictive purposes, it has been available for asymptomatic individuals with a family history of early-onset AD. However, it is rarely utilized in clinical practice as more evidence is needed to understand the implications of learning such results though direct-to-consumer testing without the involvement of a genetic counselor [70]. Nevertheless, APOE genotyping will be used to inform treatment decisions regarding recently approved anti-amyloid therapies so that patients at higher risk for drug side effects can be identified [71]. Moreover, with the advent of recent technological advancements, artificial intelligence models are being optimized to explore possible associations between data modalities that could help in the identification of predictive patterns to facilitate early AD diagnosis [72]. In addition, since many healthcare systems lack the necessary MRI capabilities to confirm every case of AD, and with the emergence of novel therapies that mandate an early and precise diagnosis, a potentially ultrafast MRI technique [73] is being explored that may decrease the procedure duration from roughly 30 minutes to just 5 minutes. If this technological innovation is proven effective, it could expedite the adoption of such techniques by healthcare systems, thus improving healthcare providers' ability to accurately diagnose AD at an early stage.

Author contributions

All authors contributed to manuscript development, review, and content revisions. All authors approved the version to be published and agree to be accountable for all aspects of this work.

Financial disclosure

The development of this manuscript was funded by Novo Nordisk.

J Hahn-Pedersen and Luis Rafael Solís Tarazona are employees of Novo Nordisk.

S Mattke serves on the board of directors of Senscio Systems, Inc., and on the scientific advisory board of AiCure Technologies, ALZPath, and Boston Millennia Partners. He has received consulting fees from Biogen, C2N, Eisai, Novartis and Roche/Genentech.

S Gauthier has served on scientific advisory boards for Advantage Therapeutics, Alzheon, AmyriAD, Biogen Canada, Eisai Canada, Enigma, Lilly Canada, Lundbeck, Medesis, Roche Canada, Sharon Francis Foundation and TauRx.

H Zetterberg has served on scientific advisory boards and/or as a consultant for AbbVie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics Inc., AZTherapies Inc., Cognition Therapeutics Inc., Denali Therapeutics, Eisai, NervGen, Novo Nordisk, OptoCeutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics and Wave Life Sciences. He has given lectures in symposia sponsored by Cellectricon, Fujirebio, AlzeCure, Biogen and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work).

M Boada is an employee of the Ace Alzheimer Center and an advisory board member for Grifols, Roche, Eli Lilly, Araclon Biotech, Merck, Zambon, Biogen, Novo Nordisk, Bioiberica, Eisai, Servier and Schwabe Pharma.

V Pytel and X Morato are employees of the Ace Alzheimer Center.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing disclosure

Medical writing and editorial support were provided by R Kurtkoti, T Huggins, G Ferrari and C Petraki from IQVIA, and fully funded by Novo Nordisk.

Acknowledgments

The manuscript represents the views of the authors, who had complete editorial control over it.

Competing interests disclosure

KS Frederiksen serves on a scientific advisory board for Novo Nordisk, for which no compensation is received.

The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The development of this manuscript was funded by Novo Nordisk.