AD: Bull! Scientists have found that some centenarians are tolerant to the aggregation of Alzheimer's disease "toxic proteins"!

*For medical professionals only

As we age, most people's cognitive function declines, and some people even develop dementias such as Alzheimer's disease (AD
).

However, there are also many elderly people who still have normal cognitive function
when they are over 100 years old.

In the face of the cognitively normal elderly population, some scientists are very curious: Are there no β amyloid (Aβ) and phosphorylated tau protein (p-tau) deposits in the brains of these centenarians? Or did Aβ and p-tau deposition have little effect on their perception?

Recently, the team of Henne Holstege from Vrije Universiteit Amsterdam and Jeroen J.
M.
Hoozemans from Vrije Universiteit Amsterdam and University Medical Center Amsterdam evaluated the pathological state and cognitive function of brain AD in 85 centenarians and 2131 AD patients of different ages (16-103 years), non-AD dementia patients and cognitively normal control people, and the relevant results were published in Alzheimer's & Dementia magazine [1].

The results showed that Aβ and p-tau deposition in the brain of cognitively normal people also increased gradually with age, i.
e.
, the accumulation of amyloid plaques and neurofibrillary tangles is a common manifestation
of aging.
In those centenarians, Aβ and p-tau deposition varied widely, and no clear correlation
was found between Aβ and p-tau deposition.

In addition, although some centenarians have obvious AD neuropathological manifestations in the brain, they can still maintain good cognitive function, suggesting that the role of Aβ and p-tau as AD biomarkers may not be applicable
in older adults.
For this group of elderly people with obvious Aβ and p-tau deposition but maintaining normal cognitive function, it is worth conducting more in-depth research to explore the internal mechanism
of resistance to the effects of Aβ and p-tau deposition.

Screenshot of the first page of the paper

The 85 centenarians (74% women, aged 100 to 111 years at the time of death) included in this study were from the 100-plus study cohort [2], and all had normal cognitive function (assessed by the Mini-Mental State Examination Scale [MMSE], higher scores indicate better cognitive function) at the time of inclusion in the 100-plus study baseline test, and all had cognitive function assessment results several months prior to death.
The median MMSE score is 25 points
.

Basic data on the 100-plus study cohort population

The researchers also collected neuropathological data from 2131 people from the Dutch Brain Bank (NBB) population, including 851 AD patients (aged 37-102 years), 626 non-AD dementia patients (aged 16-103 years), and 654 cognitively normal control populations (ND, aged 16-103 years).

For people from the 100-plus and NBB cohorts, researchers evaluated the neuropathic status
of Aβ, neurofibrillary tangles, and neuroinflammatory plaques (NPs) by National Institute on Aging (NIA) Amyloid stage [3], Braak stage [4], and Alzheimer's Disease Joint Registry Collaborative (CERAD) scores [5], respectively.
In addition, the researchers counted the brain weight
of the study population.

Basic data on the NBB study cohort population

The researchers first investigated the trend of the NIA amyloid stage (the higher the stage, the more severe) in AD patients and ND people with age, and found that the average NIA amyloid stage of AD patients was high throughout the age group, while the average NIA amyloid stage of ND people increased with age, and the difference between the average NIA amyloid stage of AD patients and ND people was age-related, from 2.
5 at 60 years old to 1.
5 at 95 years old
。

Among all centenarians, 9.
4% had NIA amyloid stage 0, 35.
3% stage 1, 32.
9% stage 2, and 22.
4% stage 3, and there was no significant association between NIA amyloid stage and MMSE score
.

9.
4% of centenarians had a NIA amyloid stage of 0, indicating that some elderly people had strong resistance to Aβ deposition
.
In 22.
4% of NIA amyloid stage 3 centenarians, 26% maintained a high level of cognitive performance (MMSE score ≥26), which the researchers speculated was more likely to be "diffuse plaques" [6]
in this part of the cognitively normal but obvious Aβ deposition.

The stage of NIA amyloid varies with age

For Braak NFT staging (the higher the stage, the more severe), ND population staging increases with age, while AD patients decrease with age, and the mean difference between Braak NFT staging for AD patients and ND people decreases from about 6 at age 55 to about 2
at age 95.
The Braak stage decreases with age in AD patients, suggesting that in older patients, patients may die
due to associated diseases or complications before the Braak stage is at its highest.

In the 100-plus cohort, there was no Braak Phase 0, 2.
4% Phase I, 14.
1% Phase II, 42.
4% Phase III, 35.
3% Phase IV, and 5.
9% Phase V, Braak NFT staging was similarly not significantly correlated
with MMSE scores.
However, the MMSE scores of centenarians with Braak staging between I-III were significantly higher than those of centenarians in Braak stage IV-V
.
Three of the five Braak stage V centenarians had a last MMSE score ≥ 25 points, indicating that some older adults had considerable tolerance for p-tau accumulation
.

Braak NFT stance trend with age

For the CERAD NP score (the higher the score, the more severe), from about age 75, the CERAD score of ND people increases with age, while the CERAD score of AD patients decreases with age, although these changes are limited
.
Therefore, the average CERAD score of elderly ND patients remains at a low level, while the average CERAD score of elderly AD patients is at a high level
.
The difference in mean CERAD scores between AD patients and ND populations has been consistently high (>2).

In the 100-plus cohort, 43.
5 percent of centenarians had a CERAD score of 0, 29.
4 percent rated 1, 22.
4 percent rated 2, and 4.
7 percent rated 3, with no significant correlation
between CERAD scores and MMSE scores.
Most centenarians have CERAD NP scores between 0 and 2, indicating that most centenarians are resistant to neuroinflammatory plaques after they have accumulated to some extent
.
It is worth mentioning that 2 out of 4 centenarians with a CERAD score of 3 had an MMSE score of ≥ 26 before death, indicating that some elderly people have a better tolerance for neuroinflammatory
plaques.

CERAD scores trend with age

For the last indicator, brain weight, AD patients' brain weight was relatively stable across the age group, with a median brain weight of 1003 grams for women and 1170 grams
for men.
In middle age, the average gender-corrected brain weight in ND people was 200 grams higher than in AD patients, but the gap narrowed with age, until the difference in average brain weight narrowed to 100 grams
by age ≥ 90.

In addition, in the ND population and centenarians, the extremely low brain weight (< 750 g) observed in young patients with dementia was not found
.
Centenarian brain weight was similarly not significantly correlated with the last MMSE score, suggesting that maintaining a high brain weight is not a prerequisite for
maintaining cognitive health.

Brain weight trends with age

Finally, the researchers combined AD patients, non-AD dementia patients, and ND populations in the NBB cohort into a single dataset to assess the change
in pairwise correlation between the three pathological scores across the age range.

The results showed that all pathology scores were highly correlated at the youngest age stage (correlation coefficient r close to 1), while their correlation decreased with age, especially the NIA amyloid stage versus Braak NFT stage, which dropped to 0.
6
at the age of > 90.
The correlation coefficients between the NIA amyloid stage and the CERAD NP score, and the Braak NFT stage and the CERAD NP score, remained at a high level, reaching about 0.
85
at the age of > 90.

In the 100-plus cohort, the correlation coefficient between the NIA amyloid stage and the CERAD NP score remained at about 0.
75, while the correlation coefficient between the NIA amyloid stage and the Braak NFT stage was only about 0.
45
.
Similarly, the correlation coefficient between Braak NFT staging and CERAD NP score is only about 0.
55
.
This suggests that in older people, the accumulation of these AD pathological products may be partially independent
.

Variation in pairwise correlation between the 3 pathological scores across the age range

Overall, the study shows that some centenarians are able to maintain high cognitive function despite having high levels of AD neuropathological manifestations, on the one hand, resistance to the accumulation of AD pathological products, on the other hand, tolerance to accumulated AD pathological products, and mining its internal mechanism will help develop new AD treatment methods
.

References

1.
Zhang M, Ganz AB, Rohde S, Rozemuller AJM, Bank NB, Reinders MJT, Scheltens P, Hulsman M, Hoozemans JJM, Holstege H: Resilience and resistance to the accumulation of amyloid plaques and neurofibrillary tangles in centenarians: An age-continuous perspective.
Alzheimers Dement 2022.

2.
Holstege H, Beker N, Dijkstra T, Pieterse K, Wemmenhove E, Schouten K, Thiessens L, Horsten D, Rechtuijt S, Sikkes S et al: The 100-plus Study of cognitively healthy centenarians: rationale, design and cohort description.
Eur J Epidemiol 2018, 33(12):1229-1249.

3.
Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E et al: National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease.
Alzheimers Dement 2012, 8(1):1-13.

4.
Braak H, Braak E: Neuropathological stageing of Alzheimer-related changes.
Acta Neuropathol 1991, 82(4):239-259.

5.
Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K: Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry.
Acta Neuropathol 2006, 112(4):389-404.

6.
Ganz AB, Beker N, Hulsman M, Sikkes S, Netherlands Brain B, Scheltens P, Smit AB, Rozemuller AJM, Hoozemans JJM, Holstege H: Neuropathology and cognitive performance in self-reported cognitively healthy centenarians.
Acta Neuropathol Commun 2018, 6(1):64.

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