Dement Neuropsychol 2024;18:e2024C001 Consensus

https://doi.org/10.1590/1980-5764-DN-2024-C001

Guidelines for the use and interpretation

of Alzheimer’s disease biomarkers
in clinical practice in Brazil:
recommendations from the Scientific
Department of Cognitive Neurology and Aging
of the Brazilian Academy of Neurology
Adalberto Studart-Neto1,2 , Breno José Alencar Pires Barbosa1,3,4 , Artur Martins Coutinho5,6 ,
Leonardo Cruz de Souza1,7 , Lucas Porcello Schilling1,8 , Mari Nilva Maia da Silva1,9 ,
Raphael Machado Castilhos1,10 , Paulo Henrique Ferreira Bertolucci1,11 ,
Wyllians Vendramini Borelli1,12 , Hélio Rodrigues Gomes13,14,15 , Gustavo Bruniera Peres Fernandes16 ,
Maira Tonidandel Barbosa7 , Marcio Luiz Figueredo Balthazar1,17 , Norberto Anízio Ferreira Frota1,18,19 ,
Orestes Vicente Forlenza20 , Jerusa Smid1,2 , Sonia Maria Dozzi Brucki1,2 , Paulo Caramelli1,7 ,
Ricardo Nitrini1,2 , Eliasz Engelhardt1,21,22 , Elisa de Paula França Resende1,7

This study was conducted by the Brazilian Academy of Neurology.

1
Academia Brasileira de Neurologia, Departamento Científico de Neurologia Cognitiva e do Envelhecimento, São Paulo SP, Brazil.
2
Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Departamento de Neurologia, Grupo de Neurologia Cognitiva e do Comportamento, São Paulo SP, Brazil.
3
Universidade Federal de Pernambuco, Hospital das Clínicas, Recife, Centro de Ciências Médicas, Recife PE, Brazil.
4
Universidade Federal de Pernambuco, Empresa Brasileira de Serviços Hospitalares, Hospital das Clínicas, Departamento de Neurologia, Recife PE, Brazil.
5
Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Instituto de Radiologia, Centro de Medicina Nuclear, Laboratório de Investigação Médica (LIM 43),
São Paulo SP, Brazil.
6
Hospital Sírio-Libanês, Medicina Nuclear e Serviço de PET-CT, São Paulo SP, Brazil.
7
Universidade Federal de Minas Gerais, Faculdade de Medicina, Unidade de Neurologia Cognitiva e do Comportamento, Belo Horizonte MG, Brazil.
8
Pontifícia Universidade do Rio Grande do Sul, Escola de Medicina, Serviço de Neurologia, Porto Alegre RS, Brazil.
9
Hospital Nina Rodrigues, Serviço de Neuropsiquiatria, São Luís MA, Brazil.
10
Hospital de Clínicas de Porto Alegre, Serviço de Neurologia, Centro de Neurologia Cognitiva e Comportamental, Porto Alegre RS, Brazil.
11
Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Neurologia e Neurocirurgia, São Paulo SP, Brazil.
12
Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Departamento de Ciências Morfológicas, Porto Alegre RS, Brazil.
13
Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Laboratório de Líquido Cefalorraquidiano, São Paulo SP, Brazil.
14
Universidade de São Paulo, Faculdade de Medicina, Laboratório de Investigação Médica (LIM 15), São Paulo SP, Brazil.
15
Departamento Científico de Líquido Cefalorraquiano, Academia Brasileira de Neurologia, São Paulo SP, Brazil.
16
Hospital Israelita Albert Einstein, Laboratório Clínico, São Paulo SP, Brazil
17
Universidade Estadual de Campinas, Faculdade de Ciências Médicas, Departamento de Neurologia, Campinas SP, Brazil.
18
Hospital Geral de Fortaleza, Serviço de Neurologia, Fortaleza CE, Brazil.
19
Universidade de Fortaleza, Fortaleza, CE, Brazil.
20
Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Instituto de Psiquiatria, Laboratório de Neurociências, São Paulo SP, Brazil.
21
Universidade Federal do Rio de Janeiro, Instituto de Neurologia Deolindo Couto, Rio de Janeiro RJ, Brazil.
22
Universidade Federal do Rio de Janeiro, Instituto de Psiquiatria, Rio de Janeiro RJ, Brazil.
Correspondence: Adalberto Studart-Neto; Email: [email protected].
Disclosure: The authors report no conflicts of interest.
Funding: ASN has received honoraria for participation in advisory board for Roche. BJAP has participated as a speaker in symposiums promoted by the laboratories Sandoz, Roche,
Knight Therapeutics, Novo Nordisk, and Libbs, participated in the advisory board of Roche and received financial support for participation in events from Novo Nordisk. OVF is a
principal investigator in a clinical trial for Biogen (ENVISION). EPFR received support from Proneuro for the preparation of educational materials, from Novo Nordisk for conference
attendance, and from Roche for participation in educational activities. PHFB has received honoraria from Neuroimmun, RMC received Alzheimer’s Association Grant (AARGD-21-846545)
and is funded by CNPq, Brazil (research productivity grant). GBPF has received participation as speaker in symposium sponsored by Lilly and Roche. MLFB participates in research
sponsored by Roche. NAFF has received honoraria for participation in advisory boards for Roche. LPS has received honoraria for participation in advisory boards for Biogen, Knight,
Lilly, Novo Nordisk e Roche and for the development of continuing medical education material by Aché, Apsen, Biogen, Knight, Libbs, Novo Nordisk e Roche. LCS has received
honoraria for participation in advisory boards for Biogen and Lilly, for the development of continuing medical education material, and participation as a speaker in a symposium
sponsored by Abbott, Biogen, Knight, and Novo Nordisk; he is a principal investigator in a clinical trial for PassageBio. SMDB has received honoraria for participation in the advisory
board for Biogen, Novo Nordisk, Lilly, Roche, and Adium. PC has participated in a clinical trial sponsored by Novo Nordisk, has participated in consulting activities for Aché, Danone,
Eurofarma, Knight Therapeutics and Roche and has prepared continuing medical education materials and participation as speaker in symposia sponsored by Aché, Danone, Grupo
Fleury, Novo Nordisk and Roche. RN and SMDB are funded by CNPq, Brazil (research productivity grant). AMC, WVB, MNMS, HRG, MTB, JS, EE have no conflicts of interest to declare.
Received on August 01, 2024; Accepted on August 16, 2024.

Studart-Neto A et al.   Alzheimer’s disease biomarkers in clinical practice in Brazil.   1

 Dement Neuropsychol 2024;18:e2024C001

ABSTRACT. In recent years, the diagnostic accuracy of Alzheimer’s disease has been enhanced by the development of different types of biomarkers that
indicate the presence of neuropathological processes. In addition to improving patient selection for clinical trials, biomarkers can assess the effects of new
treatments on pathological processes. However, there is concern about the indiscriminate and poorly supported use of biomarkers, especially in asymptomatic
individuals or those with subjective cognitive decline. Difficulties interpreting these tests, high costs, and unequal access make this scenario even more
challenging in healthcare. This article presents the recommendations from the Scientific Department of Cognitive Neurology and Aging of the Brazilian
Academy of Neurology (Departamento Científico de Neurologia Cognitiva e Envelhecimento da Academia Brasileira de Neurologia) regarding the rational
use and interpretation of Alzheimer’s disease biomarkers in clinical practice. The clinical diagnosis of cognitive-behavioral syndrome is recommended as
the initial step to guide the request for biomarkers.
Keywords: Alzheimer Disease; Cognitive Dysfunction; Diagnosis; Biomarkers; Neuroimaging.

Diretrizes para o uso e interpretação dos biomarcadores da doença de Alzheimer na prática clínica no Brasil: recomendações do Departamento
Científico de Neurologia Cognitiva e do Envelhecimento da Academia Brasileira de Neurologia
RESUMO. Nos últimos anos, a precisão diagnóstica da doença de Alzheimer tem sido aprimorada pelo desenvolvimento de diferentes tipos de biomarcadores
que indicam a presença dos processos neuropatológicos. Além de melhorar a seleção de pacientes para ensaios clínicos, os biomarcadores podem avaliar
os efeitos de novos tratamentos nos processos patológicos. No entanto, há preocupação com o uso indiscriminado e mal fundamentado de biomarcadores,
especialmente em indivíduos assintomáticos ou com declínio cognitivo subjetivo. As dificuldades na interpretação desses testes, os altos custos e o acesso
desigual tornam esse cenário ainda mais desafiador no cuidado assistencial. Neste artigo, são apresentadas as recomendações do Departamento Científico
de Neurologia Cognitiva e Envelhecimento da Academia Brasileira de Neurologia quanto ao uso racional e interpretação de biomarcadores da doença de
Alzheimer na prática clínica. O diagnóstico clínico da síndrome cognitivo-comportamental é recomendado como o passo inicial para orientar a solicitação
de biomarcadores.
Palavras-chave: Doença de Alzheimer; Disfunção Cognitiva; Diagnóstico; Biomarcadores; Neuroimagem.

INTRODUCTION However, there is concern about the indiscriminate

I n recent years, the diagnostic accuracy of Alzheimer’s

disease (AD) has been enhanced by the development
of different types of biological markers (biomarkers)
and poorly founded use of biomarkers, especially in
asymptomatic individuals or those with subjective
cognitive decline (SCD). The development of plasma bio-
that indicate the presence of the neuropathological pro- markers and greater access to these tests make it even
cesses associated with AD. Beyond being very important more necessary to exercise caution in requesting these
for the research of new therapies, by improving the biomarkers, as they will become increasingly available.
selection of patients for clinical trials, biomarkers are Besides the intrinsic difficulties in interpreting these
able to access the effects of new treatments on patho- tests, this scenario is also challenging due to their high
logical processes much earlier than neuropsychological costs and unequal access in Brazil5 and even in high-in-
and functional evaluations1. come countries6. Concerned about the inappropriate
Since 2011, the use of biomarkers as a tool to use of biomarkers, a European consensus established
increase the diagnostic accuracy of the symptomatic criteria for their application in clinical practice for mild
phases of AD in clinical practice has been debated. cognitive impairment (MCI) and mild dementia7.
Subsequently, biomarkers began to be used to op- Given the recent advances in the field of AD biomark-
timize the selection of patients and asymptomatic ers, the main objective of this article was to establish
individuals (pre-clinical phase) for clinical trials recommendations from the Scientific Department
and research. In 2018, biomarkers were definitively of Cognitive Neurology and Aging of the Brazilian
incorporated into research (biological diagnosis). Academy of Neurology (Departamento Científico de
In recent years, much progress has been achieved in Neurologia Cognitiva e Envelhecimento da Academia
molecular neuroimaging methods2 and in the tech- Brasileira de Neurologia) regarding the rational use and
niques for measuring biomolecules in body fluids — interpretation of AD biomarkers in clinical practice.
cerebrospinal fluid (CSF) and plasma3. More recently, These recommendations may serve as a guide for phy-
in 2024, a workgroup from the Alzheimer’s Associ- sicians who assist patients with cognitive impairment
ation (AA) updated the 2011 and 2018 diagnostic and dementia. Therefore, the diagnosis of the patient’s
criteria, reaffirming that the diagnosis of AD should cognitive-behavioral syndrome through anamnesis and
be biological, based on biomarkers, besides having cognitive, behavioral, and functional clinical evaluations
recommended biomarkers for biological staging of should always be the initial step to guide the request
the disease4. for biomarkers.

2   Alzheimer’s disease biomarkers in clinical practice in Brazil.   Studart-Neto A et al.

 Dement Neuropsychol 2024;18:e2024C001

METHODS NFTs18-20. The hypothesis explains the genetic forms

The recommendations were prepared by a group of of AD, but not the far more common sporadic forms.
medical specialists and researchers in AD and other
dementias (neurologists, geriatricians, psychiatrists, The amyloid beta peptide and amyloid plaques
nuclear medicine physicians, and clinical pathologists). Aβ peptides initially appear as monomers that can form
A non-systematic review of the literature was conducted various aggregates, from small oligomers to larger pro-
from searches in the MEDLINE, Scopus, SciELO, and tofibrils and fibrils. While amyloid fibrils are insoluble
LILACS databases until July 2024, using the descrip- and form amyloid plaques characteristic of AD, oligo-
tors “Alzheimer’s disease” or “biomarkers”. We selected mers are soluble and can spread throughout the brain.
mainly articles published in the last ten years as well Under physiological conditions, most Aβ peptides are
as relevant older publications. The authors then met Aβ40, and less than 10% are Aβ42, which is more prone
several times for discussion, and consensus points were to aggregation and is associated with the formation of
included in the recommendations. amyloid oligomers, fibrils, and plaques21. Aβ production
is balanced by degradation, clearance, transport, and
deposition processes. Around 10–15% of Aβ may enter
DEFINITION OF BIOMARKERS the CSF and bloodstream from the brain22.
Biomarkers in medicine can be defined as measures or Amyloid fibrils aggregate with other molecules,
indicators of normal or pathological physiological pro- forming plaques in the brain’s extracellular space,
cesses or responses to a therapeutic intervention8. The predominantly near synapses, in three types: diffuse,
ideal biomarker for AD should reflect the neuropatho- dense-core, and neuritic plaques11,13,14,23. Plaques grad-
logical characteristics of the disease; demonstrate ually grow in the brain’s interstitial space from con-
diagnostic accuracy in pathologically confirmed cases; tinuous extracellular deposition of Aβ peptides at
have a sensitivity of at least 85%; have specificity to “seed” sites.
differentiate AD from cognitively healthy individuals
and other diseases causing cognitive impairment of Neurofibrillary pathology and
at least 75%; indicate the real presence of AD and not phosphorylated tau protein
merely an increased risk; allow monitoring of disease Neurofibrillary pathology in AD includes NFTs, neu-
severity or progression; indicate the effectiveness of ropil threads, and dystrophic neurites14,24,25. NFTs are
the therapeutic intervention; be non-invasive; and be abnormal bundles of p-tau in neurons24.
economically accessible9,10. There are six tau isoforms in the adult human
brain26,27, with 3R and 4R isoforms present in approx-
imately equal levels28,29. In AD, NFTs contain both 3R
GENESIS OF BIOMARKERS - WHERE DO THEY and 4R isoforms. Other human tauopathies present
COME FROM? pathological aggregates of either 3R or 4R tau iso-
The neuropathological signature of AD includes forms27,30,31. P-tau, primarily found in neurons, stabilizes
amyloid plaques formed by extracellular deposits of microtubules 27,31 and is regulated by phosphorylation.
amyloid beta (Aβ) peptides and neurofibrillary tangles Pathological phosphorylation of tau reduces its microtu-
(NFTs) formed by intracellular aggregates of hyper- bule affinity, leading to cytoskeletal destabilization32,33.
phosphorylated tau proteins (p-tau), inflammatory P-tau can be released into interstitial fluid, CSF, and
reaction, astrocyte and microglial activation, as well blood, where it can be detected as indirect evidence of
as synaptic and neuronal loss11-14. AD32,34. Pathological p-tau can be phosphorylated at
several specific amino acids, such as 181, 217, and 231.
The amyloid cascade hypothesis
Amyloid plaques, composed of amyloid fibrils in a
beta-sheet conformation, are considered the primary CLINICAL AND BIOLOGICAL DIAGNOSES
cause of AD according to the “amyloid cascade hypoth- OF ALZHEIMER’S DISEASE: THE
esis”15-17. This theory suggests that altered metabo- EVOLUTION OF DIAGNOSTIC CRITERIA
lism of the amyloid precursor protein (APP) by secre- Although the description of the disease that bears his
tases (α, β, γ) leads to the release and aggregation of name was published in 1907 by the German neuropsy-
Aβ peptides (mainly Aβ40 and Aβ42), causing microglial chiatrist and neuropathologist Dr. Alois Alzheimer35,
activation, astrocytic reactivity, neuroinflammation, the first diagnostic criteria were proposed only in 1984
oxidative stress, p-tau hyperphosphorylation, and by McKhann et al.36. At that time, they considered only

Studart-Neto A et al.   Alzheimer’s disease biomarkers in clinical practice in Brazil.   3

 Dement Neuropsychol 2024;18:e2024C001

the amnestic presentation of AD and admitted diagnosis Table 1. Diagnostic categories defined by the Amyloid-Tau-
only in the dementia phase. In 2011, new criteria for Neurodegeneration system within the continuum of the biological
diagnosing AD were published by the National Institute definition of Alzheimer’s disease, according to the 2018 National Institute
on Aging and the Alzheimer’s Association (NIA-AA)37-39. on Aging and the Alzheimer’s Association Research Framework43,44.
In contrast to previous recommendations, the 2011 ATN Category according to biomarkers profile
NIA-AA criteria began to admit prodromal (i.e., pre-de-
A-T-N- Normal Alzheimer’s disease biomarkers
mentia) phases and the possibility of non-amnestic
variants of AD 37,39. The 2011 criteria anticipated the use A+T-N- Alzheimer’s disease pathological changes
of biomarkers for the etiological diagnosis of dementia A+T+N- Alzheimer’s disease (without neurodegeneration)
syndrome37 or MCI38, proposing the terms “dementia
due to AD”37 and “MCI due to AD”38. Subsequent stud- A+T+N+ Alzheimer’s disease (with neurodegeneration)
ies showed that these 2011 clinical criteria, without Alzheimer’s disease pathological changes +
A+T-N+
biomarkers, had a sensitivity of 70.9–87.3% and a low non-Alzheimer pathology
specificity of 44.3–70.8% when compared to patholog- A-T+N- Suspected non-Alzheimer’s pathophysiology (SNAP)
ical diagnosis40. In another study, the use of biomarkers
led to a change in diagnosis in 36% of dementia cases A-T-N+ Suspected non-Alzheimer’s pathophysiology (SNAP)
with uncertain diagnosis41. It is estimated that in spe- A-T+N+ Suspected non-Alzheimer’s pathophysiology (SNAP)
cialized memory centers, diagnostic errors range from Abbreviations: ATN, Amyloid-Tau-Neurodegeneration.
25–30% when biomarkers are not used42.
Subsequently, in 2018, the NIA-AA proposed a new
conceptual model for the biological definition of AD of SCD and MCI, to the dementia phase. In 2018, the
based on biomarkers according to the Amyloid-Tau-Neu- authors of this diagnostic consensus made it clear that
rodegeneration - AT(N) system. In this 2018 model, this biological definition, independent of the presence
the presence or absence of symptoms would not be of cognitive symptoms, should only be used in research
necessary for AD diagnosis, with biomarkers A and T and not in clinical practice due to the lack of effective
being sufficient. According to this model, AD is biolog- treatments for preclinical diagnoses of the disease.
ically defined by evidence of disease-related pathology In 2024, an AA workgroup published an update to
through biomarkers, independent of the clinical syn- the 2018 criteria; before being published, an initial draft
drome. The goal was to improve AD diagnosis specificity of the article was made public for scientific contribu-
and apply it in clinical research, while the 2011 criteria tions for a few months4. The motivations for updating
would remain valid for use in clinical care43,44. the 2018 criteria were:
According to this proposal, AD is defined by the pos- • Approval of anti-amyloid drugs by regulatory
itivity of biomarkers for amyloid (A+) and p-tau (T+), agencies, which can only be used in patients with
regardless of the presence or absence of neurodegener- a confirmed AD diagnosis by biomarkers and in
ation (N+ or N-). Practically, the biological diagnosis of the early stages of the disease;
AD would require low concentrations of Aβ42 and high • Recent advances in the development of plasma
concentrations of p-tau in the CSF or positivity on am- biomarkers; and
yloid-PET (positron emission tomography) and tau-PET • Evidence that fluid and molecular neuroimaging
(Table 1). When there is only the presence of Aβ42 (A+) biomarkers are not equivalent and constitute
without evidence of tau pathology (T-), the term used is different categories.
“Alzheimer’s pathologic change,” representing the initial
stage of the AD pathological spectrum according to the The goal of the new criteria is to establish AD diag-
amyloid cascade hypothesis. Conversely, when there nosis by incorporating new advances in biomarkers, re-
is positivity for p-tau (T+) and/or neurodegeneration inforcing the idea that the definition of AD is biological
(N+), but negativity for amyloid pathology (A), the and that symptoms are not necessary for its diagnosis.
diagnosis of Alzheimer’s pathology should be excluded, Another proposed update is that biomarkers be used not
and it would be termed “suspected non-Alzheimer’s only for diagnosis but also for staging and monitoring
pathophysiology” (SNAP). treatment response4. Although the authors state that
Although the 2018 criteria consider only biomarkers these new criteria can inform diagnosis in both research
for AD diagnosis and not for the clinical syndrome, the and clinical care, they caution that these criteria are not
model recognizes that AD can manifest along a con- intended to be step-by-step guidelines for clinical prac-
tinuum from an asymptomatic phase, through stages tice or treatment protocols. The authors also recognize

4   Alzheimer’s disease biomarkers in clinical practice in Brazil.   Studart-Neto A et al.

 Dement Neuropsychol 2024;18:e2024C001

that these new criteria may not be operationalizable in cases are also in Braak stages III to VI, meeting the
many medical centers, even in high-income countries4. criteria for intermediate/high AD neuropathologi-
The 2024 AA workgroup criteria suggest dividing cal change4.
biomarkers into three categories (Table 2): On the other hand, tau PET and other tau analytes,
• Core (or specific) biomarkers of AD (biomarkers such as p-tau205 and MTBR-tau243 (microtubule-bind-
of amyloid and tau proteinopathies); ing region of tau-containing residue 243) change later,
• Non-specific biomarkers involved in the patho- when fibrillar tauopathy is at Braak stages IV to VI.
genesis of AD (biomarkers of neurodegeneration Hence, these biomarkers are termed T2, indicating in-
and inflammation); and soluble (or aggregated) phosphorylated tau proteinopa-
• Biomarkers of common co-pathologies associated thy46–48. Thus, amyloid and T1 biomarkers are considered
with AD (e.g., alpha-synuclein and cerebrovascu- core 1 biomarkers, while T2 biomarkers are core 2. Core 1
lar disease)4. biomarkers change in the early stages of AD (still in an
asymptomatic phase), while core 2 biomarkers become
Tau biomarkers are divided into two categories: abnormal later, when the first symptoms begin.
T1 and T2. This division is being proposed due to the The 2024 AA workgroup criteria propose that an
chronological difference in the alterations of tau bio- abnormality in one of the specific core 1 biomarkers (or
markers4. Some p-tau isoforms (181, 217, 231) change a combination of them) is sufficient for the diagnosis
earlier, around the same time that amyloid PET becomes of AD: amyloid PET, CSF Aβ42/40, CSF p-tau 181/Aβ42,
positive45-47. Although these soluble p-tau analytes in or CSF t-tau/Aβ42 (Table 2). The workgroup raises the
CSF and plasma are tau biomarkers, they may indicate possibility that plasma biomarkers could be used for
that the patient already has moderate/frequent amyloid diagnosis in the future, as long as they have an accura-
plaques (high CERAD score, Consortium to Establish cy equivalent to already approved CSF biomarkers or
a Registry for Alzheimer’s Disease) and most of these amyloid PET. Core 2 biomarkers alone are not sufficient
for diagnosis, but the combination of core 1 and core
Table 2. New categorization of Alzheimer’s disease fluid and molecular 2 biomarkers can be used for AD biological staging4.
neuroimaging biomarkers according to the 2024 Alzheimer’s Association The AA workgroup currently recommends against di-
Workgroup criteria4. agnostic testing in asymptomatic individuals outside
the context of research studies.
Core AD biomarkers (or specific AD biomarkers)
These criteria were criticized by the scientific com-
Core 1 munity, particularly by the European group, the Interna-
A Aβ proteinopathy: Aβ42 (CSF or plasma) and amyloid PET
tional Working Group (IWG), which proposed a parallel
diagnostic criterion49. The IWG does not consider the
Soluble (or secreted) phosphorylated tau proteinopathy: p-tau presence of biomarkers as a sole diagnosis of AD because
T1
181, p-tau 217, p-tau 231(CSF or plasma)
many people have positive biomarkers but never devel-
Core 2 op clinical symptoms49. Additionally, the IWG argues
Insoluble (or aggregated) phosphorylated tau proteinopathy:
that the presence of biomarkers is a risk factor for AD,
T2 but alone, does not allow for a diagnosis of the disease,
p-tau205, MTBR-243 (CSF or plasma), and tau PET
in contrast to the criteria suggested by the AA in 2024.
Non-specific biomarkers involved in the pathogenesis of AD
These differences reflect some of the criticisms about
Neurodegeneration: NfL (CSF or plasma), anatomic MRI, and the AA’s proposed criteria, including the lack of access
N
FDG PET to biomarkers in resource-limited settings, leading to
I Astrocytic inflammation and reactivity: GFAP (CSF or plasma) disparities in diagnostic access, uncertainty regarding
the prognosis of “asymptomatic” disease, and diffi-
Common AD associated co-pathologies biomarkers
culties in managing the AD nomenclature. Still, there
Vascular (cerebrovascular disease): infarction or WMH on MRI is a significant stigma associated with the name “Alz-
V
(or CT) heimer’s disease” due to its invariably progressive and
S Alfa-synuclein proteinopathy: αSyn-SAA (CSF) irreversible nature once symptoms begin. Moreover, the
impact of such a diagnosis on asymptomatic individuals
Abbreviations: AD, Alzheimer’s disease; Aβ, amyloid beta; αSyn-SAA, alpha-synuclein
seed amplification assay; CSF, cerebrospinal fluid; CT, computed tomography; FDG,
or those in the early stages of the disease is unknown.
fluorodeoxyglucose; GFAP, glial fibrillary acidic protein; MRI, magnetic resonance imaging; Finally, despite the existence of anti-amyloid therapies
MTBR, microtubule-binding region; NfL, neurofilament light chain; PET, positron emission that show some clinical effect, these drugs have modest
tomography; p-tau, ; WMH, white matter hyperintensity. efficacy, potentially serious and fatal adverse events, and

Studart-Neto A et al.   Alzheimer’s disease biomarkers in clinical practice in Brazil.   5

 Dement Neuropsychol 2024;18:e2024C001

high costs, which currently do not justify screening for concentrations in CSF and plasma increase at the same
AD in the population, as is done with other diseases like time amyloid PET becomes positive and before tau PET
diabetes mellitus, colon or cervical cancer, that can be changes45–47,56. Compared to p-tau181, p-tau217 exhib-
diagnosed in asymptomatic individuals. ited a better correlation with amyloid PET and better
differentiated A+ individuals from A- individuals57.
Additionally, p-tau217 proved to be a better marker of
BIOMARKERS IN CEREBROSPINAL FLUID cognitive progression to dementia in patients with MCI
The most widely validated and studied CSF biomarkers than p-tau18158. On the other hand, p-tau205 changed
are the proteins that characterize AD: the Aβ42 peptide later and was better associated with tau PET than with
and p-tau. In CSF, AD is characterized by a reduction in amyloid PET57.
Aβ42 and an increase in p-tau. This pattern is known as Although the p-tau dosage in CSF serves as a bio-
the AD pathology signature in CSF50. marker for tau pathology, the soluble tau isoforms do
Recently, Aβ40 has been included in the diagnostic not correlate with the load of insoluble p-tau aggregates
biomarker panel for AD, as evidence shows that the (represented by NFTs). Recently, the measurement of
Aβ42/Aβ40 ratio outperforms Aβ42 dosage alone, demon- MTBR-tau243 residues was investigated as a new CSF
strating better concordance with amyloid PET positivity. biomarker specific for insoluble tau aggregates59. Chang-
The Aβ40 peptide has high concentration levels in CSF es in MTBR-tau243 in CSF occur simultaneously with
and does not vary in AD, unlike Aβ42. This causes the changes in tau PET59.
Aβ42/Aβ40 ratio in CSF to gradually decrease as the dis- Total p-tau (t-tau) measures all isoforms of p-tau,
ease progresses51. regardless of phosphorylation state; therefore, is not
A meta-analysis of 131 studies revealed that CSF specific to AD. In fact, elevated t-tau levels can be ob-
concentrations of Aβ42 in AD patients decrease by about served in other conditions involving neuronal damage,
56% from normal levels52. A steeper decline in CSF Aβ42 both degenerative (e.g., Creutzfeldt-Jakob disease) and
levels occurs at the onset of the disease’s pathological acute non-degenerative (e.g., cerebrovascular accident).
process, followed by relative stability as the disease Thus, t-tau is considered a nonspecific biomarker of
evolves. In contrast, p-tau levels change slowly over the neurodegeneration. Recently, the measurement of t-tau
course of the disease53. in CSF has been increasingly replaced by other neurode-
Most studies showed approximately 90% concor- generation markers, especially neurofilament light chain
dance in comparing amyloid PET and CSF Aβ42 levels (NfL). Similar to t-tau, increased NfL concentrations
in LCR51. In a longitudinal study with older individuals are not specific to AD and can rise in other neurode-
without dementia, Palmqvist et al. observed that those generative disorders, such as amyotrophic lateral scle-
with low CSF Aβ42 levels and negative amyloid PET had a rosis (ALS) and frontotemporal dementia (FTD). NfL is
higher rate of PET positivity over time than individuals promising as it may predict disease progression and
with normal Aβ42 levels54. This finding suggests that potentially response to disease-modifying treatments60.
CSF changes precede amyloid PET changes, explaining Recent CSF AD biomarkers time course study involv-
why the concordance between the two biomarkers is ing Chinese participants during the 20 years preceding
below 100%. It is important to note that these studies clinical diagnosis of sporadic Alzheimer’s disease,
involved asymptomatic individuals. In patients at the showed changes in CSF biomarkers concentration,
dementia stage, a higher concordance between amyloid as follows: Aβ42, 18 years; Aβ42/Aβ40 ratio, 14 years;
PET results and CSF Aβ42 levels is observed. p-tau 181, 11 years; t-tau, 10 years; and NfL, 9 years.
The accumulation of p-tau is the other component As cognitive impairment progressed, the changes in CSF
that defines AD besides Aβ peptide. The main assays biomarker levels in the AD group initially accelerated
used to measure p-tau quantify p-tau181, which pre- and then slowed61.
sented the best accuracy in differentiating AD from Despite numerous studies demonstrating the good
cognitively healthy controls or other degenerative accuracy of CSF biomarkers for AD, one of the major
dementias. Assays using p-tau231 and p-tau199 also challenges has been the significant variability between
demonstrated good accuracy51. The ratio of p-tau/Aβ42 laboratories51,62. This variability often leads clinicians
levels has also proven useful in AD diagnosis, with a to disregard CSF results when they conflict with the
sensitivity of 91.6% and a specificity of 85.7%55. diagnostic hypothesis and to seek molecular neuroim-
More recently, several studies showed that p-tau217 aging methods as biomarkers. This variability primarily
is the phosphorylated tau isoform with the earli- stems from errors and failures in the pre-analytical
est changes 45-47. Evidence indicated that p-tau217 (sample collection, storage, and transportation) and

6   Alzheimer’s disease biomarkers in clinical practice in Brazil.   Studart-Neto A et al.

 Dement Neuropsychol 2024;18:e2024C001

analytical (actual execution of the test) phases. It is es- A recent study demonstrated that the ratios of different
timated that pre-analytical problems account for up to automated platforms (p-tau/Aβ42 and Aβ42/Aβ40) in CSF
70% of errors in clinical laboratories63. To address this show excellent concordance (positive and negative) with
issue, the AA, in partnership with the Neurochemistry amyloid PET classification65. These data suggest that the
Laboratory at the University of Gothenburg (Sweden), p-tau/Aβ42 and Aβ42/Aβ40 ratios provide similar clinical
established an external quality control (QC) program information in evaluating amyloid pathology, thereby
in 2009. The program aims to monitor variations in bringing greater reliability to clinical practice results.
biomarker tests across different locations and batches However, these automated platforms are still costly.
and to help the participating laboratories synchronize Two automated electrochemiluminescence platforms
their procedures. This external QC program is free for have received regulatory approval in the United States
participating laboratories, whether they are devoted to (through FDA, Food and Drug Administration) and
research or clinical activities62. in the European Union (EMA, European Medicines
Among the core biomarkers for AD, the measure- Agency) to date66,67. The approval of these two plat-
ment of Aβ42 is the most affected by the pre-analytical forms was conditioned on achieving accuracy close to
phase. Falsely reduced results, or potential false posi- 90% compared to amyloid PET. The sensitivity of these
tives, can occur due to the adsorption of the peptide platforms ranges from 88–97%, while specificity ranges
onto the walls of the tubes used for CSF collection. from 84–89%66,67.
The Aβ42/Aβ40 ratio shows less variation than the con- We strongly recommend that clinicians observe the
centration of Aβ42 alone62. The recommendation is to use methodology used in these measures and, whenever
low-binding polypropylene tubes for the collection and possible, choose laboratories that use fully automated
storage of CSF, avoiding glass tubes. Other interfering platforms to minimize analytic bias.
factors include sample handling, tube transfers (ali- Finally, it is important to emphasize that CSF anal-
quoting), freeze-thaw cycles, and storage temperature. ysis is recommended in cases of rapidly progressive de-
Recently, a working group led by the AA, consisting mentia, early-onset dementia, or atypical dementias, to
of experts from academia and industry, proposed a new exclude infectious, inflammatory autoimmune, or neo-
simplified and standardized pre-analytical protocol for plastic diseases38. In these cases, the CSF examination
CSF collection, handling, and analysis for clinical routine must include a red blood cell and nucleated cell count,
use. This proposal came up after a comprehensive analy- differential leukocyte analysis, total protein measure-
sis of the impact of pre-analytical factors, including the ment, and glucose levels. If an infection is suspected,
type of tube, sample handling procedures, and storage/ the analysis should include venereal disease reaction
transport conditions62. level, Gram stain, fungal and acid-fast bacilli tests, and
The most used methods for measuring biomarkers culture with antibiogram. At the physician’s discretion,
are manual immunoassays, specifically enzyme-linked other analyses may be included (e.g., neoplastic cell
immunosorbent assay (ELISA). Even when following search, specific immunological reactions, or oligoclonal
the recommendations suggested by the AA, the coef- band search).
ficient of variation (CV) for this technique between
laboratories can reach 15–25% (medium to high).
Recently, single molecule array (SIMOA™) technology, BLOOD-BASED BIOMARKERS
which involves encapsulating individual molecules In recent years, there has been significant improvement
in femtoliter reaction chambers using paramagnetic in the technologies that enable the measurement of
markers, has also been used for biomarker measurement Aβ peptide and different epitopes of p-tau in plasma.
due to its ability to detect very small concentrations of The latest availability of plasma assays for these bio-
substances in CSF and plasma. markers was made possible by developing more precise
Fully automated platforms have been developed in techniques, as the plasma concentration of these pro-
recent years. Bittner et al. published a 100% automated teins is much lower than in CSF. The use of assays based
method based on electrochemiluminescence immuno- on mass spectrometry or more sensitive immunoassays
assay64. Automated assays offer significant advantages (e.g., SIMOA™) has made it a reality to measure these
over the ELISA methodology as they eliminate manual biomarkers in plasma42,68,69.
steps, reducing the possibility of human interference Compared to well-established CSF and PET meth-
in the analytical process, and they exhibit superior per- ods, plasma biomarkers offer a less invasive, more
formance (low CVs: Aβ42 ≤ 6%; p-tau and t-tau: ≤ 2.5%) feasible, and potentially more cost-effective option in
with a shorter test execution time (~20 minutes). clinical practice. Additionally, they have the potential

Studart-Neto A et al.   Alzheimer’s disease biomarkers in clinical practice in Brazil.   7

 Dement Neuropsychol 2024;18:e2024C001

to significantly reduce screening time and costs in Other important issues include the need for “re-
clinical trials and can be used as surrogate outcomes al-world” studies to verify the robustness of the test,
to evaluate the efficacy of therapies. However, the studies that validate it in diverse populations, and
validation of these plasma biomarkers is still in devel- an understanding of intra-individual variability and
opment, and currently, they cannot be used alone for disease-associated variability, as well as the potential
diagnosis. While a recent study suggests the possible impact of comorbidities and medications42,68. For these
superiority of plasma over CSF biomarkers45, another reasons, it is not recommended to use the Aβ42/Aβ40
study using machine learning to predict AD-asso- ratio alone as the sole amyloid biomarker, for example,
ciated cognitive decline suggests the superiority of to indicate anti-amyloid therapy42,68. Plasma biomarkers
CSF biomarkers70. are not recommended as unique diagnostic criteria for
Besides the mixed results regarding the superiority anti-amyloid therapy.
of plasma biomarkers for AD diagnosis, the limitation Combining the Aβ42/Aβ40 ratio with other bio-
of real-world clinical validation, lack of studies in eth- markers can improve its accuracy. West et al. designed
nically diverse populations and local norms (e.g., for a mass spectrometry platform to quantify plasma
the Brazilian population), and some methodological levels of Aβ42 and Aβ40 and identify specific peptides of
issues (pre-analytical care protocols and QC programs the apolipoprotein E (ApoE) isoform — proteotyping,
like those existing for CSF biomarkers) hinder the ap- an indirect method of determining ApoE genotype72.
plicability of plasma biomarker68. For all these reasons, In this study, the accuracy of Aβ42/Aβ40 increased from
the systematic and routine use of plasma biomarkers 81 to 86% when combined with ApoE proteotyping.
in clinical practice is not currently recommended. Ad- The authors also developed an amyloid probability
ditionally, none of the plasma biomarker assays have score (APS) by combining the Aβ42/Aβ40 ratio, ApoE
been approved by the FDA as of June 20244. proteotyping, and the patient’s age. The scores are cat-
egorized as low (0–35), intermediate (36–57), and high
Plasma Aβ42, Aβ40 and Aβ42/Aβ40 ratio (58–100), corresponding to the likelihood of amyloid
The development of various immunoprecipitation PET positivity, with a sensitivity of 84.9% and a speci-
methods based on mass spectrometry has greatly im- ficity of 96.0%73. Although this platform is already being
proved the Aβ42/Aβ40 ratio accuracy. However, accuracy commercialized, it is emphasized that the measurement
varies among the different methods used. While mass methods for Aβ42 and Aβ40 peptides still require better
spectrometry-based assays have an area under the validation, particularly in the Brazilian population. An-
curve (AUC) ranging from 0.76–0.87, immunoassay other aspect to consider in a blood matrix is identifying
methods have lower performance, with AUC ranging confounding factors that affect levels and their clinical
from 0.64–0.7848. This significant variability in accuracy utility before routine implementation. Recent evidence
between assay types is one of the main limitations to suggests that reduced renal function may be associated
the clinical use of plasma Aβ peptide biomarkers48,71. with increased plasma biomarker concentrations74.
The measurement of Aβ42 alone has not shown good No platform for measuring Aβ42 and Aβ40 in plasma has
accuracy and is therefore not performed; the Aβ42/Aβ40 received regulatory approval in the United States or the
ratio is always recommended. European Union4.
An inherent problem with the plasma Aβ42/Aβ40 ra-
tio, regardless of the method used, is that AD patients Plasma phosphorylated tau
show only a small reduction in this parameter compared Similar to advancements in detecting plasma Aβ peptide
to controls. For reference, in the plasma of AD patients, through mass spectrometry, in recent years, several as-
the Aβ42/Aβ40 ratio is reduced by 8–15% compared to says using this method have been developed for detect-
controls, while in CSF, the reduction is 40–60%42,68,71. ing p-tau in the blood. However, these assays are not yet
This makes the plasma test less robust than the CSF validated and standardized for routine use (real-world
Aβ42/Aβ40 ratio. One possible explanation for this differ- studies) outside the context of clinical research. An in-
ence is that the reduction in the Aβ42/Aβ40 ratio quanti- herent problem with p-tau is its extremely low plasma
fied in plasma reflects only a fraction of the Aβ detected concentration. This consideration is necessary for in-
in the blood, as the test does not distinguish between Aβ terpreting study results and, obviously, for considering
derived from the brain and that of extracerebral origin, its application in clinical practice. Significant progress
the latter presumably not affected by AD pathology42,68. was achieved in p-tau measurement techniques, and in
Developing plasma biomarkers that reflect the brain-de- some cases, accuracy values equivalent to tau PET and
rived fraction of Aβ remains a challenge. even superior to CSF have been achieved45.

8   Alzheimer’s disease biomarkers in clinical practice in Brazil.   Studart-Neto A et al.

 Dement Neuropsychol 2024;18:e2024C001

The referenced assays use antibodies to detect tau the percentage of p-tau217 relative to np-tau217 to
epitopes, as the intact protein is even less available in produce an amyloid probability score 2 (APS2) had
peripheral blood due to proteolytic processes. These epi- accuracy of 88% (AUC=0.94; 95%CI 0.92–0.96), with
topes are named according to the position of the amino 88% agreement with amyloid PET84.
acid at which they are phosphorylated. The most widely As with plasma Aβ, the presence of certain comorbid-
used epitopes in assays are p-tau181, p-tau217, and ities can significantly affect the plasma concentration of
p-tau231. Tests with each of these variants have shown tau epitopes. Understandably, chronic kidney disease —
that they can differentiate patients with and without AD once it affects protein clearance—is associated with high-
pathology56,75-77. Studies with neuropathological informa- er levels of p-tau181 and p-tau217. Additionally, con-
tion have shown that plasma levels of p-tau217 reflect ditions such as hypertension, stroke, and myocardial
both the density of NFTs and amyloid plaques78. Notably, infarction also elevate these levels85. These conditions
the increase in levels of these p-tau forms seems specific may presumably modify the safe cutoff points for the
to AD and does not occur in other tauopathies such as test, but this relationship has not yet been established.
corticobasal degeneration (CBD), progressive supranu-
clear palsy (PSP), or frontotemporal lobar degeneration
(FTLD)68,75. Both p-tau181 and p-tau217 have also shown NEUROIMAGING BIOMARKERS
excellent accuracy in predicting the progression of pa- Among the neuroimaging biomarkers for evaluating AD,
tients with MCI to a stage of dementia due to AD56,75. On structural neuroimaging methods such as computed to-
the other hand, p-tau231 is the first to change on the AD mography (CT) and magnetic resonance imaging (MRI)
continuum, indicating a closer association with amyloid stand out, along with nuclear medicine techniques.
pathology than with tau pathology itself 79. Molecular neuroimaging and nuclear medicine meth-
Of all the isoforms, p-tau217 has shown the highest ods include conventional brain scintigraphy, acquired in
sensitivity and specificity for the diagnosis of AD80. gamma cameras in three-dimensional form (single-pho-
Unlike the Aβ42/Aβ40 ratio, which decreases by less ton emission computed tomography — SPECT), and the
than 15% in AD patients, p-tau217 increases by 300 to PET. In these exams, the radioactive source emanates
700%42. This makes p-tau217 a much more robust test from the patient, who receives an intravenous injection
for detecting AD compared to the Aβ42/Aβ40 ratio. In of radiotracers. These procedures are safe, with no sig-
a study comparing ten different plasma p-tau assays, nificant adverse events or reported allergies. PET has a
the measurement of p-tau217 using a mass spectrom- higher spatial resolution than SPECT. These exams are
etry-based assay presented an AUC of 0.947 and a currently performed on hybrid multimodal machines
correlation of 0.891 with CSF p-tau concentration56. (SPECT/CT, PET/CT, and, more recently, PET/MRI) to
Interestingly, p-tau217 levels also showed an excellent compensate for their lack of spatial resolution. Today,
correlation with amyloid pathology42. Brum et al. devel- almost all PET machines have a PET/CT configuration86.
oped an algorithm using p-tau217, ApoE genotyping, These methods are highly sensitive for selecting
and age as a screening test to determine Aβ patholo- patients for anti-amyloid therapies and for prognosis
gy positivity in patients with MCI81. This algorithm evaluation/stratification. They are commonly used for
could predict amyloid pathology in 80% of cases (in outcome assessments in most recent AD studies, mainly
the remaining 20%, the Aβ42/Aβ40 ratio in CSF was due to their ability to detect specific pathological or
needed). In another study with 786 participants from physiological changes. However, their use is limited in
three cohorts using an immunoassay, plasma p-tau217 monitoring the safety of new anti-amyloid therapies
concentration had high accuracy in predicting Aβ compared to MRI, the gold standard in neuroradiology.
pathology (AUC=0.92–0.96; 95%CI 0.89–0.99) and MRI has recognized superiority in detecting general
tau pathology (AUC=0.93–0.97; 95%CI 0.84–0.99)76. conditions such as bleeding, stroke, edema, and amy-
Despite the need for more real-world validation stud- loid-related imaging abnormalities (ARIA)87.
ies, plasma p-tau217 (especially when using mass MRI is very useful in the initial evaluation of individ-
spectrometry-based assays) emerges as a promising uals with dementia due to its ability to detect structural
biomarker for detecting proteinopathies (amyloid and causes (e.g., cerebrovascular disease) or potentially revers-
tau)45. The ratio of plasma p-tau217 concentrations to ible causes (e.g., benign neoplasms) of cognitive decline88.
phosphorylated p-tau at different sites (np-tau217) In some cases, especially when MRI is not accessible, CT
has been used in some studies to further increase the can be used as a substitute. However, RM use is not limited
diagnostic accuracy of p-tau21782,83. Most recently, an to initial evaluation; it can also be employed as a biomarker
algorithm combining the plasma Aβ42/Aβ40 ratio and of neurodegeneration, as highlighted hereinafter.

Studart-Neto A et al.   Alzheimer’s disease biomarkers in clinical practice in Brazil.   9

 Dement Neuropsychol 2024;18:e2024C001

Imaging exams can function as biomarkers for AD with the limited availability of others (amyloid PET)
throughout the entire AT(N) staging44. Using PET scans in routine clinical practice, and, most notably, the high
with amyloid or tau tracers, it is possible to detect the cost of combining multiple tests, as detailed thereafter.
cerebral deposition of Aβ peptide plaques (“A” staging)
or intracellular tangles of phosphorylated p-tau (“T” Amyloid plaque marker positron emission tomography
staging), respectively, as well as their removal after The PET scan with an amyloid plaque marker (amyloid
treatments. While fluid biomarkers (CSF and plasma) PET) represents a significant technical advancement in
reflect the production or clearance of the soluble forms AD imaging assessment, being included as an “A” staging
of proteinopathies, PET tracers mark the insoluble marker in the latest diagnostic criteria4,44,49.
aggregates, measuring the cumulative effects of the This method detects extracellular cerebral deposits
proteinopathies and providing information on the neu- of Aβ peptide in moderate/frequent neuritic plaques
roanatomical distribution of the pathology89,90. with high sensitivity and specificity (96% and 100%,
PET scans assessing glucose metabolism [18F]-Flu- respectively)2,93. A normal amyloid PET scan excludes
orodeoxyglucose (FDG-PET), cerebral perfusion by AD as a diagnosis in patients with cognitive impair-
SPECT, and MRI can identify signs of neurodegener- ment. Therefore, it is indicated as a prerequisite to
ation (“N” staging)91. FDG-PET, besides being an N confirm or exclude a clinical syndrome related to AD,
biomarker for investigating AD, can aid in differential di- with high specificity and reproducibility, making it an
agnosis by demonstrating neurodegeneration patterns excellent tool for selecting patients for clinical trials
suggestive of AD or other non-AD degenerative diseas- and approved treatments.
es, as outlined by the NIA-AA Research Framework43 and There are four most common and commercially
confirmed in a Brazilian study92. Furthermore, FDG-PET available amyloid PET tracers. One of them, labeled
is particularly useful for characterizing atypical forms of with carbon-11, 11C-Pittsburgh compound-B ([11C]-
AD (logopenic variant, posterior cortical atrophy, and PiB), is considered open-access; however, it requires the
dysexecutive-behavior variant). presence of a cyclotron at the exam location due to the
In Brazil, the main limitations of molecular neuro- very short half-life of carbon-11. The other three tracers,
imaging assessment are the unavailability of certain labeled with fluorine-18, have commercial use due to
tracers (especially tau PET), the high cost combined the longer half-life of fluorine-18 and were approved

Source: Images from the personal archive of one of the authors (A.M.C.) and acquired at the Nuclear Medicine Center of the Institute of Radiology,
Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil.
Figure 1. Axial images of amyloid PET of two individuals with [11C]-PiB showing significant cortical uptake of the tracer (A - upper row - a “positive” scan, or A+)
and absence of significant uptake of the tracer (B - lower row - a “negative” scan, or A-). In the A+ individual, a diffuse uptake is seen in the frontal, parietal, and
temporal neocortices, as well as in the medial parietal and frontal lobes (precuneus, posterior and anterior cingulate gyrus), with an intensity similar to or more
intense than the physiological uptake in the white matter. A negative scan (B) shows an uptake restricted to white matter tracts. Red localizers show the correct
way to visualize the medial parietal and medial frontal cortices in the medial views (at the cortex level as localized in the coronal or axial views). Note the absence of
uptake in the cerebellar cortex (a reference for negativity) and the physiological uptake in the brain stem (a reference for positivity).

10   Alzheimer’s disease biomarkers in clinical practice in Brazil.   Studart-Neto A et al.

 Dement Neuropsychol 2024;18:e2024C001

by European and United States regulatory agencies for It is important to note that these recommenda-
clinical use: [18F]-Florbetaben, [18F]-Florbetapir, and tions were published in 2013, before the adoption of
[18F]-Flutemetamol. Currently, the tracers available in biological diagnostic criteria for AD research based on
Brazil are [11C]-PiB and [18F]-Florbetaben. biomarkers.
Amyloid PET scans are generally dichotomous and Amyloid PET scans have been included as biomark-
classified as positive or negative (A+ or A-), facilitat- ers used as biological outcome variables in all clinical
ing the selection of individuals for clinical studies trials of anti-amyloid drugs approved so far on the
(Figure 1). Negative tests (A-) rule out the possibil- United States market to monitor the biological success
ity of AD. The incidence of A+ in cognitively normal of anti-amyloid therapy. Based on their high specificity,
individuals can range from 2.7% in people aged 50 the reduction of amyloid load was considered one of
to 59 years to 41.3% in people aged 80 to 89 years94, the aspects that contributed to the approval of these
typically varying around 10–20% in individuals aged drugs97-101. In October 2023, the Centers for Medicare
between 60 and 70 years. Conversely, about 25–30% & Medicaid Services in the United States approved
of individuals with a clinical diagnosis of AD have coverage for one amyloid PET scan during the lifetime
negative (A-) scans in most studies, indicating a high of patients with AD, primarily to appropriately select pa-
percentage of patients with clinically suggestive AD tients for anti-amyloid treatment102. Regarding clinical
but with another underlying pathology95. There are use for early detection or differential diagnosis of neuro-
minimal variations in the percentage of A+ between degenerative diseases, some authors have suggested the
cohorts and concordant results with international ideal timing for using this method, including its optimal
studies using [11C]-PiB. The Brazilian setting demon- timing relative to other molecular imaging methods2,86.
strates 18% positivity among controls (mean age ± The interpretation of typical images obtained
standard deviation [SD] = 71.19±6.1 years) and 76% with amyloid PET depends on the knowledge of the
in individuals with clinically suggestive AD (mean age progression of amyloid deposition and its topography
± SD = 73.7±7.3 years)92, highlighting the limitation during the course of AD. Initially, plaques form in the
of solely clinical diagnosis of the disease. neocortex (frontal, parietal, temporal, occipital) (Thal
In response to the initial results of studies with am- phase 1); next, in the allocortex (entorhinal cortex,
yloid PET, joint recommendations from the Society of subiculum, hippocampus [CA1]), cingulate cortex, and
Nuclear Medicine and the AA for the use of amyloid PET amygdala (Thal phase 2); then the basal ganglia, thal-
were published in 201396. This consensus recommended amus, and hypothalamus are affected (Thal phase 3);
the method in the following cases: and finally, the midbrain, pons, and cerebellum (Thal
• Persistent or progressive MCI of unexplained cause; phases 4 and 5)25,103,104.
• Patients with clinical criteria for possible AD, but
with atypical clinical presentation or possible Tau protein positron emission tomography
mixed etiology; and PET scans with p-tau deposit tracers are not yet part of
• Patients with progressive dementia and atypical routine clinical practice, even in centers in developed
age of onset (pre-senile), defined as symptom countries. However, research results indicate that this
onset at 65 years or younger. exam may eventually be included in clinical practice due
to its potential to replace older exams by combining the
The same recommendations suggested not using detection of pathological processes with disease staging
amyloid PET in the following situations: and differential diagnosis86,105-107.
• Patients who meet clinical criteria for probable In the revised criteria for diagnosis and staging of
AD with typical age of onset; AD, published by AA workgroup, it is clearly stated that
• To determine the severity of dementia; tau PET can discriminate between biological stages,
• Based solely on a family history of dementia or categorized from A to D, whereas fluid biomarkers
the presence of the ApoE ε4 allele; can only establish that an individual is in stage A or
• Patients with SCD; higher. Stage A corresponds to positive amyloid PET
• As a substitute for genotyping in carriers of au- and negative tau PET (A+T2); tau PET with uptake only
tosomal dominant mutations; in the medial temporal region (A+T2MTL+) is equivalent
• Asymptomatic individuals; and to stage B; tau PET with moderate neocortical uptake
• Non-medical use (e.g., legal purposes, insurance (A+T2MOD+) is stage C; and high tau PET high neocortical
coverage evaluation, employment, or occupation- uptake (A+T2HIGH+) represents stage D. So, for staging
al assessment). AD, tau PET is currently the only available biomarker4.

Studart-Neto A et al.   Alzheimer’s disease biomarkers in clinical practice in Brazil.   11

 Dement Neuropsychol 2024;18:e2024C001

P-tau tracers have been validated by post-mortem PSP110. Currently, [18F]-Flortaucipir is the only p-tau tracer
pathological studies, showing a strong association with approved for clinical use in the United Sates111.
NFTs47,89,107. However, studies comparing p-tau levels Second-generation tau tracers appear to overcome
in fluids with tau PET have shown that p-tau increases the limitations related to primary tauopathies and
in both CSF and plasma before tau PET becomes posi- are mainly represented by [18F]-MK6240 and [18F]-
tive42. Despite this, tau PET is highly associated with the PI2620. Their use allows for the identification of
neuroanatomical distribution of NFTs, thus reflecting 3R/4R tau deposits in AD with high affinity, stag-
the clinical manifestations, including the phenotypic ing/stratifying AD, and differentiating it from other
variants of AD (i.e., non-amnestic presentations)107. tauopathies both by the spatial distribution of tracer
The interpretation of typical images obtained with deposition and by lower affinity and intensity of
tau PET depends on the topographical knowledge and uptake in 4R tauopathies105,112,113. This method could
progressive distribution or staging of NFT appearance also evaluate the evolutionary stage as a staging
in the course of AD. Initially, the transentorhinal stage marker in these conditions.
is identified (Braak & Braak stages I–II), followed by the Once clinically tested and approved, these sec-
limbic stage (Braak & Braak stages III–IV), and finally ond-generation radiopharmaceuticals could be used
the isocortical stage (Braak & Braak stages V–VI)25,108. to select individuals based on their pathological status
The first generation of tau tracers, most notably the (strongly T+ individuals are generally A+), perform
radiopharmaceutical [18F]-FAV1451 (formerly [18F]-T807 differential diagnoses with other tauopathies, and si-
and commercially known as [18F]-Flortaucipir), has affinity multaneously stratify and classify diseases with 3R/4R
only for 3R/4R helical tau filaments, which are exclusive or 4R tau deposition. They could also help differentiate
to AD. These methods are excellent for selecting T+ or AD from both tauopathies and alpha-synucleinopathies,
T- individuals in AD and for staging the disease, as their the latter presenting negative scans (absence of tracer
deposition follows the Braak & Braak staging observed deposition). Thus, this method has enormous potential
in pathological studies109, which can help assess disease for routine clinical use in the future. These tracers rep-
progression. However, this marker has not been able to resent a significant advancement not only in selecting
identify deposits of 3R or 4R tau related to primary tauop- individuals for AD trials but also for anti-tau treatments
athies, which are mainly represented by FTLD, CBD, and in diseases such as PSP.

Source: Images from the personal archive of one of the authors (A.M.C.) and acquired at the Nuclear Medicine Center of Institute of Radiology,
Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil.
Note: *3D-SSP images obtained by Cortex ID Suite, GE Healthcare. Color scales to the right – upper bars in standardized uptake value ratio (SUVr) with the global cortex mean as the
normalization reference; lower bars in Z-score values relative to an age-matched normal control database.
Figure 2. Typical pattern of neurodegeneration in Alzheimer’s Disease as seen on FDG-PET at different stages of progression in two individuals with
predominantly amnestic presentation and confirmed cortical deposition of beta-amyloid plaques by [11C]-PiB PET. (A) Hypometabolism in the posterior temporal
neocortex, temporoparietal associative cortex, posterior cingulate, and precuneus, slightly more evident on the left side, highlighted by white arrows. (A1)
Images in axial and coronal planes, showing preserved frontal metabolism (yellow arrows). (A2) 3D-SSP* quantification images demonstrating in the top
row the projection of metabolism on the cortical surface in left lateral, medial, and superior projections; in the bottom row, the projection of the Z-score of
hypometabolic areas in relation to a normal control database by the same method is shown. (B) Patient in the moderate phase of the neurodegeneration
process, with prefrontal hypometabolism (red arrows) in addition to hypometabolism in posterior temporoparietal regions (white arrows). Notable is the
preservation of metabolism in polar and supraorbital frontal regions (yellow arrows), an important differentiation from other pathological processes (e.g.,
frontotemporal dementia). (B2) 3D-SSP* quantification images demonstrating in the top row the projection of metabolism on the cortical surface in right lateral
and superior projections; in the bottom row, the projection of the Z-score of hypometabolic areas in relation to a normal control database is shown.

12   Alzheimer’s disease biomarkers in clinical practice in Brazil.   Studart-Neto A et al.

 Dement Neuropsychol 2024;18:e2024C001

Tau PET methods are not currently available in and specificity from 80–95%40. Generally, older studies, in
Brazil, and there are no perspective for their clinical which exams were not reviewed by specialists or did not
use in the short term. Additionally, the costs of these use quantitative methods in clinical practice, presented
procedures are expected to be high. There are also no more modest results.
well-defined criteria for their visual analysis in clinical Motara et al. evaluated the clinical impact of using
practice. This is a hindrance to the use of the newly pro- FDG-PET according to its indications: diagnostic diffi-
posed revised criteria for staging AD in clinical practice culty after formal clinical procedures and inconclusive
in Brazil and in many other countries. structural analysis, pre-senile dementia, differentiation
between AD and FTD, atypical cases of AD and FTD,
[18F]- Fluorodeoxyglucose psychiatric comorbidities associated with cognitive
positron emission tomography decline, and inconclusive neuropsychological evalua-
FDG-PET remains the primary molecular neuroimag- tion116. In this evaluation, FDG-PET impacted clinical
ing method available in clinical practice. The pattern management in 81% of individuals (79/98), changing
of regional hypometabolism in the temporoparietal the pre-test diagnosis in 35% of cases, reducing the need
association areas, medial temporal, precuneus, and pos- for further investigations by 42%, and altering therapy
terior cingulate shows high sensitivity and specificity in in 32%. These results are similar to those of Laforce Jr
indirectly detecting AD-related pathology (Figure 2). et al., who showed a clinical management impact of 56%,
The accuracy is around 90% in AD or slightly higher in with a diagnosis change in 29% of cases117.
various recent cohorts, including in the prediction of A consensus article based on expert opinions from
in vivo amyloid in national series, both in individuals the European Associations of Nuclear Medicine (four in-
with a broad spectrum of amnestic syndrome92 and in dividuals) and Neurology (three individuals) determined
non-amnestic variants such as corticobasal syndrome114. in 2018 several clinical situations in the context of neu-
It is important to note that the test shows higher ac- rodegenerative diseases where FDG-PET had sufficient
curacy in the dementia phase or in cases of MCI due to evidence to recommend its clinical use, in addition to
AD in more advanced stages of neurodegeneration, and clinical/neuropsychological examination. Naturally, there
lower accuracy in the early stages of MCI due to AD. were differences in the degree of evidence and recommen-
On the other hand, while a normal FDG-PET scan dation of indication among the evaluators, but ultimately,
does not exclude the diagnosis of a degenerative disease, FDG-PET was recommended in several circunstances:
it suggests a favorable prognosis of potential cognitive • To aid in the diagnosis of atypical AD;
stability over an average follow-up period of three • To differentiate AD from DLB, FTD, and vascular
years115. Additionally, the combination of PET with CT dementia;
in PET/CT equipment provides the advantage of simul- • To differentiate DLB from FTD, and Parkinson’s
taneously evaluating cerebral metabolism, structural disease from PSP; and
changes, and vascular load. Although this is less refined • To suggest pathophysiology in corticobasal syn-
than MRI, it is often sufficient for clinical purposes. drome, primary progressive aphasia, and assess
Ossenkoppele et al. indicated that the neuroanatomical cortical dysfunction in Parkinson’s disease.
pattern of hypometabolism in FDG-PET showed a strong
negative correlation with areas of tracer hyper-uptake for In all indications, the routine use of semi-automat-
p-tau. In other words, the hypometabolism pattern (neuro- ed quantification to assist visual analysis was recom-
degeneration) reflects the distribution of tau pathology in mended, which has been internalized in the European
AD106. This overlap between p-tau accumulation (tau PET) guidelines for performing the exam118. The indications
and areas of hypometabolism (FDG-PET) has a significant of FDG-PET related to AD were those where in general,
implication: FDG-PET can be a good substitute for tau there was the greatest consensus among specialists119.
PET in locations where it is unavailable43,92. However, it is Cerebral perfusion assessment by SPECT can be a
important to note that, according to the amyloid cascade more cost-effective alternative to FDG-PET but has sev-
hypothesis, tau PET changes precede those observed in eral disadvantages, including lower spatial resolution and
FDG-PET, a marker of neurodegeneration. In post-mortem accuracy120, fewer commercially available semiquantita-
analyses in which FDG-PET was evaluated by physicians tive programs for the method, and the lack of integrated
who were not molecular imaging specialists, the exam CT in most available machines. However, SPECT can be
showed a sensitivity of 80% and a specificity of 84%40. useful for differential diagnosis between AD and FTD,
Previous studies, however, demonstrated wide variability provided that the exam is interpreted by an experienced
in these values, with sensitivity ranging from 88–98% nuclear medicine physician121. Additionally, the accuracy

Studart-Neto A et al.   Alzheimer’s disease biomarkers in clinical practice in Brazil.   13

 Dement Neuropsychol 2024;18:e2024C001

of SPECT is not affected by glycemic control or diabetes, make AD diagnosis more accessible and less expensive.
which can potentially influence FDG-PET results122,123. However, the quality of studies remains variable. Re-
cently, the Global CEO Initiative on Alzheimer’s Disease
Magnetic resonance imaging convened a BBM Workgroup to consider the minimum
as a marker of neurodegeneration acceptable performance of blood-based biomarkers
In addition to its role in excluding reversible and ir- (BBM) tests for clinical use127. A BBM test should have a
reversible structural causes of cognitive decline, MRI sensitivity ≥90% with a specificity ≥85% in primary care
can also be used as a biomarker of neurodegeneration. and ≥75–85% in secondary care in case of screening test
However, its accuracy in this evaluation is generally prior to subsequent confirmatory testing (PET or CSF).
inferior to FDG-PET when only visual analysis of struc- If it is used as a confirmatory test, a plasma biomarker
tural images is used. Structural changes occur later than should have performance equivalent to that of CSF tests
those detected by other biomarkers, except for cognitive (with sensitivity and specificity of at least ~90%)127.
markers, which may appear even later or coincide with The BBM Workgroup also suggests that plasma
the structural changes observed on MRI. biomarkers could have two cutoffs to define three cate-
However, MRI shows a significant increase in accu- gories of result: positive, intermediate, and negative127.
racy when its analysis is optimized using quantitative Patients with a result below the lower cutoff (negative)
analysis programs, such as those for measuring gray are highly likely not to have AD, and those with a result
matter volume or cortical thickness reduction. Initially above the upper cutoff (positive) are highly likely to be
available in research settings, these programs have diagnosed with AD. In cases where the result is between
recently been adapted for commercial use. More spe- the two cutoffs (intermediate), a confirmatory test
cifically, the most commonly used neurodegeneration (PET or CSF) or a repeat plasma biomarker should be
marker of atrophy of the medial temporal lobe is prefer- considered in one year. However, the BBM Workgroup
ably characterized by the medial temporal lobe atrophy does not yet endorse any specific test127.
(MTA) score124. The interpretation of the MTA score is In addition to the improvement of Aβ and p-tau
based on age and degree of atrophy, with a score above pathology biomarkers, there is a search for biomarkers
1 considered abnormal for patients up to 74 years and related to other aspects of pathology. For example,
a score above 2 considered abnormal for patients aged biomarkers of neuroinflammation associated with AD,
75 years or older. Other scales used for measuring such as markers of astrocytic and microglial activation.
the atrophy commonly found in AD patients are the Among these, the plasma measurement of glial fibril-
Koedam and entorhinal cortical atrophy scale (ERICA), lary acidic protein (GFAP), expressed in astrocytes,
respectively quantifying parietal and entorhinal regions. stands out42,128,129. Similar to fluid-based biomarkers of
neuroinflammation, molecular neuroimaging for neu-
roinflammation has shown promise with several studies
BIOMARKERS IN ETHNICALLY in the last decades130–135. Radiopharmaceuticals have
DIVERSE POPULATIONS been developed, some that demonstrate both microglial
Despite the recent increased availability of biomark- activation (e.g., [11C]-PK11195)131,133, and others that
ers, many of the studies validating cutoff points have show astrocytic activity (e.g., [11C]-Acetate)134,135. How-
been conducted in populations of white people living ever, PET for neuroinflammation is still restricted to
in high-income countries, like the United States and research, with no applicability in clinical practice to date.
European countries. Biomarkers seem to behave differ- Another area of intense study is the search for bio-
ently in black individuals42,125,126. Recent clinical trials markers of other proteinopathies and cerebrovascular
of anti-amyloid therapies that used AD biomarkers as diseases that frequently occur as co-pathologies in
inclusion criteria had a large disproportion of black par- patients with AD. Among these, alpha-synuclein is one
ticipants who did not meet the inclusion criteria based of the most relevant136.
on these biomarkers, suggesting that the cutoff points
in this population may differ99,101. In the lecanemab
clinical trial, only 2% of the participants were black99. PRACTICAL RECOMMENDATIONS FOR
REQUESTING BIOMARKERS IN CLINICAL PRACTICE
Biomarkers for AD are not yet perfect but play an import-
PERSPECTIVES ant role in aiding the clinical diagnosis in symptomatic
The field of biomarker research has grown significantly. patients, particularly those with atypical presentations,
Certainly, the development of plasma biomarkers will and have implications for indicating disease-modifying

14   Alzheimer’s disease biomarkers in clinical practice in Brazil.   Studart-Neto A et al.

 Dement Neuropsychol 2024;18:e2024C001

therapy. The request and interpretation of biomarkers AD138. In all situations mentioned above, the interpre-
are not trivial and should be performed by physicians tation of biomarkers should be done with caution, in the
well-trained in the field, usually from the medical context of the clinical picture, and by a clinician with
specialties of Geriatrics, Neurology, Psychiatry (Old- solid experience in the area.
Age Psychiatry). Biomarkers should only be requested Therefore, requesting biomarkers for AD is not a
for cognitively symptomatic patients with objectively trivial procedure and should not be performed in the
demonstrated deficits in cognitive testing, i.e., with a absence of clinical symptoms. It should also not be done
clinical dementia rating (CDR) score of 0.5 or above. by medical professionals who are not trained to correctly
They may be also requested in FTD patients, with sig- interpret the results and manage the consequences of
nificant behavioral changes for differential diagnosis. the diagnosis for the patient and family.
Biomarkers can be indicated when it is necessary to make The current objective of biomarkers for AD is to
a precise etiological diagnosis of cognitive impairment. assist in the diagnosis of symptomatic patients. A fu-
Thus, biomarkers for AD are not indicated in as- ture objective may be the monitoring of therapeutic
ymptomatic individuals, patients with SCD, or in cases response and disease progression. The diagnosis of AD
of advanced dementia (where etiological diagnosis will based on biomarkers has important implications for
not change clinical management). treatment with new disease-modifying therapies, being
Biomarkers should not be requested to predict the fundamental in the indication or contraindication of
risk of developing cognitive decline in asymptomatic these therapies. Table 3 summarizes the commercially
individuals for several reasons: accessible biomarkers for clinical use (some of which
• There is no disease-modifying treatment for the are not yet available in Brazil). We recommend that
preclinical phase; and laboratories provide the ratios between analytes in CSF
• Not all individuals with positive biomarkers will (Aβ42/Aβ40, p-tau181/Aβ42) as they have better accuracy
progress to MCI or dementia stages in AD. than the isolated value of the analyte (especially in the
case of Aβ42).
However, biomarkers can be recommended in the The validation of some biomarkers, especially plasma
following clinical contexts: analytes, is in the process of development, particularly
• Early-onset dementias (symptoms onset before in populations underrepresented in clinical research,
65 years of age); which is generally conducted in high-income countries
• Rapidly progressive dementias; with a predominance of white participants.
• Atypical dementia; We have elaborated a flowchart to assist physicians
• Available disease-modifying treatment (e.g. an- in requesting biomarkers, as shown in Figure 3. Plas-
ti-amyloid therapy); and ma biomarkers were not included in this algorithm
• Differential diagnosis with other neurodegener- because they still need to be validated and have a quality
ative dementias41,137. control certificate. These tests are promising, such as
p-tau217, and once they are adequately validated, the
Biomarkers can also be recommended when patients algorithm will certainly be updated to include these plas-
want to know if their cognitive decline is caused by ma biomarkers. For a plasma biomarker to be indicated,

Table 3. Currently available biomarkers for clinical use.

Category CSF biomarkers Plasma biomarkers Neuroimaging biomarkers

↓ Aβ42/Aβ40 Positive amyloid PET

Proteinopathy Aβ (A) ↓ Aβ42/Aβ40
↑ p-tau/Aβ42 [11C]-PiB, [18F]-Florbetaben, [18F]-Florbetapir*, [18F]-Flutemetamol*

Proteinopathy ↑ p-tau181 ↑ p-tau 217*

Positive tau PET ([18F]-Flortaucipir*)
phosphorylated tau (T) ↑ p-tau181/Aβ42 ↑ p-tau217/np-tau217

FDG-PET with temporoparietal, posterior cingulate and

↑ NfL ↑ NfL* precuneus hypometabolism
Neurodegeneration (N)
↑ t-tau ↑ t-tau Brain MRI with medial temporal lobe atrophy (particularly the entorhinal
cortex), precuneus and temporoparietal cortex.
Abbreviations: CSF, cerebrospinal fluid; Aβ, amyloid beta; p-tau: phosphorylated tau; PET, positron emission tomography; NfL, light chain neurofilaments; FDG, [18F]-Fluorodeoxyglucose;
MRI, magnetic resonance imaging.
Note: *Biomarkers not commercially available in Brazil.

Studart-Neto A et al.   Alzheimer’s disease biomarkers in clinical practice in Brazil.   15

 Dement Neuropsychol 2024;18:e2024C001

Abbreviations: AD, Alzheimer’s disease; MCI, mild cognitive impairment; PPA, primary progressive aphasias; MRI, magnetic resonance imaging; CT, computed tomography; PET, positron
emission tomography; FDG, fluorodeoxyglucose; FTD, frontotemporal dementia; CBD, corticobasal degeneration; LATE, Limbic-predominant age-related TDP-43 encephalopathy.
Notes: *CSF biomarker should be performed on automated platforms (e.g., electrochemiluminescence immunoassay or mass spectrometry); **Caution should be exercised when
interpreting amyloid PET in patients aged >80 years, as they may be positive in cognitively normal individuals in this age group; ***In the absence of FDG-PET, a SPECT with quantification
can be considered.
Figure 3. Suggestion for a rational use algorithm of biomarkers based on typical variant, and atypical cognitive syndromes of Alzheimer’s disease.
At present, plasma biomarkers require better validation and, therefore, have not been included in this flowchart.

it must demonstrate an accuracy of at least ~90% com- recommend that laboratories adopt automated plat-
pared to an amyloid PET or an already approved CSF forms, such as electrochemiluminescence immunoassay,
biomarker platform by regulatory agencies. instead of the ELISA technique.
Regarding CSF biomarkers, we suggest verifying Regarding PET scans, we propose that they be conduct-
if the laboratory is compliant with pre-analytical and ed in clinics with experienced nuclear medicine physicians
analytical procedures and if there is quality control qualified at evaluating brain PET scans, and whose analysis
as required by the Alzheimer’s Association. We also

16   Alzheimer’s disease biomarkers in clinical practice in Brazil.   Studart-Neto A et al.

 Dement Neuropsychol 2024;18:e2024C001

includes semiquantitative methods, not just visual. We Laboratory tests and structural neuroimaging (ideally
recommend avoiding amyloid PET and other amyloid cranial MRI, with CT as a second option) should always
research tests isolated in patients aged 80 or older due be requested for all patients to exclude non-degenerative
to the high positivity rate in asymptomatic individuals etiologies. Much has been discussed about diagnosing
in this age group, except when the goal is to rule out AD AD exclusively through biomarkers (biological diagnosis),
diagnosis (i.e., negative result). We also consider that mea- regardless of clinical manifestations44,49. However, we recom-
suring biomarkers in CSF is more available and less costly mend that the search for an AD diagnosis should begin with
than amyloid PET (though more invasive due to lumbar the presence of symptoms and that the characterization of
puncture), and therefore recommend CSF examination as the cognitive-behavioral syndrome should be the starting
the first option over amyloid PET. Finally, the request for point for selecting which biomarkers to request7. It should
biomarkers should be made after a structured clinical eval- also be noted that in many cases of patients diagnosed with
uation, including detailed history, physical examination, AD in vivo, post-mortem evaluation reveals multiple pathol-
and cognitive and functional assessments, in addition to ogies (e.g., alpha-synuclein, TDP-43, and cerebrovascular
neuropsychological evaluation if necessary137,139. disease)14,140,141. This means that the positivity of an AD

Box 1. Recommendations from the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology for the use and
interpretation of Alzheimer’s disease biomarkers in clinical practice in Brazil.
• Before requesting AD biomarkers, a structured clinical evaluation should be performed (detailed history, physical and neurological examination, and
cognitive/functional assessment).
• Requests should only be made by well-trained physicians with solid experience in the field, usually from the following medical specialties: Geriatrics,
Neurology, and Psychiatry (Old-Age Psychiatry).
• Requests should not be made by medical professionals who are not qualified to interpret the results and handle the consequences of the diagnosis
for the patient and their family.
• Biomarkers should only be requested for cognitively and/or behaviorally symptomatic patients (objectively demonstrated in cognitive testing and
clinical evaluation).
• Biomarkers for AD are not indicated in asymptomatic individuals and patients with subjective cognitive decline (cognitive complaints without test
abnormalities)
• Biomarkers for AD are not indicated in cases of advanced dementia (except when the goal is to rule out AD diagnosis, which may change
treatment; e.g., discontinuation of cholinesterase inhibitors or memantine).
• Biomarkers can be recommended in the following clinical contexts: early-onset dementias (symptoms onset before 65 years), rapidly progressive
dementias, atypical AD manifestations (e.g., non-amnestic presentations), and other atypical clinical manifestations (e.g., when there is a suspected
overlap of symptoms of two or more neurodegenerative dementias).
• Biomarkers can be recommended when there is suspicion of mild cognitive impairment or mild dementia due to AD and there is a possibility of
indicating anti-amyloid therapy (or other disease-modifying therapies that may be approved in the future).
• Laboratory tests and structural neuroimaging (ideally cranial MRI, with CT as a second option) should always be requested for all patients to exclude
non-degenerative etiologies.
• CSF biomarkers should be conducted in laboratories with the required pre-analytical and analytical procedures and quality control as required by the
Alzheimer’s Association.
• Laboratories should adopt automated platforms (e.g., electrochemiluminescence immunoassay or mass spectrometry) instead of the
ELISA technique.
• Laboratories should provide ratios between analytes in CSF (Aβ42/Aβ40, p-tau181/Aβ42) as they have better accuracy than the isolated value of the
analyte (especially in the case of Aβ42).
• Plasma biomarkers still need to be validated and have a quality control certificate (an accuracy of at least close to 90% is recommended compared
to an amyloid PET or a CSF biomarker platform already approved by regulatory agencies).
• We recommend caution in performing amyloid PET and other amyloid research tests in patients aged 80 or older due to the high positivity rate in
asymptomatic individuals in this age group.
• We recommend CSF examination as the first option over amyloid PET (see flowchart in Figure 3), as measuring biomarkers in CSF is more available
and less costly than amyloid PET.
• Regarding PET scans, we suggest to be performed in clinics with experienced nuclear medicine physicians who are experienced in evaluating brain
PET scans, and whose analysis includes semiquantitative methods, not just visual.
• In the absence of FDG-PET, a SPECT with quantification can be considered.
• We recommend that validated CSF and PET biomarkers for clinical use be submitted to ANVISA for regulatory approval in Brazil.
• We recommend that ANVISA-approved biomarkers be implemented in both the Brazilian Unified Health System (SUS) and the supplementary
health system.

Studart-Neto A et al.   Alzheimer’s disease biomarkers in clinical practice in Brazil.   17

 Dement Neuropsychol 2024;18:e2024C001

biomarker does not necessarily indicate that the patient’s data curation, formal analysis, writing – original draft,
symptoms are solely due to AD. Therefore, the interpretation writing – review & editing. AMC: writing and review of
of biomarkers should be made in the context of the clinical neuroimaging biomarkers section. GBF, HRG: writing
syndrome to avoid the risk of false diagnoses. and review of biofluids biomarkers section. ASN, BJA-
Finally, we recommend that validated CSF and PET PB, AMC, LCS, LPS, MNMS, RMC, PHFB, WVB, HRG,
biomarkers for clinical use be submitted to the Brazilian GRPF, MTB, MLFB, NAFF, OVF, JS, SMDB, PC, RN, EE,
Health Regulatory Agency (ANVISA, Agência Nacional EPFR: approval of final version and responsibility for
de Vigilância Sanitária) for regulatory approval in Brazil. all aspects of the work.
This would enable their implementation in both the
Brazilian Unified Health System (SUS, Sistema Único Supplementary Material
de Saúde) and the supplementary health system. Box 1 Diretrizes para o uso e interpretação dos biomarcadores
provides a summary of the main recommendations. de Doença de Alzheimer no Brasil: Recomen­dações do
Departamento Científico de Neurologia Cognitiva e
do Envelhecimento da Academia Brasileira de Neuro-
AUTHORS’ CONTRIBUTIONS logia, available at: https://www.demneuropsy.com.br/
ASN, BJAPB, LCS, LPS, MNMS, RMC, WVB, MTB, wp-content/uploads/2024/10/DN_2024C01_PT_15-
MLFB, NAFF, OVF, JS, PC, EPFR: conceptualization, 10-aprovado.pdf.

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