New important review: research advances in Alzheimer's disease over the past two decades

Over the past two decades, the landscape of dementia research has changed
dramatically due to advances in knowledge at the molecular, cellular, animal and human levels.
Not limited to Alzheimer's disease, but also includes a progressive understanding
of other diseases that can lead to dementia.
In this anniversary review, the authors discuss the most important advances
in Alzheimer's disease research since The Lancet Neurology was first published 20 years ago.
Birth of Alzheimer-specific markers

At the turn of the 21st century, several cerebrospinal fluid biomarkers were considered specific markers of Alzheimer's disease: amyloid β42 (Aβ42) and phosphorylated tau, and were used
in some research institutions and clinics.
Since then, a range of PET ligands
specific for Alzheimer's disease (β-amyloid plaques and tau tangles) have also been developed.

In 2004, Pittsburgh compound B successfully demonstrated β-amyloid plaque-labeled PET ligand for the first time in humans
.
About a decade later, humanity's first successful tau PET ligand, T807 (now known as flortaucipir), was developed
.
Moderate to high levels of β-amyloid plaques and tau tangled pathologies
present in the human brain can now be detected.

Soon after the development of Alzheimer's disease biomarkers, they were included in longitudinal observational cohort studies
.
This allows researchers to study how different biomarkers relate to each other in number and morphology over time, as well as with the onset and progression of clinical symptoms
.
These findings dramatically changed the understanding of the natural history of Alzheimer's disease and were summarized
in a time model.

Amyloid PET becomes abnormal
before neocortical tau PET signaling.
β-amyloidosis appears to facilitate or facilitate the spread
of tau disease.
The temporal and morphological distribution of neurodegenerative disease (determined by MRI or FDG PET) and tau PET are closely related to each other, which in turn is closely
related to the onset and phenotypic expression of symptoms.
In contrast, the onset time and morphological distribution of amyloid PET abnormalities were not closely related
to symptoms.

Liquid biomarkers of Aβ (in cerebrospinal fluid and plasma) were abnormal
earlier before amyloid PET abnormalities.
The liquid phosphorylated tau biomarker was abnormalized
slightly later after the onset of abnormal amyloid PET.
The entire process can last 20 years or more
.
The figure shows an updated model
of the temporal evolution of biomarkers and cognitive impairment.
Figure 1: Hypothetical model of dynamic biomarkers and cognition in Alzheimer's disease

Different biomarkers do not become abnormal at the same time, but rather intersect over time into overlapping S-shapes

Plasma biomarkers are the most important advance
in Alzheimer's disease diagnosis over the past few years.
Plasma Aβ42/40 is associated
with cerebrospinal fluid Aβ42/40 and amyloid PET.
Plasma phosphorylated tau (181, 217, and 231) distinguishes clinically defined Alzheimer's disease patients from those with non-Alzheimer's neurodegenerative diseases and is associated with
amyloid PET and tau PET.

Other plasma biomarkers have also been developed, such as light chains of nerve filament, which may aid prognosis and surveillance, but are not specific
for Alzheimer's disease.
Plasma biomarkers address the fundamental problem
of limited and costly access in some cases.
Unlike PET and CSF biomarkers, plasma biomarkers are not invasive and are therefore expected to be transformative
.
Development of diagnostic criteria for Alzheimer's disease

In 2000, the diagnosis of Alzheimer's disease was based on a clinician's impression that there was a progressive neurodegenerative disease, but it did not always begin with memory impairment and eventually progressed to the point
where the individual was unable to independently manage activities of daily living.
Over time, the term Alzheimer's disease has been used to describe the neuropathology and progressive dementia of Alzheimer's disease in older adults, and the dual use of this term has led to great confusion
.
However, with the advent of Alzheimer's disease-specific PET and humoral biomarkers, diagnostic criteria including biomarker information have also evolved
.

Two main groups developed these standards and guidelines: the International Working Group (IWG) and the National Institute on Aging-Alzheimer's Association (NIA–AA).

Both groups have published several sets of guidelines
.
The main conceptual difference is that the NIA–AA group defines Alzheimer's disease biologically, i.
e.
, in humans, by β-amyloid plaque and tau tangled biomarker evidence
.
Intrinsic to this view is that Alzheimer's disease consists of a continuum that begins with biomarker evidence of β-amyloid and tau pathology in asymptomatic individuals, extends to downstream biomarker events (e.
g.
, neuronal damage and neurodegeneration), culminating in the emergence of clinical symptoms that can manifest as various phenotypic variants (Figure 1).

The IWG's position is that individuals will not develop Alzheimer's disease until symptoms and Alzheimer's disease
biomarkers become abnormal.

In addition to developing up-to-date criteria for assessing neuropathological changes in Alzheimer's disease, a major development in neuropathology is the recognition of the multietiological nature
of Alzheimer's disease.
In 2000, the common perception, including about Alzheimer's disease, was the single entity model, in which patients were generally considered to have a single disease process responsible for symptoms
.
Large-scale autopsy studies revealed a very different picture
.

At the population level, several different disorders are often the basis of age-related cognitive decline, and any combination of these disorders may be present in
an individual.
In addition to Alzheimer's disease, the most common diseases are vascular brain injury and α-synuclein and TDP43 protein pathies
.
In older people, a single disease process is the exception rather than the rule, and the older an individual is, the greater the likelihood of multiple diseases
.
A milestone in neurodegenerative disease neuropathology was the discovery of TDP43, one of the key protein disorders in the frontotemporal degenerative lineage but also common in the aging brain and may be an important component of
cognitive impairment in older adults.

Amyloid precursor protein and progerin mutations in rare autosomal dominant manifestations of Alzheimer's disease were identified before 2000, and APOE4 has been recognized as the main genetic risk
of sporadic Alzheimer's disease.
However, over the past two decades, GWAS studies have found a number of loci associated with an increased risk of clinically defined late-onset Alzheimer's disease, but these loci have a smaller range of influence and a lower prevalence in the population, or both compared to APOE4
.
These studies point to the importance
of immune response, endocytosis, lipid metabolism, and pathways other than amyloid β and TAU in the pathogenesis of Alzheimer's disease.
Many variants point to the role of microglia being particularly important
.

A new model for Alzheimer's research

Over the past two decades, a data-sharing model has emerged that centralizes the collection, management, anonymization, and availability of multimodal data
from research volunteers to the scientific community.
Data can include clinical, psychometric, imaging and fluid biomarkers, neuropathology, and genetics
.
An example of widespread use of such resources is the Alzheimer's Disease Neuroimaging Initiative
, which began in 2004.
Other similar data-sharing initiatives are currently under way, providing an important public resource
for large-scale observational research.

The emergence of disease-modifying clinical trials since the beginning of the 21st century is as important
as the development of Alzheimer's disease-specific biomarkers.
The intertwined evolution of Alzheimer's disease-specific biomarkers and disease modification assays is no accident, as the former greatly contributed to the development of
the latter.

The earliest disease-modifying trials involved active immunity to β-amyloid plaques, but were terminated
early due to some participants developing meningoencephalitis.
The next phase of immunotherapy involves passive immunity
against various forms of Aβ.
Phase 2 or Phase 3 results of several different monoclonal anti-Aβ antibody regimens have shown a significant reduction in PET amyloid plaque load, and in some cases clearance below detection limits
.

In the near future, results will be reported for some large key anti-Aβ trials (registration numbers: NCT02008357, NCT03444870, NCT003443973, NCT087455, NCT04437511, NCT05108922).

Active disease modification trials include symptomatic and preclinical cohorts involving biologics or small molecules
.
In addition to trials targeting amyloid β, trials targeting tau phosphorylation, aggregation and transmission, inflammation, neuroprotection, and other aspects of the Alzheimer's pathway are ongoing or planned
.

Summary

Determining the optimal role of different classes of biomarkers (plasma, cerebrospinal fluid and PET) in clinical trials and clinical practice will continue to be an important area of research
.
Biomarkers are used to identify the pathology of non-Alzheimer-type dementia, in particular α-synuclein and TDP43 protein pathies, and also to identify processes in the Alzheimer's pathway, in particular neuroinflammation
.
More treatment regimens
and targets are needed.

Many researchers believe that a multi-pronged approach is
needed.
Combination therapies that target different mechanisms in the Alzheimer's pathway, as well as combination therapies for diseases that often occur simultaneously, will be tailored to the individual and guided
by biomarkers.
A virtuous cycle can be envisaged in which the development of new biomarkers can lead to more effective and specific clinical trials, and the need to target different aspects of the Alzheimer's disease and non-Alzheimer's dementia processes in trials has led to the development of
new biomarkers.

A milestone in Alzheimer's disease research over the past two decades