Alzheimer's disease may usher in a landmark treatment! In-depth interpretation of the important results of AAIC 2022, Subcutaneous injection therapy for Alzheimer's disease is expected to slow down the depth of cognitive decline singularity

In 1991, scientists such as John Hardy and Colin L.

This voyage was a long voyage

Despite a series of ups and downs, anti-amyloid drugs are still the strongest pulse

It takes enough dose, it takes enough time

"At this year's AAIC Annual Meeting, Gantenerumab released a series of findings, the most appealing to me was a study

Gantenerumab is a fully human IgG1 antibody that binds to the conformational epitope on amyloid (Aβ) polymers with an affinity of yana molars to remove various forms of Aβ polymers (including oligomers, fibrils, and plaques) by recruiting microglia and activating phagocytosis [5].

Gantenerumab initiated Phase 3 clinical trials of SCarlet RoAD (SR) and Marguerite RoAD (MR) in patients with prodromal AD and mild AD in 2010 and 2014, respectively [6-7].

Subsequently, SR and MR were converted into an open-label extended study (OLE) in which participants were gradually titrated to 1200 mg of Gantenerumab

High doses of Gantenerumab showed strong amyloid plaque removal.


At the OLE stage, PET subgroup analysis at 36 months showed that PET amyloid decreased below the positive threshold in 80 percent of patients (24 out of 30 participants
) [8].

This indicates that amyloid plaques in the brains of these patients have been cleared to normal levels
.

High doses of Gantenerumab have a powerful ability to remove amyloid plaques

In October 2021, Gantenerumab's tireless efforts earned a welcome result, and Gantenerumab was recognized as a breakthrough therapy by the FDA [9].

Of course, clearing amyloid plaques is not the goal, improving cognition is the key
.

Since both studies lacked a control group at the OLE stage, exploring cognitive improvement required a highly matched xref cohort
.

At this year's AAIC Annual Meeting, Roche presented the cognitive improvement of the OLE phase of the SR & MR study, referring to external cohorts [10].


The reference queue comes from the well-known ADNI queue
.

SR &MR OLE and ADNI reference cohorts were highly matched in terms of baseline features, and the dimensions characterizing baseline features included age, sex, BMI at baseline, years of schooling, APOE4 carrying, CDR-SB at baseline, MMSE, and ADAS-Cog13
scores.

SR&MR OLE and the ADNI reference queue are highly matched in terms of baseline characteristics

In terms of the primary cognitive endpoint CDR-SB, Gantenerumab deferred CDR-SB relative to baseline change by 0.
753, or 23.
9%, compared to the reference cohort; By 156 weeks, the values were 1.
844 and 38.
9%,
respectively.

CDR-SB changes in R&MR OLE and ADNI reference queues

"CDR-SB was the primary cognitive endpoint in early clinical studies
of AD.

We saw that in this study, over time, the value of CDR-SB in the Gantenerumab treatment group relative to the baseline change gradually opened up with the reference group, and by 156 weeks, the absolute value of the difference had reached 1.
844," Professor Wang Yanjiang told Singularity Network, "from the absolute value of the change, it should have a certain significance of
clinical cognitive improvement.
"
”

The Clinical Dementia Rating Scale (CDR), proposed by Hughes Equals in 1982, is a cognitive evaluation tool
used by physicians to interrogate insiders and patients.

There are two scoring methods for the CDR scale, namely the total score calculation (CDR-GS) and the six-item additive calculation method (CDR-SB
).

CDR-SB is relatively more widely used, divided into 0, 0.
5-4.
0, 4.
5-9.
0, 9.
5-15.
5, 16.
0-18.
0 points of five grades, corresponding to CDR-GS no dementia (0), suspicious dementia (0.
5), mild dementia (1), moderate dementia (2) and severe dementia (3).

In a 2019 study, the smallest clinically significant difference in cognitive scale score improvement was systematically estimated and stratified
by the severity of cognitive impairment.

The results showed that the improvement in score corresponding to the smallest clinically significant difference increased
with disease severity.

For mild cognitive impairment (MCI) and mild AD, the smallest difference in CDR-SB was 0.
98 and 1.
63, respectively, representing clinically significant cognitive changes [11].

In this study, the absolute difference in CDR-SB in the Gantenerumab treatment group at 156 weeks was 1.
844, higher than 1.
63 points, suggesting that this improvement may have a tangible clinical significance
compared to the reference cohort.

"The failure of early clinical trials of many anti-Aβ drugs has given us a lot of inspiration, such as: the dose we administered may not be large enough, our treatment time and observation time may not be long enough, and for some previous anti-Aβ drug analysis, the clearance of amyloid plaques is indeed accompanied by a slowdown in cognitive decline, and the difference in cognitive decline between the treatment group and the control group may further expand
over time.
"
Professor Wang Yanjiang commented
.

At this year's AAIC conference, Roche scientists demonstrated a predictive model based on extensive observational research, Q-ATN
.

Using this model, the scientists estimated that Gantenerumab treatment over a period of five years would further increase the improvement of CDR-SB [12].

However, whether based on comparisons of reference cohorts or prediction model calculations, gantenerumab treatment for cognitive improvements ultimately requires rigorous Phase III clinical trial validation
.

In 2017, Gantenerumab initiated a GRADUATE study for prodromal and mild AD, using high-dose subcutaneous injections [13
].

The results of this study, which will be published in the fourth quarter of this year, provide a solid validation
of cognitive improvements in high doses of Gantenerumab.

Monitor the effect of treatment, blood markers or open up new possibilities

On July 21, 2022, a report in the journal Science pointed out that several papers by renowned neuroscientist Sylvain Lesné were suspected of image falsification, including one that cited the top five papers
in the field of AD.

The focus of this paper is on the Aβ oligomer Aβ*56
.

In this regard, Professor Wang Yanjiang said: "The report of Science magazine, coupled with the follow-up of many Chinese media, has caused a certain degree of misunderstanding
.

Academic fraud is indeed intolerable, but it is unscientific to trigger a complete denial of the AD amyloid hypothesis
.

”

In fact, Aβ*56, which has not been confirmed so far, is only one
of many possible oligomers of Aβ.

Aβ monomers are produced by sequential hydrolysis of APP proteins, which aggregate into oligomers, fibrils, and eventually deposit into amyloid plaques
.

The Aβ oligomer is actually a polymorphic, heterogeneous population in a metastable state [14].


Therefore, the problem with an academic paper on Aβ*56 does not negate the many years of research by scientists on Aβ oligomers, nor can it be extended to questioning
the entire Aβ hypothesis.

Today, imaging Aβ42 or PET amyloid in cerebrospinal fluid (CSF) has become indispensable evidence for defining dementia in the AD lineage, which shows the foundation of
the amyloid hypothesis.

However, because CSF is an invasive examination, and PET is expensive and difficult to popularize, the search for more convenient liquid biomarkers has become an absolute hot topic
in recent years.

Unfortunately, studies of plasma Aβ levels have been disappointing, and many studies have shown contradictory results
.

Overall, plasma Aβ levels vary little (approximately 15 percent) in the normal population and in patients with AD [15].

"At this year's AAIC annual meeting, another study by Gantenerumab showed us the potential of plasma biomarkers in detecting drug efficacy, which is worth exploring more
in the future.
"
Professor Wang Yanjiang introduced
to Singularity Network.

In the SR & MR OLE study, the researchers measured biomarkers such as Aβ42, Aβ40, and pTau217 and pTau181 in blood using The Elecsys immunoassay from Roche Diagnostics® to calculate the average percentage change from baseline to year 3 for all participants [16].

The findings found that long-cycle Gantenerumab treatment of 1200 mg every 4 weeks increased Aβ42 and Aβ40 levels in the blood in both trials
.

Treatment simultaneously reduces the amount of pTau in the blood, which may suggest that Gantenerumab mediates amyloid plaque removal and simultaneously acts on downstream tau pathology
.

Effect of Gantenerumab treatment on blood markers

"This result expands our thinking
very well.

An increase in Aβ42 in the blood after treatment, possible mechanisms include, drugs induce amyloid to be removed or degraded in the brain, thereby increasing the content of Aβ42 in the blood; It is also possible that the drug prolongs the time
that Aβ42 is in the surrounding circulation.

Professor Wang Yanjiang further expected, "If AD's disease modification therapy really goes to the clinic, then we are in great need of a convenient biomarker to monitor the efficacy, Gantenerumab's study shows the prospect
of blood markers in the monitoring of efficacy.
"
”

More than 100 years ago, Alois Alzheimer first discovered amyloid plaques and neurofiber tangles in the brains of AD patients through dissection, and for the first time humans saw this monster
that devours our memories up close.

This year, more than 100 years later, we're still battling
this monster.

"We have come into contact with many patients in the clinic, and they are brought by their children to see a doctor
.

I asked these old men, who is standing next to them? They are at a loss because they don't know their children
.

The AD field is in great need of a breakthrough drug, so I am very much looking forward to Gantenerumab's GRADUATE study and hope to surprise
us.

Professor Wang Yanjiang said with great anticipation, "If this drug finally proves to improve cognition and can be injected subcutaneously at home, it will be a breakthrough
in AD treatment.
"
”

References:

[1] Beyreuther, K.
& Masters, C.
L.
, 1991.
Amyloid Precursor Protein (APP) and ΒZA4 Amyloid in the Etiology of Alzheimer's Disease: Precursor-Product Relationships in the Derangement of Neuronal Function.
Brain Pathology, 1(4), pp.
241–251.

[2] Selkoe DJ (1991) The molecular pathology of Alzheimer’s disease.
Neuron6:487–498.

[3] Hardy, J.
, & Allsop, D.
(1991, January).
Amyloid deposition as the central event in the aetiology of Alzheimer's disease.
Trends in Pharmacological Sciences.
Elsevier BV.

[4] Ostrowitzki, S.
, 2012.
Mechanism of Amyloid Removal in Patients With Alzheimer Disease Treated With Gantenerumab.
Archives of Neurology, 69(2), p.
198.

[5] Bard, F.
et al.
, 2000.
Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease.
Nature Medicine, 6(8), pp.
916–919.

[6] Ostrowitzki, S.
et al.
, 2017.
A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease.
Alzheimer's Research & Therapy, 9(1).

[7]https://clinicaltrials.
gov/ct2/show/NCT02051608

[8] Klein, G.
et al.
, 2020.
Thirty-Six-Month Amyloid Positron Emission Tomography Results Show Continued Reduction in Amyloid Burden with Subcutaneous Gantenerumab.
The Journal of Prevention of Alzheimer’s Disease, pp.
1–4.

[9] Using an external control to contextualise efficacy data from patients with prodromal and mild Alzheimer’s disease treated with gantenerumab in SCarlet RoAD and Marguerite RoAD open-label extension studies，AAIC2022

[11] Liu, K.
Y.
, Schneider, L.
S.
& Howard, R.
, 2021.
The need to show minimum clinically important differences in Alzheimer's disease trials.
The Lancet Psychiatry, 8(11), pp.
1013–1016.

[12] Lee SJ, et al.
Understanding amyloid beta oligomers: characterization, mechanisms of toxicity, and inhibitors.
Journal of Chemical Industry, 23 January 2017; 46 (2) : 310-323.

[15] Blennow, K.
& Zetterberg, H.
, 2018.
The Past and the Future of Alzheimer’s Disease Fluid Biomarkers1 G.
Perry et al.
, eds.
.
Journal of Alzheimer's Disease, 62(3), pp.
1125–1140.

[16] Gantenerumab treatment increases plasma beta-amyloid(1–42) and decreases plasma pTau，AAIC2022

The author of this article Candy