Alzheimer’s disease overview
Unmet needs in Alzheimer’s disease management
Listen to Charlotte Teunissen, Professor of Neurochemistry at the Vrije Universiteit Amsterdam, Netherlands, discuss unmet needs in Alzheimer's disease (AD). In the second video clip, Professor Teunissen summarises AD, and why curative treatments are urgently needed.
Current unmet needs in Alzheimer’s disease include the development of biomarkers to aid in early disease detection and diagnosis, and disease-modifying treatments
Alzheimer's disease pathophysiology
Alzheimer’s disease (AD) is the most common cause of dementia, representing 60–80% of cases1. AD prevalence in 2018 was estimated at 50 million people worldwide, which is projected to double in Europe, and triple worldwide by 20502,3.
AD is characterised by brain tissue abnormalities, which are diagnostic biomarkers of the disease and targets for medication development3. The abnormalities in AD include accumulation of3:
- Amyloid-β (Aβ) plaques (Figure 1)
- Aβ oligomers outside of neurons
- Twisted fibrils of tau proteins inside neurons (Figure 2)
AD is a heterogeneous and complex disease that is challenging for healthcare professionals to differentiate from other forms of dementia3. The National Institute on Aging and Alzheimer’s Association developed the Alzheimer’s Diagnostic Framework to classify AD and differentiate it from non-AD causes of cognitive impairment, following biomarker criteria5. The biomarkers of AD pathology—extracellular deposition of Aβ (‘A’), intracellular tau tangles (‘T’) and neurodegeneration (‘N’)—were included in the ‘A/T/N’ framework5.
Risk of AD is 60–80% dependent on heritable factors, with more than 40 AD-associated genetic risk loci already identified, of which the APOE alleles have the strongest association with AD (Figure 3)6-8.
Review the relationship between clinical phenotypes and biomarkers in Alzheimer’s
AD progresses through a continuum comprising three phases: preclinical disease, mild cognitive impairment (MCI) and clinically evident dementia. Although cognitive decline and biomarker measurements progress over time, biomarker progression begins prior to the onset of symptoms10. Recent studies have improved the pathophysiological description of AD11, although how biomarkers emerge through the AD continuum remains to be fully understood.
Early diagnosis of Alzheimer’s disease is an unmet need
The diagnosis of AD is clinical-biological: diagnosis requires a specific clinical phenotype of AD (phenotype-positive) and biomarker evidence of AD pathology (amyloid-positive, tau-positive)12.
Diagnosis of AD is commonly not made until the patient has progressed to mild or moderate dementia1. Many patients with AD are undiagnosed. For example:
- Approximately 29–76% of patients with dementia in primary care are undiagnosed13
- Only 47% of US primary care physicians routinely assess older adults for cognitive impairment1
Diagnosis of AD in the MCI phase, rather than in the dementia phase could save approximately US$7 trillion in medical and long-term care costs1.
Early detection and diagnosis of AD, prompting early initiation of AD therapies, is associated with improved quality of care and quality of life, and improved economic and caregiver outcomes14,15. Barriers to early diagnosis of AD include healthcare professional time restraints for patient testing and counselling, hesitancy of patient and caregiver reporting of symptoms, and lack of diagnostic resources in primary care14,16-18.
Many challenges frustrate early diagnosis of MCI in primary care, including a lack of assessment tools, training, time and infrastructure19
In special or vulnerable patient groups, diagnosis of dementia remains an unmet need given the lack of validated diagnostic criteria. For example, in people with Down syndrome, symptoms of AD can be obscured by the intellectual disability20.
Clinical tools that support decision-making and communication about AD diagnosis, such as web-based tool for clinicians in a memory clinic setting, are needed21.
Biomarkers and diagnosis of Alzheimer’s disease
A biomarker is a naturally occurring, detectable indicator that can evaluate or monitor a physiological or pathological state22.
More accurate diagnostic biomarkers for AD are an important unmet need, partly because 15–30% of patients with clinically apparent Alzheimer-type disease (CATD) do not meet post-mortem diagnostic criteria for AD1.
Diagnostic biomarkers that differentiate AD from other forms of dementia include brain neuroimaging and cerebrospinal fluid (CSF) markers. However, there is an unmet need for markers that can stratify more forms and subtypes of dementia. For example, given the similarities in presentation, it can be challenging for healthcare professionals to distinguish AD from frontotemporal dementia23.
Diagnostic biomarker measures for Aβ neuropathology are low CSF Aβ42, lower CSF Aβ42–Aβ40 ratio, or increased tracer retention in amyloid positron emission tomography (PET). High CSF phosphorylated tau (pTau), pTau–Aβ42, or increased ligand retention in tau-PET, is advised for tau neuropathology10,12,24-26.
Aβ-PET scanning agents approved by the US Food and Drug Administration (FDA) include florbetapir, flutemetamol and florbetaben3,12,27,28. However, the high financial cost of PET examinations, and the invasiveness of CSF measurements limit their interest to, and usefulness in, clinical practice, for evaluating Aβ pathology3,29,30. Both PET scanning and CSF measurement are not widely available, especially in low-income countries31,32. Validated digital biomarkers may complement biological biomarkers in the diagnosis of AD33.
Figure 4 shows a general four-step strategy and checklist for identifying unmet needs for biomarkers34,35.
Learn more about biomarkers for diagnosing Alzheimer’s disease
Unmet needs in Alzheimer’s disease monitoring
There is significant variability in progression rates in people with AD3,12. Patients and families often ask clinicians to predict expected rates of cognitive and functional decline36. Conventional methods for monitoring progressive decline in AD include:
- Self-report questionnaires, such as single-time point subjective rating scales
- Patient and caregiver interviews
- Clinical observation, physical or neuropsychological clinical testing
The disadvantages of such methods37-41:
- Questionnaires and interviews rely heavily on (caregiver) accurate recall
- Self-report is susceptible to bias or misinterpretation
- Questionnaires are vulnerable to inter-assessor variability
- Administration at discrete points can affect sensitivity (patient comorbidities, medications, motivation)
- Interviews and questionnaires are not sufficiently sensitive in detecting subtle symptoms, especially in the early stages of AD.
Aβ and tau biomarkers in predicting disease progression or monitoring clinical status
Early saturation of Aβ accumulation in the brain, shown in plateaus in CSF Aβ42 levels and amyloid-PET uptake following clinical symptom onset, can limit the usefulness of Aβ biomarkers for monitoring AD progression and treatment response42,43. Although tau-protein levels can better reflect clinical status of AD than Aβ44, their clinical correlations can be lost with the progression of neurodegeneration; revealing stabilisation, or a reduction in protein levels42,45.
Few biomarkers that can monitor treatment responses or index clinical severity of Alzheimer’s disease is a problem for clinical trials targeting amyloid-beta44
In clinical trials, treatment-responsive improvements in Aβ biomarkers, such as reduced Aβ uptake (amyloid-PET), increased levels of CSF Aβ46-48, or tau biomarkers46, did not lead to clinical improvements47,49,50. This evidence suggests that changes in Aβ and tau biomarkers do not always reliably predict AD progression or monitor the clinical status of AD44. Therefore, new biomarkers are needed to solve this unmet need.
New biomarkers that could monitor non-Aβ and non-tau pathology in Alzheimer’s disease
Proteins in the pathophysiological development of AD are potentially new biomarkers. Synapse or neurodegeneration-related fluid biomarkers detectable in CSF, such as neurofilament light polypeptide (NfL), neurogranin, or visinin-like protein 1, and in biomarkers detectable in blood (such as NfL), could provide information on AD progression and contribute to monitoring treatment effects29,30,44.
Neuroinflammation, lipid dysmetabolism, and dysfunctional protein clearance are components of AD pathology44. Proteins associated with inflammation measurable in CSF, including progranulin, intercellular adhesion molecule 1, or chitinase-3-like protein 1 (YKL-40), are potential options for the early detection of AD, and can indicate clinical severity44. Lipid metabolism-related biomarkers and protein clearance-linked markers are candidates for monitoring AD progression44.
A potential role for digital biomarkers in Alzheimer's disease monitoring
Digital biomarkers are objective, quantifiable, physiological and behavioural data, collected and measured on digital devices, such as embedded environmental sensors, portables, wearables, implantables or digestibles38,40,41.
Digital biomarkers capture intraindividual variability in patient performances, which may reveal evidence of early disease progression40,41,51-53, or subtle health transitions (healthy to MCI)40,41,52,54. They allow healthcare professionals to discover new digital indicators of AD progression, such as gait-speed variability over time52,55, computer use metadata51,54, or keystroke dynamics33.
Click the link to continue learning about monitoring Alzheimer’s disease
Treating Alzheimer’s disease: needs and future challenges
Medication therapy that changes the progression of Alzheimer’s disease is arguably the greatest unmet need for people with the disease3
FDA-approved medications for AD include cholinesterase inhibitors and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine3. However, these medications are symptomatic treatments: cholinesterase inhibitors and memantine do not alter the progression of AD3.
Patients on the AD continuum may take medications that impair cognition and accelerate AD, including benzodiazepines or anticholinergics56,57. Avoiding or deprescribing such medications is necessary for preserving cognition in older adults58. Medication regimens should be simplified, or unnecessary treatments deprescribed, to promote patient medication adherence, another unmet need in AD59. Caregivers should receive medication management support, with frequent monitoring and reassessment of the patient’s medication needs as AD progresses10.
Since 2007, more than 50 investigational medications have failed in Phase 3 AD clinical trials27,28,60, and more than 1,000 trials have been suspended because of the COVID-19 pandemic61. Contributing factors leading to the high failure rate of AD trials include60:
- The heterogeneous nature of AD, implicating biomarker inaccuracy
- Incomplete understanding of the medication dose-response relationship
A medication that received government approval to prevent progression of preclinical or prodromal AD could lead to unintended challenges impacting on some healthcare systems62. For example, the cost of preventive treatment could be significant63, and patient resources such as dementia specialists, PET imaging facilities or infusion centres, could be unavailable62.
Review non-medication modalities that can improve cognition in people with AD
Assessing and diagnosing Alzheimer’s disease
Professor Charlotte Teunissen, based at Amsterdam Neuroscience at the Vrije Universiteit Amsterdam, Netherlands, presents two videos: in the first, she outlines available biomarkers for diagnosing Alzheimer's disease (AD), in the second, biomarkers for monitoring AD progression.
Diagnosis of Alzheimer’s disease requires specifying a clinical phenotype of Alzheimer’s, and biomarker evidence of neuropathology12
Diagnostic pathway for Alzheimer’s disease
Diagnosis of AD is complex, and involves the use of many clinical tools and practices, across several stages (Figure 5)3,12,64.
The initial detection stage occurs when healthcare professionals (HCP) are made aware of cognitive concerns or have clinical evidence of cognitive impairment. Subsequent diagnostic stages—assessing for cognitive impairment and/or a high probability of AD pathology, and differentiating AD from other causes of cognitive impairment—involves specialised expertise (Figure 5).
Introduction of an AD specialist to diagnose early-stage AD is recommended59. Following diagnosis of AD through biomarker investigation and determination of treatments by a specialist, treatment and monitoring of patients may be assigned to a patient-centred, multidisciplinary team, with clinical skills across several disciplines (Figure 5).
The ATN diagnostic framework for Alzheimer’s disease
Initially, the diagnosis of AD was restricted to the stage of dementia, a clinical syndrome characterised by substantial progressive cognitive impairment affecting several domains, or neurobehavioural symptoms severe enough to cause negative functional impact on daily life10.
Given the developments in the biomarker field and the unmet need to make them usable in a diagnostic setting, biomarkers were grouped into A (amyloid), T (phosphorylated tau), and N (neurodegeneration, measured by total tau where applicable): the ATN framework10.
In ATN framework, diagnosis of AD is defined by the presence of amyloid-β (Aβ) and phosphorylated tau10.
Aβ is called ‘Alzheimer’s pathological change’, basing the research diagnosis of AD on biomarker evidence only. Clinical stages can range from cognitively normal, to mild cognitive impairment (MCI) and dementia, stressing the continuum of AD, which spans a period of years (Figure 6)10.
If diagnostic biomarkers are not available in the clinic, patients should receive a clinical syndromic diagnosis. For example, amnestic Alzheimer’s disease phenotype, or logopenic variant primary progressive aphasia, and staging (MCI or dementia) can be used10,12.
The ATN framework highlights the importance of Aβ and tau as the defining characteristics of AD, proposing that AD can be diagnosed by biomarkers only, and distinguishing between the concepts of AD and dementia10.
Limitations of the ATN framework
Some cognitively unimpaired individuals can have biomarker evidence of Aβ and tau neuropathology but will not develop clinical manifestations. A positive AD pattern of biomarkers can be observed in other brain diseases in which AD pathology is evident as a comorbidity12.
The International Working Group (IWG) recommends that AD diagnosis be limited to individuals who have positive biomarkers with specific clinical AD phenotypes; biomarker-positive cognitively unimpaired people should be considered only at-risk for progression to Alzheimer’s12.
Although the ATN approach is the cornerstone of current trials of disease-modifying therapies (DMT) in AD, clinical diagnosis still rests on the criteria set by the National Institute on Aging in 201166.
The large number of ATN categories, and the fact that other pathologies are not evaluated in the framework, makes the ATN approach largely impractical for clinical use67
Despite the limitations of the ATN framework, it makes possible a diagnosis before the stage of AD-associated dementia, and individualised risk-profiling for patients with MCI3. However, clinicians are normally reluctant to share specific prognostic information with patients with MCI68.
Evaluating the need for biomarker diagnosis in Alzheimer’s
Healthcare professionals and physicians are advised to assess the added value of biomarker diagnostic investigation for each symptomatic patient, according to10,12:
- Appreciation of how biomarker information could alter patient management
- The clinical situation, including age, comorbidity risk, complexity of the phenotype
- Participation in a DMT trial
- The underlying pathology associated with patient cognitive complaint
Results of biomarker or cognitive assessment that are close to the cut-off points could indicate an incomplete diagnostic AD workup. In this scenario, the current workup could be supplemented with further assessment, such as repeated pathophysiological biomarkers, clinical follow-up, or neurodegeneration biomarkers (e.g. 18F-fluorodeoxyglucose-PET [18FDG-PET])10,12. However, further assessement might not disambiguate a patient’s AD status. The patient could be at the border of the cut-off point, which does not indicate that the workup conducted was necessarily incomplete.
Clinical phenotype and biomarker relationship in Alzheimer’s
Specific clinical phenotypes associated with AD neuropathology are69-72:
- Amnestic syndrome of the hippocampal type
- Posterior cortical atrophy variant
- Logopenic variant
- Primary progressive aphasia
In people with these phenotypes, amyloid and tau biomarker positivity establishes a diagnosis of AD12. Positivity of amyloid and tau biomarkers is necessary, because an amnestic phenotype with only amyloid positivity is non-specific to AD, and is observed in other diseases of neurodegeneration with amyloid co-pathology12.
Subjective cognitive decline in Alzheimer’s disease
In the context of predementia diagnosis, subjective cognitive decline (SCD) is more challenging73. A clinical characterisation of SCD has been provided, and attempts made to provide clinicians guidance on how to manage it (which might, or might not be, attributable to underlying AD)74.
At a group level, ATN biomarkers predict incident dementia in SCD, but individualised risk-modelling is challenging75. Patients and caregivers indicate that they value precise and specific information, even when it does not provide complete certainty76.
Subjective memory complaints and SCD, if not supported by evidence of objective cognitive impairment, lack specificity and, considered alone, are not part of the AD phenotype77.
Alzheimer’s disease monitoring – clinical assessment instruments
A specific memory profile is evident in AD, characterised by a reduced free recall ability, which is only minimally improved by cueing (amnestic syndrome of the hippocampal type)69. The Free and Cued Selective Recall Reminding Test (FCSRT) can be used in the clinic to assess and monitor impairment of free and cued recall, and for identifying people with MCI78,79. Digital assessment could be more sensitive than the FCSRT; digital assessments can reasonably be conducted more frequently so within-patient changes can be more easily detected80.
There is an unmet need for more sensitive and specific instruments to assess for early-stage AD27,28,80. These tools are required to monitor subtle clinical decline, which could identify individuals with minimal symptoms, and to monitor treatment effects in individuals with earlier AD80.
Functional assessment tools are needed to monitor functional decline over time80. For example, development of new tools for assessing and monitoring of Instrumental Activities of Daily Living (IADL) functioning, including measures of financial capacities, keeping appointments, task completion time, decision-making, speed of performance and task accuracy, remain an unmet medical need81. Digital biomarkers could supplement traditional functional testing38,40,41.
Learn more about digital biomarkers for monitoring Alzheimer’s progression
More sensitive cognitive and functional instruments could expedite clinical development, by reducing clinical trial recruitment time and reducing sample size27,28.
Alzheimer’s disease monitoring – biomarkers
Biomarker advancement is necessary to aid clinical development. Diagnostic biomarkers are needed to enrol individuals in clinical trials who have AD pathology—clinical diagnosis alone of AD dementia is not always accurate4,12,82,83. However, biomarkers need to be inexpensive and simpler to use if they are to be applied in research and clinical settings3.
Topographical biomarkers can detect downstream brain regional, structural and metabolic changes, which are indicative of AD pathology12. These markers include magnetic resonance imaging (MRI)-related biomarkers for assessing or monitoring hippocampal atrophy, ventricular volume, whole brain volume or cortical thickness12,80. While valuable as AD progression markers in clinical trials, topographical biomarkers lack the specificity of diagnostic biomarkers, and may lack sensitivity in early AD stages80.
Surrogate biomarkers, indicating that an agent is having an effect that could improve cognition or function, are also needed80. Surrogate markers are required, given the unpredictable nature of AD.
Treating Alzheimer’s disease
Charlotte Teunissen, Professor of Neurochemistry at Vrije Universiteit Amsterdam, Netherlands, discusses risk factors for Alzheimer's disease (AD) that can be modified with lifestyle (non-pharmacological) interventions. In the second video, Professor Teunissen summarises the pharmacological drugs that are being developed for treating AD pathology.
Treatment options for Alzheimer’s disease – pharmacological
Cognitive-enhancing treatments for Alzheimer’s disease
Approved treatments that achieve the standard-of-care for many people with AD include cholinesterase inhibitors and the N-methyl-D-aspartate receptor antagonist memantine. No further symptomatic cognitive-enhancing medication has been approved for AD since 20162. Programs assessing the clinical effectiveness of 5-hydroxytryptamine subtype 6 (5-HT₆) receptor antagonists for cognitive improvement show that this pathway is not an effective approach for treating cognition in AD84.
Investigational medications that treat neuropsychiatric symptoms of Alzheimer’s disease
Treating psychosis in Alzheimer’s disease
Pimavanserin, a 5-HT2A receptor inverse agonist, was evaluated for dementia-related psychosis in patients with psychosis in the setting of AD, among other forms of dementia85. The clinical trial was terminated early for success. However, pimavanserin was rejected by the US Food and Drug Administration (FDA) as a treatment option for dementia-related psychosis3,86.
Options to manage agitation in Alzheimer’s disease
Agitation is evident in up to 70% of patients with AD3. Clinical trials support treatment of agitation in AD with brexpiprazole, citalopram or nabilone87. These trials suggest that personalised interventions for people with AD can reduce agitation. Current trials are investigating the efficacy and safety of brexpiprazole, escitalopram, prazosin, dextromethorphan with quinidine, and dextromethorphan with bupropion for agitation associated with AD3.
Managing sleep and night-time behavioural disturbances in Alzheimer’s disease
Suvorexant is a dual orexin antagonist approved for insomnia, and FDA-approved prescribing information includes clinical trial and adverse event information on the use of the agent to treat insomnia in AD88. A clinical trial of suvorexant showed significant increases in total sleep time and decreased awakening after falling asleep in patients with AD3. Lemborexant, another dual orexin antagonist, is being evaluated in a trial for irregular sleep-wake rhythm disorder in patients with AD3.
Investigational disease-modifying therapies for Alzheimer’s disease
Encouraging pharmacological treatments for Alzheimer’s disease are at advanced stages of clinical trials, including anti-amyloid-β, anti-tau and anti-inflammatory strategies27,28,89
Most drug development in the AD setting is devoted to evaluating disease-modifying therapies (DMT)27,28. DMTs are being evaluated in primary prevention trials in people with early onset AD caused by the genetic mutation90, and in secondary prevention trials in patients with preclinical AD27,28. Ongoing trials are investigating the effects of DMTs on prodomal or early AD91-93.
Amyloid-β pharmacological treatments for Alzheimer’s disease
Amyloid-β (Aβ) is the most common target of drug development in Phase 2 and 3 clinical trials3.
Evidence indicates that by removing Aβ oligomers (soluble aggregates of Aβ) and plaques (insoluble extracellular aggregates of fibrillar Aβ) with monoclonal antibodies, AD progression can be delayed94. Aducanumab, lecanemab, and gantenerumab reduce formation of Aβ plaques95. Some studies of these molecules have shown evidence of a treatment effect in some patient subgroups95.These agents also lower levels of phosphorylated tau, neurogranin and neurofilament light chain in the cerebrospinal fluid (CSF)3.
Despite positive Phase 1 or 2 clinical trial results, approval and widespread use of Aβ agents has yet to manifest. One exception is aducanumab, which was FDA approved in 2021 under the accelerated approval pathway96. A drug approved under this pathway may provide clinical benefit compared to existing treatments, when the drug is shown to have an effect on a surrogate endpoint that could predict a clinical benefit to patients. There remains some uncertainty about the drug’s clinical benefit96.
A recent Phase 2 trial of donanemab suggests that this antibody, directed against the pyroglutamate-modified form of Aβ (an oligomer of Aβ–pE3, and Aβ42), holds potential as an amyloid-targeted treatment97. The published findings of ongoing Phase 3 trials, CLARITY, GRADUATE 1 and 2, could further support this claim and potential approval92,98,99.
Aβ vaccines are being investigated in immunotherapy trials (Figure 7). β-secretase BACE1 and BACE2 inhibitors were a potential class of DMTs for AD that significantly reduce concentrations of CSF Aβ. Some of these trials have been terminated because of accelerated deterioration in cognition, or elevated liver enzymes100.
Tau pharmacological treatments for Alzheimer’s disease
Tau biology is a promising DMT target for AD (Figure 7)101. Monoclonal antibodies targeting different epitopes are currently in clinical trials. These antibodies are intended to engage extracellular tau, as it spreads cell to cell. Small molecules targeting tau aggregation and neurofibrillary tangle formation are being investigated3. Potential side effects of monoclonal antibodies suggest the need for better dose finding and measurements of therapeutic target engagement3.
Pharmacological treatment of neuroinflammation in Alzheimer’s disease
Neuroinflammation can contribute to AD progression and neurodegeneration (Figure 7)3. Oligomannate was approved in China in 2019, following a Phase 3 trial that showed cognitive improvement102, and is under investigation in other parts of the world. Based on non-clinical observations, oligomannate is considered efficacious in reducing brain inflammation in patients with AD, through its effect on the gut microbiome and in restoring normal gut bacterial composition3.
Potential options that treat infection and provide neuroprotection
Infections could contribute to AD onset or progression, and agents that target bacteria or viruses are in clinical trials for AD103. Neuroprotection is necessary for successful modification of AD, and some agents target neuroprotection directly through growth factors to slow disease progression104.
Treatment options for Alzheimer’s disease – non-pharmacological
Evidence for lifestyle changes in Alzheimer’s disease
Table 1 shows selected recommended non-pharmacological treatment options for the management of AD105.
Table 1. Non-pharmacological treatment options for the management of Alzheimer’s disease (Adapted105).
Modality | Type of dementia | Evidence |
Enjoyable leisure activities (per patient preference) |
Mild cognitive impairment, Mild-to-moderate dementia |
Decreased neuropsychiatric symptoms and functional capacity, slowing of memory loss |
Mental stimulation programmes (e.g. puzzles, word games, past/reminiscence therapy, indoor gardening, baking) |
Mild-to-moderate dementia | Improved cognition and self-reported quality of life and well-being; no effect on functional status, mood, or behaviour |
Occupational therapy training in coping strategies and cognitive aides | Mild-to-moderate dementia | Improved cognition |
Structured physical exercise programmes | Mild-to-severe Alzheimer disease | Improved physical function, reduced neuropsychiatric symptoms (including depression), slower rate of functional decline, no improvement in cognition |
Lifestyle factors do not directly affect the pathology of Alzheimer’s disease, but can contribute to positive outcomes in some individuals3
Guidelines published by the World Health Organization (WHO) on reducing the risk of cognitive decline in AD and dementia recognise that for some factors, such as physical activity, diet, obesity, tobacco or alcohol use, hypertension or diabetes, recommendations can be given, but with different degrees of confidence106. For example, over 36-months, souvenaid slowed decline on clinical and other measures related to cognition, function, brain atrophy, and disease progression, in people with prodomal AD107.
Limitations in the evidence base for non-pharmacological treatments include the scarcity of harmonisation, such as exposure definition, and long-term, randomised controlled trials, as well as little evidence from low-income or middle-income countries, where dementia prevalence is increasing106.
Nine potentially modifiable risk factors for dementia were presented in the 2017 Lancet Commission on dementia prevention, intervention and care: less education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes and low social contact108. A 2020 report of the 2017 Lancet Commission proposed three further evidence-based risk factors for dementia109:
- Excessive alcohol consumption
- Traumatic brain injury
- Air pollution
The total 12 modifiable risk factors explain approximately 40% of global dementias, which could be prevented or delayed109. The prospect for prevention of dementia is significant, and could be higher in low-income and middle-income countries, where more dementias occur109.
The SPRINT-MIND trial found that intensive blood pressure control (systolic blood pressure [SBP] goal <120 mmHg) reduces the risk of cognitive impairment better than standard blood pressure control (SBP goal <140 mmHg)110. This finding highlights that “what is good for the heart is good for the brain”, although the optimal therapeutic target is unknown, especially for older adults3.
Multidomain lifestyle-based Alzheimer’s disease trials
The failure of single-intervention treatment reveals the need for a multimodal preventive approach to AD, which has been successfully implemented in cardiovascular and diabetes prevention111.
FINGER randomised, controlled trial
FINGER showed that a multidomain lifestyle-based intervention can reduce the risk of cognitive impairment among individuals at risk of AD or dementia112. FINGER combined healthy, balanced nutrition, physical exercise, cognitive training, social activities, vascular and metabolic risk management. The trial demonstrated benefits on cognition, even in people at genetic risk of AD112.
MAPT and PreDIVA randomised, controlled trials
MAPT investigated the association of a lifestyle intervention with omega-3 fatty acid supplements in older adults with memory complaints113, and the PreDIVA trial evaluated pharmacological management of vascular and metabolic risk factors114. Both trials did not meet their respective primary outcomes, but subgroup analyses indicated cognitive improvements in subgroups of people at increased risk of AD or dementia. In a substudy using amyloid-PET in MAPT113, lifestyle intervention alone or in combination with omega-3 fatty acids was associated with improved cognition in people with positive Aβ status.
Role of biomarkers in prevention of Alzheimer’s disease
The discovery of in vivo biomarkers has shifted AD diagnosis from the dementia phase in the AD continuum towards the prodromal phase3,10,12,115,116. This shift makes preclinical diagnosis (before symptom onset) possible and is relevant for evaluating the efficacy and safety of potential therapies for secondary prevention of the disease3,10,12,115,116.
Biomarkers allow clinicians to differentiate primary prevention, through interventions before the identification of positive AD biomarkers, from secondary prevention, through interventions when positive biomarkers are identified
Time-ordered biomarkers provide a biomarker-driven approach to AD that could aid prevention clinical trials4.
View an image showing biomarker trajectories in Alzheimer’s disease
Given the uncertainty in reliably prognosing people who are asymptomatic with biomarker-positive status (amyloid-positive and tau-positive), the evaluation of biomarkers in cognitively unimpaired individuals is not advised12. However, prevention programmes (or future therapies) that demonstrate efficacy in delaying AD onset could change the need for biomarker assessment in this group12.
The need for biomarkers in Alzheimer’s disease diagnosis
Clinical practice and clinical trials
Timely and accurate diagnosis of AD in clinical practice is an unmet clinical need. Current unmet needs include4,12:
- Providing patients with diagnostic and prognostic information
- Optimising treatment strategies, and providing appropriate support and care
- Giving patients opportunities to join clinical treatment trials
Misdiagnosis can lead to suboptimal treatment and costly clinical investigations as a result of diagnostic uncertainty117.
Roughly 30–50% of patients with mild cognitive impairment (MCI) have incipient AD, but the underlying aetiology is difficult to assess without biomarkers4.
Biomarkers are required to improve AD diagnosis, especially in the evaluation of early disease stages, and for monitoring disease progression (digital biomarkers). An accurate diagnosis will be essential for therapeutic decision-making, particularly if disease-modifying therapies (DMT) are approved for use. Many AD clinical trials require biomarker evidence of amyloid-β (Aβ) pathology for inclusion82,83. Widely available, economical and accurate biomarkers could be used in primary care4,12.
Fluid biomarkers for monitoring AD progression is an unmet clinical need. Innovations in blood-based biomarkers (e.g. neurofilament light chain (NfL), glial fibrillary acidic protein [GFAP]), could provide prognostic information on disease progression29,30.
Neuroimaging biomarkers for diagnosing Alzheimer’s disease
Established Alzheimer’s biomarkers: MRI, 18fluorodeoxyglucose (18FDG)-PET, amyloid-PET
Amyloid-PET (Aβ-PET) is useful for excluding AD, and 18FDG-PET for differential diagnosis, prediction of short-term clinical outcomes, and staging of neurodegeneration4
To date, the most accurate neuroimaging biomarkers for AD are3,4,118:
- Medial temporal lobe atrophy (magnetic resonance imaging [MRI])
- Posterior cingulate and temporoparietal hypometabolism (18FDG-PET)
- Cortical Aβ deposition (Aβ-PET neuroimaging)
These three biomarkers have nearly achieved analytical and clinical validity, although evidence for their clinical utility is incomplete119.
Large, prospective studies could aid in understanding the clinical impact and usefulness of Aβ neuroimaging:
- ABIDE: Aβ neuroimaging improved diagnostic accuracy and confidence in a memory clinic, with patients under the age of 70 years120
- IDEAS: Aβ-PET neuroimaging improved clinical diagnosis and diagnostic confidence in roughly 60% of patients aged 65 years and older, with mild cognitive impairment (MCI) or dementia121
Uncertainty regarding the order of tests has delayed the clinical implementation of these neuroimaging biomarkers3.
Although MRI is advised as the first step after clinical evaluation, the decision on the next biomarker test relies on the clinical profile and the individual diagnostic question3,4,12
Compared with global cortical Aβ deposition, evaluation of regional Aβ could detect with greater sensitivity, the earliest Aβ stages in temporobasal and frontomedial brain regions122.
Tau-PET for diagnosing Alzheimer’s disease
Tau-PET, although not widely available, is a useful biomarker for differential diagnosis between Alzheimer’s disease-tauopathy and neurodegenerative tauopathies123
Tau-PET ligands assist with in vivo description of tau tracer retention124. Tau-PET binding topography associates with cognitive decline, can target different AD phenotypes, and is predictive of rates of cognitive decline and brain atrophy125-128.
Longitudinal studies show that tau-PET can track AD progression129 and the spread of tau in brain networks130. Tau-PET is contributing to a more complete understanding of interactions between tau and Aβ131.
Concentrations in blood of phosphorylated tau are correlated with corresponding tau concentrations in tau-PET29,30.
Recommended PET measures for tau neuropathology are increased ligand retention in tau-PET10,12.
Other Alzheimer’s disease neuroimaging biomarkers
Progress in PET ligands targeting SV2A (a synaptic vesicle membrane protein) neuroimaging opens new avenues to investigating brain synaptic density132. This is relevant to AD, with evidence showing decreased SV2A binding in the hippocampus in patients with MCI or AD133.
Fluid biomarkers in Alzheimer’s disease
Aβ, phosphorylated tau and neurodegeneration can be detected through body fluid biomarkers134,135. Reference methods and materials have been developed, and assay outcomes between providers of cerebrospinal fluid (CSF) biomarker assays for AD have been coordinated136,137. Standardised operating procedures for CSF collection and analysis have been developed, and a quality-control program for monitoring analysis consistency in results has been established138. These protocols have contributed to universal cut-off points for determining if a patient’s clinical profile resembles AD. However, as discussed below, in the AD setting, uncertainty exists regarding biomarker cutoff determination.
Diagnosing Alzheimer’s using cerebrospinal fluid biomarkers
Established CSF biomarkers include Aβ1–42, Aβ1–40, phosphorylated tau 181, and total tau3,4,139. Concentrations in blood of Aβ are associated with analogous concentrations in CSF, and with amyloid-PET neuroimaging29,30. CSF diagnosis is recommended over PET diagnosis because it gives concurrent information on Aβ and tau extent, and is less expensive than amyloid-PET or tau-PET, or both10,12.
Levels of CSF Aβ42 (but not Aβ40) are decreased by around 50% in AD, and the decrease is evident before Aβ-PET becomes abnormal (Figure 8)4.
Advised biomarker measures for Aβ neuropathology are10,12,25,26,140:
- Low CSF Aβ42
- Increased pTau–Aβ42 ratio
Recommended CSF measures for tau neuropathology are high CSF phosphorylated tau10,12.
The use of CSF biomarkers through lumbar puncture, the method for collecting CSF, is limited by several factors, including patient anxiety about lumbar puncture and its related adverse effects, physician concern about the invasiveness of lumbar puncture and a lack of confidence in performing it, and, at the level of health system infrastructure, resource and time constraints141.
For physicians, international guidance is available to reduce the risk of adverse effects following lumbar puncture for CSF collection141:
- Assess potential contraindications
- Identify patient-related risk factors
- Place patient in the lateral recumbent position
- Use an atraumatic narrow-bore (≥22-gauge) needle
- Avoid multiple attempts (≤4)
- Implement passive rather than active withdrawal of CSF
- Collect <30 mL of CSF
- Communicate to reduce patient’s concerns
A ratio of Aβ42–Aβ40 or pTau–Aβ42 results in high concordance with Aβ-PET, typically above 90%3,4,12,25,26,140. The accuracy of biomarker ratios could depend on4,142,143:
- Control of inter-individual variations in overall production or secretion of Aβ from neurons
- Production and clearance of CSF
- Pre-analytical management of CSF samples, which affects both Aβ isoforms
Learn about cerebrospinal fluid biomarker innovations in Alzheimer’s disease
Serum and plasma biomarkers for Alzheimer’s
Technological progress has enabled greater accuracy in measuring central nervous system proteins in blood. For example, neurofilament light chain (NfL), an axonal cytoskeleton protein, is a biomarker of neurodegeneration, and in other forms of dementia144,145. Levels of NfL are increased in blood, as in CSF, making application of this marker clinically feasible. Though not AD-specific, blood NfL appears promising for the detection of neurodegeneration and could potentially be used to detect the effects of disease-modifying therapies145. Plasma P-tau appears to be the best candidate marker during symptomatic AD (prodromal AD, AD dementia) and preclinical AD, when combined with Aβ42–Aβ40145.
Biomarker cutoff issues in Alzheimer’s disease
A diagnosis of AD based on positive biomarkers requires an accurate definition of positivity cutoff values, since alteration of these values would modify diagnosis and disease stages3,4,12
The intended use of biomarker cutoff points in AD diagnosis is to identify the first signs of Aβ neuropathology, or to predict the occurrence of clinical symptoms4. Cut-off values raise fundamental medical questions, which remain unresolved in the field.
Amyloid-β and tau biomarkers
Separation between negative and positive patients in relation to Aβ or tau biomarkers does not accurately reflect Aβ and tau pathology, which is continuous and minimally present in most people aged 70 years and older146. Neuropathology criteria for AD do not specify a cut-off for diagnosing AD, but only specify low, intermediate or high levels of change in AD neuropathology147.
Amyloid-β biomarker cut-off values
Use of binary cut-offs (positive, negative) of Aβ-PET uptake value ratio restricts the measure of Aβ deposition to intermediate or high quantities148. Aβ-PET tracers also cause variability in measurements, although Centiloid quantification can mitigate this variability149.
- Use of the Centiloid scale, or longitudinal Aβ-PET, could identify earlier stages of amyloid accumulation150,151
- A positive amyloid measure in CSF, despite a negative Aβ-PET, could be an accurate marker of early amyloid deposition152
Tau biomarker cut-off values
There is a discrepancy in tau biomarkers between identifying neuropathology, as in post-mortem studies146,153, and in vivo measures of tau-PET aggregates—36% of patients are tau-positive after the age of 70 years154.
Current in vivo detection of tau positivity using 18FDG-PET appears to relate only to tau pathology in the brain (Braak stages ≥IV), but CSF phosphorylated tau elevation can detect earlier stages of tauopathy155,156.
In vivo tau measurements could detect very early tau deposits (tau Braak stages I–II), with second generation tau-PET tracers, or by detection of phosphorylated tau 217 in the CSF or the plasma157.
Intersection of biomarker cut-off values and clinical practice
In clinical practice, an extension to earlier cut-off values in Aβ or tau biomarkers, described above, could prolong the asymptomatic stages of AD and decrease the probability of disease progression.
Although biomarker cut-off points should be used as intended, no agreement has been reached on their use in specific clinical contexts, as in evaluating asymptomatic compared with symptomatic people, or in people with intellectual disabilities compared with neurotypical people10
Assessing cognitive changes and determining objective, cognitive impairment (MCI or dementia) also prompts cut-off value issues. Lower cut-off points in cognitive testing, to detect subtle cognitive shifts, further extends the clinical stages of neurodegenerative diseases, including AD, before the occurrence of MCI158. However, there is a potential trade-off: improved sensitivity in the detection of cognitive decline could reduce specificity, since causes other than neurodegeneration could explain the observed changes, including sleep apnoea, or metabolic or psychiatric disorders159.
To aid in clinical accuracy, precise and stable automated technology can be used in routine chemistry laboratories26.
Biomarker innovations in Alzheimer’s disease
Charlotte Teunissen, Professor of Neurochemistry at the Vrije Universiteit Amsterdam, describes the five-step process for developing Alzheimer's disease (AD) biomarkers. In the second video, she explains why this process has accelerated in recent years.
Development of blood-based biomarkers for AD could improve the diagnostic workup of Alzheimer’s disease3,4,29,30,118
Biomarker innovations in Alzheimer’s disease links
Unmet needs in biomarkers for Alzheimer’s disease
Positron emission tomography (PET) and cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers are not widely available and are costly (PET) or viewed as invasive (CSF). These factors could restrict their use in routine clinical practice to a more limited number of specialised centres3,4,29,30,118.
Thus, there is a pressing unmet medical need to identify cost-effective biomarkers for AD that are viewed as less invasive to patients, and widely available. Blood-based biomarkers could fulfil this need (Figure 9)29,30.
Advances in cerebrospinal fluid biomarkers in Alzheimer’s disease
CSF biomarkers revealing axonal damage and synaptic dysfunction are relevant for AD diagnosis. This is because synaptic pathology is evident early in the disease and is associated with functional and cognitive outcomes. Biomarkers that are promising candidates for revealing synaptic pathology in AD are160–164:
- Neurogranin
- SNAP25
- Synaptotagmins
- VLP1
Of these candidates, neurogranin could have the best diagnostic potential, given its specificity for neurodegeneration, and its increase in early disease stages3. The non-specificity of neurogranin for AD could improve its utility in primary care, as primary care physicians refer many patients with a cognitive complaint for specialist assessment.
YKL-40 (CHI3L1), a microglia and astrocyte biomarker, a possible monitor of treatment effect, is increased in AD164.
TREM2 is a major AD risk gene3,165. Evidence indicates an important role of TREM2 in AD at the level of amyloid and tau pathologies and inflammation, alone or together with other molecules, such as ApoE166.
Serum and plasma biomarker innovations in Alzheimer’s
There is a close link between amyloid and phosphorylated tau proteins in CSF and blood: concentrations of amyloid and phosphorylated tau proteins in blood are associated with concentrations in CSF, and with amyloid-PET (Aβ-PET) and tau-PET scans3,29,30.
New, sensitive technologies make possible the accurate measurement of central nervous system proteins in blood3. For example, neurofilament light chain (NfL), an axonal cytoskeleton protein, is a biomarker of neurodegeneration in AD and in other forms of dementia144. Levels of NfL are increased in blood, as in CSF, making application of this marker clinically feasible29.
Reductions in plasma Aβ concentrations in AD can be accurately captured by immunoprecipitation, mass spectrometry, automated electro-chemiluminescent assays, microfluidics or other technologies, such as immunoreduction167–173. It is not known which technology will emerge as the most accurate or robust for screening, stratification or effect monitoring, or the most promising for use in high-throughput analysis, which is necessary when medications become available, and pre-screening and monitoring of Aβ changes become important29,30.
Plasma Aβ could show benefit in early, or even pre-symptomatic, screening and monitoring, or recruitment to AD clinical trials (Table 2)29,174.
Table 2. Different uses of blood-based biomarkers in clinical trial design (Adapted29). Aβ, amyloid β; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain; pTau, phosphorylated-tau.
Markers | Consequence | |
Prescreening in at-risk populations (Predementia stage) |
Aβ, pTau | Cost-effective and practical early Alzheimer's disease detection |
Inclusion criterion (Predementia and dementia stage) |
Aβ and pTau to prescreen for Alzheimer's disease, eventually combined with NfL and GFAP and cognitive measures in an algorithm, yielding cutoffs for an inclusion vs exclusion decision | Cost-effective and practical early Alzheimer's disease detection |
Enrichment and stratification during inclusion (Predementia and dementia stage) |
pTau, GFAP and NfL concentrations, eventually split into different progression cutpoints to use their prognostic value | Improves the power of trials |
Target engagement (Predementia and dementia stage) |
Drug-specific targets; Aβ markers to show targeted Aβ-interfering effects | Detects a biological effect |
Outcome measures (Predementia and dementia stage) |
NfL, Aβ and pTau; NfL has more widespread use than Aβ or pTau; surrogacy to be proven for all | Treatment efficacy and effects; understanding the biological effects of drugs |
Evidence shows specificity of plasma phosphorylated tau 181 and 217 as diagnostic biomarkers for AD, compared with other dementia forms, and for concordance with Aβ and phosphorylated tau neuropathology through PET157,175,176.
Prospective studies are required in primary care to determine if blood-based diagnostic algorithms can improve the diagnostic workup of AD, and improve treatment and care (Figure 9)3,29,30.
Review the clinical role of digital biomarkers in Alzheimer’s progression
Biomarkers and disease-modifying therapy development for Alzheimer’s
Biomarkers are crucial for the development of disease-modifying therapies (DMT) for AD. Aβ-PET or tau-PET are often suitable for determining agent-target engagement of investigational anti-Aβ or anti-tau treatments3,29,30.
In clinical trials of patients with pre-symptomatic or prodromal disease, non-invasive and low-cost biomarkers are needed to identify potential study participants most likely to respond to treatment (Table 2). Screening using different combinations of plasma phosphorylated tau, Aβ42–40 and NfL could identify people with pre-symptomatic and prodromal AD, although it will be necessary to confirm AD neuropathology using CSF or PET in patients who screened positive using blood-based biomarkers3,29,30,91,177.
Final questions on blood-based biomarkers
As blood-based biomarkers of amyloid and tau neuropathology and neurodegeneration near clinical implementation, it is important to learn what factors affect the concentrations of these markers. Understanding these factors is relevant for the development of reference ranges3,29,30.
Investigation of blood-based biomarkers in diverse racial, ethnic and geographic communities is needed, as these factors affect AD CSF biomarker and Aβ-PET values178.
Blood-based biomarkers representing the complexity of AD pathology, such as biomarkers of microglia activation or synaptic dysfunction are needed29.
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