Brain Research 1758 (2021) 147342

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Brain Research
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Review

History in perspective: How Alzheimer’s Disease came to be where it is?

Tehniat F. Ahmed a, *, Affan Ahmed b, Fauzia Imtiaz c
a
Department of Biochemistry, Institute of Biomedical Sciences, Dow University of Health Sciences, Karachi, Pakistan
b
Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan
c
Department of Biochemistry, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan

A R T I C L E I N F O A B S T R A C T

Keywords: Treatment of Alzheimer’s Disease (AD) remains an unsolved issue despite the pronounced global attention it has
Neurodegenerative dementia received from researchers over the last four decades. Determining the primary cause of the disease is challenging
Alzheimer’s Disease due to its long prodromal phase and multifactorial etiology. Regardless, academic disagreements amongst the
History
scientific community have helped in making significant advancements in underpinning the molecular basis of
Diagnosis
disease pathogenesis. Substantial development in fluid and imaging biomarkers for AD led to a sharp turn in
Pathogenesis
Biomarkers defining the disease as a molecular construct, dispensing its clinical definition. With conceptual progress, re­
visions in the diagnostic criteria of AD were made, culminating into the research framework proposed by Na­
tional Institute on Aging and Alzheimer’s Association in 2018 which unified different stages of the disease
continuum, giving a common language of AT(N)1 classification to researchers. With realization that dementia is
the final stage of AD spectrum, its early diagnosis by means of cerebrospinal fluid biomarkers, Positron Emission
Tomography and Magnetic Resonance Imaging of the brain holds crucial importance in discovering ways of
halting the disease progression.
This article maps the insights into the pathogenesis as well as the diagnostic criteria and tests for AD as these
have evolved over time. A contextualized timeline of how the understanding of AD has matured with advancing
knowledge allows future research to be directed and unexplored avenues to be prioritized.

1. Introduction Positron Emission Tomography (PET), Cerebrospinal Fluid (CSF) and

blood. Due to its proximity to the brain, CSF can directly reflect the
Since its identification in 1906, continued efforts have been made in biochemical changes occurring there, however, the invasiveness of
understanding the neuropathology of Alzheimer’s Disease (AD) and in lumbar puncture limits its use in routine clinical practice. Imaging
developing diagnostic tools for effective therapeutic measures which biomarkers are the most widely employed diagnostic tool in clinics, but
halt the disease process (Dubois et al., 2016). The pathologic process of they too pose the threat of radiation exposure and are an economic
AD is characterized by the extracellular deposition of Amyloid-β pep­ burden for the patients (Hampel et al., 2018; Ramusino et al., 2020).
tides in the form of plaques, intracellular aggregates of truncated and Keeping in mind the challenges faced in diagnosing AD in primary care
hyperphosphorylated tau proteins which form neurofibrillary tangles, setting, an international interdisciplinary workgroup was convened in
accompanied by neuronal loss in specific brain regions (Chen et al., 2016 by the Alzheimer’s Precision Medicine Initiative to prioritize the
2017; Zhang et al., 2018). With this understanding, biomarkers are research for identifying potential blood-based biomarkers (Hampel
sought which reflect the core pathology of plaque and tangle formation et al., 2018).
and measure the degree of synaptic and axonal degeneration. No disease modifying treatment exists more than a century after the
Although the symptoms of different neurodegenerative dementias identification of AD (Yiannopoulou and Papageorgiou, 2020). By the
overlap greatly, each is usually characterized by the deposition of its time symptoms appear, the disease has advanced to a stage where
own distinctive proteins’ isoform in specific brain regions. Most widely treatment is rendered ineffective. The long prodromal phase however
used modalities in which biomarkers are being investigated include holds the opportunity of intercepting the pathologic process through

* Corresponding author at: Department of Biochemistry, Institute of Biomedical Sciences, Ojha Campus, Dow University of Health Sciences, Suparco Road, Gulzar-
e-Hijri Scheme-33, Karachi, Pakistan.
E-mail address: [email protected] (T.F. Ahmed).
1
AT(N): Amyloid-β biomarkers, Pathologic tau biomarkers, Neurodegenerative/Neuronal injury biomarkers.

https://doi.org/10.1016/j.brainres.2021.147342
Received 24 October 2020; Received in revised form 18 January 2021; Accepted 28 January 2021
Available online 4 February 2021
0006-8993/© 2021 Elsevier B.V. All rights reserved.
T.F. Ahmed et al. Brain Research 1758 (2021) 147342

disease modifying drugs before functional impairment occurs. Efforts soon discovered that senile plaques could also be present in the brains of
have long been made towards correct diagnosis of AD, the main hurdle cognitively unimpaired individuals (Todorov et al., 1975).
being the heterogeneity of the neuropathologic process which increases Cholinergic hypothesis put forward in 1976 by Peter Davies and A. J.
the chance of misdiagnosing the disease (Au et al., 2015; Ferreira et al., F. Maloney was the first biochemical theory proposing an explanation
2018). These misdiagnosed cases give discouraging results in trials with for cognitive decline in patients. Lumbar Puncture had been introduced
disease modifying agents (see Fig. 1). Efforts are being made to improve in 1891 and it was known that neurotransmitter Acetylcholine (Ach)
the diagnosis of AD by collecting data from various studies to establish plays a key role in higher order neurologic function. Levels of Acetyl­
cut-off values for biomarkers and standardize measurement techniques cholinesterase (AChE) were found low in CSF of AD patients. At this time
to give stable results over time. research aimed at finding biomarkers for AD was directed towards
Advancement in knowledge came with improved diagnostic tech­ measuring the CSF levels of neurotransmitters, their metabolites and
niques and a paradigm shift was observed in focus of diagnostic methods enzymes involved in their metabolism. These attempts did not prove
from confirming the disease in symptomatic individuals to identifying it fruitful because various factors like concurrent illness, age and medi­
in its preclinical stage using biomarkers (Dubois et al., 2016). The aim of cation influence the levels of these chemicals (Davies and Maloney,
this review is to map the significant evolution in the field of AD in terms 1976).
of its definition and diagnosis. Knowing what avenues have already been Relentless efforts were being made in improving existing diagnostic
explored and how far we have come in unfolding this enigma can help us tools for AD. Utility of Magnetic Resonance Imaging (MRI) in this regard
set our future directions. was still not clear, but in 1980 Ferris et al had shown the importance of
PET and since then it had established itself as a useful means of
2. Timeline measuring glucose metabolism and regional cerebral blood flow (Ferris
et al., 1980). The first diagnostic criteria for AD published by National
As with many ideas, it was the Greeks that the concept of dementia Institute of Neurological and Communicative Diseases and Stroke-Alz­
can be traced back to. The word itself is derived from the Latin word heimer’s Disease and Related Disorders Association (NINCD-ADRDA) in
demens, meaning without mind. It was not until very recently in the 18th 1984 defined AD as a clinicopathological entity, where diagnosis of
century, that dementia earned recognition as a separate mental disorder, Probable and Possible AD was based on the clinical presentation of the
although it was considered as an inevitable consequence of aging and patient and exclusion of other possible causes of dementia. Confirmation
still is by 62% of healthcare providers worldwide (Alzheimer’s Disease could only be done histopathologically. As no reliable fluid or imaging
International, 2019). Dr Alois Alzheimer produced a breakthrough in biomarkers were available at that time, diagnosis by exclusion was the
the field of dementia by carrying out post-mortem examination of the only way possible (McKhann et al., 1984). In a review published in 1991,
brain of his patient Auguste Deter, who had been suffering from memory it was proposed without much success, that CSF could be a valuable
impairment and personality changes. After presenting his autopsy source of finding markers indicative of AD because of its proximity to the
findings of plaques and tangles, now considered hallmarks of AD, in the brain where senile plaques and neurofibrillary tangles had already been
meeting of Southwest German Psychiatrists, he published his paper in observed. So far no valuable CSF markers which could rule in AD had
1907, titled “On an Unusual Illness of the Cerebral Cortex’’, opening been detected, instead, CSF was used to rule out causes other than AD
new avenues in the field of dementia. Honoring his great contribution, (van Gool and Bolhuis, 1991).
the disease was named after Dr Alzheimer in 1910 by his colleague Emil Ever since the discovery of AD, proteinaceous deposits in the brain
Kraeplin (Cipriani et al., 2011). Research in dementia slowed down which could be stained by Congo red were known. After development of
again until 1963, when Robert Terry and Michael Kidd performed a method for purifying these plaques in 1984, full amino acid sequence
electron microscopic examination of neuropathological lesions showing of proteins within the deposits was published in 1985 (Glenner and
that NFTs were present in brain biopsies from 2 patients with advanced Wong, 1984). The Amyloid Hypothesis put forward in 1991 by John
AD (Kidd, 1963; Terry, 1963). These developments and the ensuing Hardy and David Allsop proposes that Aβ accumulation in the brain
progress in the understanding of Alzheimer’s disease have been sum­ drives tangle formation and neuronal loss associated with AD (Hardy
marized in Fig. 2. and Allsop, 1991). Subsequently after protein sequencing, the three
In the subsequent studies despite a positive relationship observed deterministic genes showing autosomal dominant pattern were traced to
between the number of senile plaques and severity of dementia, it was be involved in Early Onset Familial AD. Amyloid Precursor Protein

Fig. 1. Common Problems in Diagnosis of Alzheimer’s Disease. The box gives an overview of the main obstacles in the way of early diagnosis of AD. Incorrect or late
diagnosis of the disease makes it even more difficult to manage.

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T.F. Ahmed et al. Brain Research 1758 (2021) 147342

Fig. 2. History of Alzheimer’s Disease. This figure summarizes the developments in the understanding of pathogenesis (shown in green), progress in imaging
technology (shown in pink) and paradigm shift in its diagnostics (shown in red), over time. Other significant advancements are shown in blue.

(APP) gene was mapped on chromosome 21 in 1987 (Goldgaber et al., in increased Amyloid Beta (Aβ) levels (Tanzi and Bertram, 2005). ApoE4
1987; Kang et al., 1987). Not long after, Presenilin 1 and 2 were outlined gene discovered in 1993 was the first genetic risk factor identified for
on chromosomes 14 and 1 respectively (Levy-Lahad et al., 1995; Rogaev late onset AD (Travis, 1993). ApoE binds to Aβ and facilitates its clear­
et al., 1995). Mutations in these genes alter the cleavage of APP resulting ance. The allelic variant ε4 encodes the isoform which is less efficient in

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T.F. Ahmed et al. Brain Research 1758 (2021) 147342

carrying out this clearance leading to its accumulation (Van Cau­ made on the basis of histopathologic evidence, or if clinical symptoms
wenberghe et al., 2016). occurred in conjunction with genetic evidence of the deterministic genes
The other major pathologic structure involved in etiology of AD is which, being autosomal dominant have 100% penetrance (Dubois et al.,
intraneuronal neurofibrillary tangles. Paired Helical Filaments (PHFs) 2007). IWG revised its criteria in 2010, drawing a line between clinical
form the major component of these tangles, with straight filaments symptoms and disease pathology and introducing the concept of ‘mixed’
much lesser in quantity (Goedert et al., 2015). Purification of PHF and ‘atypical’ AD. This criteria was again revised in 2014 (Dubois et al.,
proteins in mid 80s led to its sequencing, and in 1988, the isolation of 2014). Meanwhile, a diagnostic criteria was published by National
cDNA proved that it coded for MAPT (Goedert et al., 1988; Wischik Institute on Aging and Alzheimer’s Association (NIA-AA) in 2011 which
et al., 1988) integrated biomarkers, but primary diagnosis was still to be made clin­
By the onset of the new century, significant advancements since the ically. This revised criteria put forward the concept of asymptomatic AD
1984 criteria in the field of AD diagnostics had occurred. MRI could now and Mild Cognitive Impairment (MCI) and recognized that the hetero­
detect structural changes in the brain in detail, use of Fluorodeox­ geneity of AD, especially in the elderly, posed a challenge in its correct
yglucose Positron Emission Tomography (FDG-PET) in diagnosis had diagnosis (Frisoni et al., 2011). With the target of confirming the disease
been approved by Food and Drug Administration (FDA), amyloid and in the living as early as possible, NIA-AA updated its 2011 criteria by
tau proteins had been sequenced and advancement in quantifiable developing a research framework, rather than providing guidelines for
methods like immunoassay techniques had given rise to the possibility of routine clinical care use. This framework divides biomarkers into AT(N)
finding biomarkers directly related to AD pathogenesis, knowledge categories, with each category comprising of fluid and imaging bio­
about neurodegenerative dementias other than AD had improved and markers and recognizes clinical symptoms as a consequence of disease as
many therapeutic trials to intervene the amyloidogenic and tau path­ compared to a means of diagnosing it (see Table 1).
ways were in process. Despite this, researchers did not know if the Rather than three distinct stages mentioned by NIA-AA in the 2011
presence of plaques in cognitively unimpaired individuals represented criteria, the updated framework blurs their boundaries and proposes the
Preclinical AD (Bennett et al., 2006; De Meyer et al., 2010; Fagan et al., term disease continuum instead, Furthermore, cohort studies and trials
2007; Gomperts et al., 2008; Morris, 1999). are suggested to improve diagnostic and therapeutic approaches to AD.
Recognizing the scientific advancements in recent years, Interna­ The framework admits the limited potential of CSF analysis and PET
tional Working Group (IWG) revised the NINCDS-ADRDA criteria in imaging because of their invasiveness and high cost. It proposes
2007, creating the possibility of diagnosis in the living by proposing the exploring biomarkers in blood, which now seems possible because of the
use of biomarkers for the first time. Definite diagnosis could still be development of ultrasensitive immunoassay techniques and mass

Table 1
Comparison of diagnostic and research frameworks published in 1984, 2011 and 2018.
Feature 1984 2011 2018

Definition AD is a clinicopathologic entity, which can AD is a clinical-biomarker construct where AD is a biologic construct, identified by biomarkers in the
only be confirmed histopathologically through biomarkers are used to support the clinical living
biopsy or at autopsy diagnosis
Classification Probable, Possible, Definite AD Probable, Possible, Definite AD Probable and possible AD replaced with the term
‘Alzheimer’s Clinical Syndrome’
Stages of the Disease Intermediate stages of AD not recognized Formalization of three stages of the disease AD regarded as a continuum. Severity of cognitive
(Preclinical, MCI and Dementia) symptoms staged through syndromal categorical scheme
and numerical clinical staging scheme
Diagnosis of Dementia Compatible with DSM III criteria Compatible with DSM IV criteria Compatible with DSM V criteria
Diagnosis of AD Clinical assessment; Neuropsychological Clinical assessment; Neuropsychological Alzheimer’s continuum diagnosed with Amyloid beta
testing; Biopsy/autopsy testing; Biopsy/autopsy; Biomarkers biomarkers and AD confirmed with tau biomarkers
complementary
Clinical-pathologic Always consistent Not always consistent Not always consistent
correspondence

Biomarkers
Incorporated No Yes; diagnosis cannot be established Yes; diagnosis cannot be established through biomarkers
through biomarkers
Categories ———— Divided into 2 major categories: Divided into 3 major categories
1. Biomarkers of A-β accumulation: 1. Biomarkers of Aβ accumulation(A): Cortical amyloid
amyloid PET imaging and CSF Aβ42 PET ligand binding, CSF Aβ42
2. Biomarkers of neurodegeneration: FDG 2. Biomarkers of neurofibrillary tangles(T): Cortical tau
PET, CSF T-tau and P-tau, MRI PET ligand binding, CSF P-tau
3. Biomarkers of neurodegeneration(N): FDG PET, MRI,
CSF T-tau
Biomarkers of (N) Not identified Considered specific for AD Not considered specific for AD
category
Flexibility of ————— Does not exist Exists
incorporating new
biomarkers
Role of CSF Examined to exclude chronic infections CSF biomarkers used to support the clinical CSF biomarkers established as reliable indicators of
diagnosis pathologic changes in vivo, diagnosing disease in the
living
Role of blood Examined to exclude chronic infections No mention Candidate biomarkers indicated in blood

Comparison of diagnostic and research frameworks published in 1984, 2011 and 2018. The table compares the diagnostic criteria for Alzheimer’s Disease published by
NINCDS-ADRDA (National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer’s Disease and Related Disorders Association) in 1984 and NIA-
AA (National Institute of Ageing-Alzheimer’s Association) in 2011, and NIA-AA’s research framework proposed in 2018. It shows the progression in understanding of
AD from a clinical to a biologic construct, making its diagnosis possible in the living through biomarkers. Recent developments are blurring the boundaries between
different stages of AD and making it a continuum which can be diagnosed in preclinical stages using biomarkers of A (Amyloidosis), T (Tauopathy) and N (Neuro­
degeneration) categories.

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T.F. Ahmed et al. Brain Research 1758 (2021) 147342

spectrometry methods, enabling researchers to measure minute quan­ (Hardy and Higgins, 1992). Of the many isomeric forms of Aβ consisting
tities. Neurofilament Light chain (NFL) and tau levels in plasma are the of 36–43 amino acids, Aβ42 is found most abundant in neuritic plaques
promising biomarkers, while Aβ levels in blood have already gained (Lee et al., 2019). Towards the end of the 20th century, value of low CSF
some trust in research (Jack et al., 2018). However, the problems with levels of Aβ42 in the diagnosis of AD was realized (Tapiola et al., 2000).
blood biomarkers cannot be ignored as well (see Table 2). The potential Aβ40 and 42 levels are being quantitatively measured in the CSF using
of exosomes for being used as a source of biomarkers is being explored in both antibody-based and antibody independent techniques such as
the field of neurodegenerative diseases, and is yielding encouraging ELISA and Mass Spectrometry. Ratiometric analysis of these two isomers
results (Soares Martins et al., 2020). Controversy still exists in amyloid is recommended for better diagnostic accuracy because it compensates
being the main cause of AD, owing to the failure of clinical trials tar­ for normal fluctuation of levels within individuals (Hansson et al.,
geting it, and Aβ-plaque burden in the brain not closely correlating with 2019).
clinical symptoms. Diffusion tensor imaging developed by Oxford Brain Pittsburgh Compound-B (PiB) was reported as a novel amyloid im­
Diagnostics can sidestep this issue by non-invasively measuring brain aging PET tracer in 2004. The degree of PiB retention had a negative
tissue integrity which should prove more sensitive than structural bio­ correlation with cerebral glucose metabolism as measured by FDG PET
markers used previously (Makin, 2020). and CSF Aβ42 levels (Klunk et al., 2004). PiB had the potential of a
useful prognostic marker for MCI patients because longitudinal studies
3. Biomarkers are suggestive of PiB positive subjects converting to AD much more
frequently than those who are PiB negative in MCI stage (Cohen and
AT(N) classification suggested by NIA-AA in the 2018 research Klunk, 2014); However, the 20 min half-life of Carbon-11 used in this
framework divides biomarkers into three categories of Amyloidosis, compound limited its use and called for the need of finding tracers with a
Tauopathy and Neurodegeneration. Each category contains a CSF and an longer half-life for better utilization in clinical and research settings
imaging biomarker. (Klunk and Mathis, 2008). The half-life of Fluorine-18 is almost 110
mins. FDA approved the use of [18F] AV-45 or Florbetapir in 2012 (Zeng
and Goodman, 2013), followed by Flutemetamol in 2013 and Florbe­
3.1. Amyloidosis taben in 2014 (FDA, 2013, 2014; Martínez et al., 2017a, 2017b).
Amyloidosis holds a central importance in the diagnosis of AD. Ac­
Accumulation of insoluble amyloid plaques in the brain is thought to cording to the NIA-AA 2018 research framework, an individual with
be a major cause of neurodegenerative diseases (Yakupova et al., 2019). abnormal amyloid biomarker profile falls into the Alzheimer’s Contin­
After the purification and sequencing of Aβ protein in 1985, it was uum (Jack et al., 2018). While enough evidence in favor of CSF and PET
suggested that the disturbed levels of neurotransmitters and enzymes based measurement of Aβ is available, the results of measurement of
responsible for their metabolism was a consequence of pathologic mu­ these proteins in plasma show significant overlap between patients and
tation in Amyloid Precursor Proteins (APP) gene, rather than being the controls.
initial cause of it (Hardy and Allsop, 1991). The Amyloid Cascade Hy­
pothesis has dominated contemporary literature on etiology of AD since 3.2. Tauopathy
1991. However, its validity as being the sole cause is challenged by
many, owing to the failure of anti-amyloid drug trials in patients with Pathological Tau plays a key role in numerous neurodegenerative
AD (Daly et al., 2020). This theory proposes that cleavage of APP by Beta diseases, collectively known as tauopathies, amongst which the most
site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1), followed by common is AD (Muralidar et al., 2020). The essential function per­
γ-secretase generates the insoluble Aβ protein fragments which aggre­ formed by Tau of stabilizing microtubules provides light into why it is a
gate to form oligomers, further collecting to produce plaques and common player in such diseases. Hyperphosphorylation of tau disrupts
contribute to cerebral amyloid angiopathy associated with AD (Green­ this function, thereby resulting in dissociation of microtubule subunits
berg et al., 2020; Moussa-Pacha et al., 2020). Accumulation of Aβ pro­ and loss of axonal transport and synaptic plasticity (Combs et al., 2019;
tein is thought to be neurotoxic and disrupts calcium metabolism within Drechsel et al., 1992; Kent et al., 2020; Muralidar et al., 2020). More­
the neurons, triggering phosphorylation of tau and formation of PHFs over, the hyperphosphorylated Tau aggregates to form intracellular
neurotoxic PHFs leading to Neurofibrillary Tangles (NFTs), as was first
Table 2 described by Dr. Alzheimer, which spread through functionally con­
Advantages and Problems of Blood-Based Biomarkers. nected networks within the brain in a prion-like manner (De La-Rocque
Advantages of Blood-Based Problems with Blood-Based Biomarkers et al., 2020; Dujardin and Hyman, 2019; Mudher et al., 2017).
Biomarkers With Tau playing a primary role in many neurodegenerative dis­
1. Less expensive Molecules must cross the BBB to reach eases, and since NFT deposition correlates more with cognitive
the blood, and hence only a minute
quantity reaches it.
dysfunction and neuronal death in AD, a new model to explain the
2. Less invasive Dilution is more pronounced in plasma pathogenesis of AD, the tau propagation hypothesis was formulated
than in CSF. (Frost et al., 2009). It is backed by the failure of drug trials targeting
3. Less expertise required Proteases in the blood may degrade the Amyloid beta to provide positive results and evidence suggesting that
proteins that enter it from CSF
amyloid plaques are present in the brains of cognitively unimpaired
4. Readily available, already These proteins might be metabolized in
established in routine labs the liver and get excreted out individuals (Bennett et al., 2006; De Meyer et al., 2010; Fagan et al.,
5. Can be performed in a variety of 2007; Gomperts et al., 2008; Liu et al., 2019). While these are competing
settings hypotheses, research has shown significant crosstalk between the two,
6. Standardized SOPs exist for the though there may be other factors at play (Busche and Hyman, 2020;
collection and storage of samples
7. Can be repeated more easily for
Götz et al., 2019). The role of inflammatory cytokines released by as­
follow up and monitoring disease trocytes and glial cells in response to plaque formation seems protective
progression early in the pathologic process but may promote tau hyper­
Advantages and Problems of Blood-based Biomarkers. There is a pressing need phosphorylation later (Frost et al., 2019; Wang et al., 2015).
for the availability of reliable biomarkers in routine clinics for early diagnosis of It was not until 1985, the same year that Aβ was sequenced, that a
AD. Blood biomarkers hold many advantages over their CSF counterparts, monoclonal antibody, Alz 50, targeting the protein in tangles, initially
however, the constraints in their use have so far kept them limited to research named A68, was identified (Barnes, 1985). 5 years later, abnormally
settings. hyperphosphorylated tau was recognized as this target (Ueda et al.,

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T.F. Ahmed et al. Brain Research 1758 (2021) 147342

1990). This discovery led to renewed interest in the protein and not long bequeaths this disease challenging to diagnose. The 2018 research
after, in 1993, the 1st ELISA method for quantifying tau in CSF was framework given by NIA-AA has contributed significantly to standardize
developed (Vandermeeren et al., 1993). the definition of Alzheimer’s Disease by giving it a biomarker construct.
Progress since has shown that CSF levels of P-Tau and T-tau reflect It has been a long journey; from no recognition of biochemical markers
different processes. These markers were grouped together in the 2011 to their central position in diagnosis in the living, from the role of im­
NIA-AA criteria, but in the 2018 NIA-AA research framework CSF T-tau aging techniques to exclude other causes of dementia to their advanced
was moved to a new non-specific Neurodegeneration category. These forms throwing light not only on structure, but also brain function in AD,
changes also included a positive CSF P-Tau measure as diagnostic of AD yet there is a long way to go. The expected benefit of biomarkers has not
for patients in the Alzheimer’s Continuum (Amyloid Positive) (Jack been achieved so far as only CSF Aβ42, t-tau and p-tau have been vali­
et al., 2018). In 2020, FDA approved the first Tau PET ligand, Flortau­ dated and their use in primary care setting is very limited owing to their
cipir, thereby paving the way for using tau PET for diagnosing AD (FDA, invasiveness and high cost. With the realization of clinical symptoms
2020). being the end stage of the disease, the progression in the diagnostic
criteria highlights the importance of early diagnosis and predictive value
3.3. Neurodegeneration of biomarkers in providing opportunity to modify the disease course
either through life-style changes or prophylactic treatment (Schaffer
This category is not used to establish diagnosis of AD but, along with et al., 2015). Baltimore Longitudinal study of Aging and The Alzheimer’s
clinical symptoms, is used for assessing disease severity. Methods used Biomarkers in Daily Practice project succeeded in producing predictive
to measure neurodegeneration have been used for long since even the models for progression to AD dementia through the use of plasma
1984 research criteria includes both imaging biomarkers from this neuronal enriched extracellular vesicles to test a range of biomarkers
category: MRI and FDG-PET (McKhann et al., 1984). The third and a combination of demographic, CSF (Aβ42 and t-tau) and MRI
biomarker, CSF T-tau, was only recently introduced to this class, and (hippocampal volume and normalized whole brain volume) imaging
others such as CSF-NFL remain experimental (Jack et al., 2018). biomarkers respectively (Kapogiannis et al., 2019; van Maurik et al.,
MRI technology has come a long way since its inception. Through 2017).
structural MRI (sMRI) researchers and clinicians can track volumetric Studies investigating Quantitative Susceptibility Mapping (QSM)
changes in gray matter and variations in cortical thickness which may have shown correlation between cortical iron accumulation and cogni­
start up to 10 years before the onset of clinical symptoms. Furthermore, tive decline, but variable results have been reported with respect to
it gives clinicians the power to visualize and rule out non- association of susceptibility with amyloid (Cogswell et al., 2021). Other
neurodegenerative causes of dementia such as subdural hematomas modern imaging techniques such as PET, single photon emission to­
and tumors (Frisoni et al., 2010). Neurodegeneration in AD is most mography, functional magnetic resonance imaging, magnetic resonance
proximate to cognitive symptoms and follows a pattern, with initial sensitive weighted imaging, magnetic resonance perfusion weighted
atrophy seen in sites such as the entorhinal cortex and hippocampus. imaging and magnetic resonance diffusion tensor imaging hold promise
This pattern shows high sensitivity for AD; however, it is also seen in in diagnosing and understanding the pathogenesis of AD (Zeng et al.,
other neurodegenerative disorders (Kehoe et al., 2014). Functional MRI 2021).
(fMRI) is commonly used to measure regional changes in microcircula­ The current knowledge about the pathogenesis of AD centers around
tion thereby mapping and visualizing brain activation. Several neural amyloid plaque formation leading to neurofibrillary tangles and
networks have been identified using fMRI amongst which the Default neuronal death, however research has just scratched the surface in un­
Mode Network (DMN) has been extensively studied and is shown to be derstanding the complex interplay between the many proteins and
one of the earliest affected in AD (Kehoe et al., 2014; Merlo Pich et al., several questions remain unanswered. Regardless of this knowledge, the
2014). Diffusion Weighted Imaging (DWI) is a relatively new type of mainstay of treatment for AD targets Cholinergic hypothesis and is
MRI that can assess the integrity of white matter fiber tracts by tracking directed towards relieving symptoms, rather than halting the disease
movement of water through the cells. Changes in brain connectivity process. Failure of clinical trials of drugs targeting amyloid and tau
associated with AD can then be detected using diffusion measures proteins can be attributed partly to the inclusion of falsely diagnosed
(Kehoe et al., 2014; Merlo Pich et al., 2014). patients in the diseased group (Olsson et al., 2016). Therefore, results
AD patients show hypometabolism seen on FDG-PET in regions from research should be viewed with the definition of AD kept in mind
related to DMN such as the parietotemporal association area, posterior and those studies that do not use the biomarker construct to define the
cingulate cortices, and precuneus areas (Bao et al., 2017). Since the first pathology must be seen in a separate light. It is thus recommended that
reported studies in 1980, of using FDG-PET in senile dementia patients, future trials be conducted on study populations stratified on the basis of
the use of this technology to measure decreased cerebral glucose uptake biomarkers using a combination of imaging, blood and CSF analyses in
and metabolism reflecting cumulative loss of neuropil, loss of synapse addition to cognitive assessment (Guest et al., 2020).
and functional impairment of the neurons, has become routine (Farkas Apart from the lack of accessibility of biomarkers, another challenge
et al., 1982; Ferris et al., 1980; Ou et al., 2019). Furthermore, mapping posed by the new definition to the clinicians in diagnosing this disease is
decreased metabolic activity in the brain can separate other neurode­ the variation in cut points of biomarker concentrations across labora­
generative causes of dementia such as Lewy Body Dementia which in­ tories, bringing considerable inconsistency in the results of different
volves occipital hypometabolism (Yakushev et al., 2010). studies. Lack of standardized protocols for conducting the tests is a
Initially a biomarker in tauopathy category, CSF Total-tau (T-tau) major contributor to this problem. BBB-PIA (Biofluid Based Biomarkers-
was moved in 2018 to the neurodegeneration category because it was Professional Interest Areas), an assembly of ISTAART has already taken
shown that, unlike P-tau, it was not specific for tau pathology but rather an initiative towards assay harmonization by developing preanalytical
a marker for neuronal damage. It was also found to be elevated in and analytical protocols (Hampel et al., 2018).
traumatic brain injuries, strokes and diseases such as Cruetzfelt-Jakob
Disease. Furthermore, CSF T-tau levels were found to be independent 4.1. Ongoing clinical trials
of PHF concentration although they are correlated to P-Tau quantities
(Blennow and Zetterberg, 2018; Jack et al., 2018). Diagnosing the disease early is one of the main focus areas and
substantial amount of effort is being made to discover novel fluid bio­
4. Future directions and prospects markers in CSF, blood and urine and standardize these biomarkers for
this purpose (Apostolova et al., 2018; Charite University and Fiebach,
More than a century’s rigorous research in the field of AD still 2019; Institute, 2017; University Hospital, 2017). Moreover, numerous

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T.F. Ahmed et al. Brain Research 1758 (2021) 147342

neuroimaging markers are under trial to assess their potential in iden­ Charite University, B., Germany, Fiebach, P.D.m.J., 2019. The Relevance of the Blood-
brain Barrier to Cognitive Dysfunction and Alzheimer’s Disease. <https://Clinic
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diagnostic criteria. Alzheimers Dement. 12 (3), 292–323. https://doi.org/10.1016/j.
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