Nature Medicine: Cognition is normal, but Aβ and Tau PET are both positive, and the risk of cognitive decline soars 18 times in the next 3-5 years!

*For medical professionals only

"Oh my God! I forgot to take the bun I bought in the convenience store just now, I won't be MCI, right!!"

"On the way from work, I still thought about doing nucleic acid, but I forgot about it, I won't be MCI!!"

In the Singularity Cake group, every day is filled with the wail
of mild cognitive impairment (MCI).

It's not all a joke either
.
We know that pathological changes
in the brain have begun to appear in the 10~20 years before the symptoms of Alzheimer's disease (AD).
But there are several 10 years in life, and I can't afford
to worry.
We still wondered if there was a way to predict the risk of
cognitive decline in the short term.

On November 10, a study from Lund University in Sweden appeared in the journal
Nature Medicine.
The study found that the group with both Aβ and tau positive (A⁺T⁺) but cognitively normal after PET verification had a 19-fold increase in the risk of progressing to MCI within 3~5 years compared with the negative group (A-T^-) [1]! In other words, during the cognitively normal phase, Aβ and tau PET positivity are important predictors
of cognitive decline in the short term.

We know that amyloid plaques and neurofibrillary tangles are two typical pathologies
of AD.
However, whether AD can be defined by the two biomarkers of Aβ and tau alone has been controversial
.
In 2018, the National Institute on Aging-Alzheimer's Association (NIA-AA) issued the famous A/T/N diagnostic framework [2].

Under this framework, as long as A⁺T⁺ is satisfied, it can be defined as AD
.

However, this framework is limited to research use, and in the clinic, doctors are still very concerned about cognitive symptoms
.
Under the AD diagnostic framework published by the International Working Group (IWG) in 2021, to diagnose AD, evidence of objective cognitive decline is required in addition to two positive markers [3].

If these two standards are put together, they can sometimes fight
.
For A⁺T⁺, but cognitively normal individuals, under the NIA-AA criteria, they are classified as "preclinical AD", but under the IWG criteria, they are "at risk of progressing to AD"
.

IWG is defined this way for a reason, because previous studies have found that A⁺T⁺ is not very accurate in predicting future cognitive decline in cognitively normal individuals, and for clinical diagnosis, markers alone are somewhat aggressive
.
However, it is worth noting that a large number of prognostic studies so far have detected soluble phosphorylated tau in CSF, which is an early marker of AD pathology
.
In the past two years, the application of tau-PET detection has given us the opportunity to capture insoluble tau protein deposits
.

So, can PET-verified A⁺T⁺ better predict future cognitive decline? Scientists at Lund University in Sweden are trying to solve this problem
.

This multicenter cohort study included 1325 cognitively normal participants
.
Among them, 843 (63.
6%) were named A-T-^, 328 (24.
8%) were named A⁺T^-; 55 (4.
2%) named A⁺T⁺ (medial temporal lobe); 65 (4.
9%) is named A⁺T⁺ (temporal lobe neocortex).

The mean follow-up period of the studies was 41.
8 ± 18.
9 months
.

Cox proportional hazard model analysis showed that the risk ratio (HR) for progression to MCI in the A+T+ (temporal lobe) group was 19.
2; A+T+ compared with the ^A-T-group The HR in the (medial temporal lobe) group was 14.
6; in the A⁺T^- group it was 2.
4
.
That is, the A⁺T⁺ population has a steep increased risk of progression to MCI compared with the negative control
.

In addition to this, the A+T+ (temporal lobe neocortex) group and the A+T+ (medial temporal lobe) group compared to the A+T- group Progress to MCI is faster, with HR of 7.
9 and 6.
0
, respectively.

Analysis of linear mixed-effects models showed that the other three groups had faster longitudinal global cognitive decline compared to the negative control, and that the A^+T+ group progressed faster
.

Notably, compared with the A+T- group, the A+T+ (temporal neocortex) group progressed more rapidly to MCI and all-cause dementia, with HR of 7.
9 and 26.
7, respectively (A⁺T⁺).
There was no significant difference between the (temporal neocortex) group and the A^+T+ (medial temporal lobe) group).

This suggests that A⁺ but cognitively normal people may already be on the spectrum of AD pathology, and the coexistence of tau pathology in the medial temporal lobe and/or temporal lobe neocortex increases the risk of cognitive decline in the short term
.

However, it should be noted that in the A⁺T⁺ group, some people still maintain normal cognition during 3~5 years of follow-up, which indicates that there are still many individual differences
in people who are positive for both markers.
The reason for this may be some kind of genetic protection, or the benefit of a healthier lifestyle, which is not yet known
.

In conclusion, this study showed that in cognitively normal people, PET detection A⁺T⁺ was significantly associated with
cognitive decline within 3~5 years.
This further demonstrates the key role
of the pathological coexistence of Aβ and tau in promoting AD cognitive impairment.
However, this study also has fly in the ointment, one is that the A^+T+ population only accounts for about 10%, and the sample size is not very large; Secondly, the price and accessibility of PET testing also limit further applications
.

Finally, I was thinking, if you really know that you have a high probability of getting MCI in 3~5 years, how will you plan your future life?

Well, I still wish there was medicine
.

References:

[1] Ossenkoppele, R.
, Pichet Binette, A.
, Groot, C.
, Smith, R.
, Strandberg, O.
, Palmqvist, S.
, .
.
.
Hansson, O.
(2022, November 10).
Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline.
Nature Medicine.

[2 Jack, C.
R.
Jr et al.
NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease.
Alzheimers Dement.
14, 535–562 (2018).

[3] Dubois, B.
et al.
Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group.
Lancet Neurol.
20, 484–496 (2021).

The author of this article Candy