Cognitively healthy centenarians are genetically protected against Alzheimer's disease

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Cognitively healthy centenarians are genetically protected against Alzheimer's disease

Niccolo’ Tesi, Sven van der Lee, Marc Hulsman, Natasja M. van Schoor, Martijn Huisman, Yolande Pijnenburg, Wiesje M. van der Flier, Marcel Reinders, Henne Holstege

First published: 18 April 2024

https://doi.org/10.1002/alz.13810

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Abstract

BACKGROUND

Alzheimer's disease (AD) prevalence increases with age, yet a small fraction of the population reaches ages > 100 years without cognitive decline. We studied the genetic factors associated with such resilience against AD.

METHODS

Genome-wide association studies identified 86 single nucleotide polymorphisms (SNPs) associated with AD risk. We estimated SNP frequency in 2281 AD cases, 3165 age-matched controls, and 346 cognitively healthy centenarians. We calculated a polygenic risk score (PRS) for each individual and investigated the functional properties of SNPs enriched/depleted in centenarians.

RESULTS

Cognitively healthy centenarians were enriched with the protective alleles of the SNPs associated with AD risk. The protective effect concentrated on the alleles in/near ANKH, GRN, TMEM106B, SORT1, PLCG2, RIN3, and APOE genes. This translated to >5-fold lower PRS in centenarians compared to AD cases (P = 7.69 × 10⁻⁷¹), and 2-fold lower compared to age-matched controls (P = 5.83 × 10⁻¹⁷).

DISCUSSION

Maintaining cognitive health until extreme ages requires complex genetic protection against AD, which concentrates on the genes associated with the endolysosomal and immune systems.

Highlights

• Cognitively healthy cent enarians are enriched with the protective alleles of genetic variants associated with Alzheimer's disease (AD).
• The protective effect is concentrated on variants involved in the immune and endolysosomal systems.
• Combining variants into a polygenic risk score (PRS) translated to > 5-fold lower PRS in centenarians compared to AD cases, and ≈ 2-fold lower compared to middle-aged healthy controls.

1 BACKGROUND

The average human life expectancy continues to grow and by 2050 there will be 3.2 million centenarians in the world.¹ At old ages, a major contributor to poor health is cognitive decline and dementia, of which Alzheimer's disease (AD) is the most common type.^{2, 3} However, AD is not an inevitable consequence of aging, as testified by a small proportion of the population that reaches at least 100 years while maintaining a high level of cognitive and physical functions.^{4, 5} This raises the question of whether these cognitively healthy centenarians have exceptional features that protect or delay the onset of dementia, and whether such mechanisms may be genetically encoded.

AD is a progressive disorder characterized by loss of cognitive functions, ultimately leading to loss of independence and death, for which an effective treatment is lacking.^{3, 6} The greatest risk factor for AD is age: the disease is rare at 60 years, and the incidence of AD reaches ≈ 40% per year at 100 years of age.⁷ Next to aging, heritability plays an important role that changes dramatically with age. While the heritability of AD with age at onset < 65 years is estimated to be 90% to 100%, mostly due to autosomal dominant or strong risk-increasing genetic variants,⁸ it decreases to 60% to 80% for ages at AD onset of ≈ 75 years (determined by twin studies), based on a unique mix of rare and common risk factors, and further declines with later ages at AD onset.⁹ Approximately 30% of the genetic risk of AD is attributable to the ε4 allele of the apolipoprotein E (APOE) gene. Large collaborative genome-wide association studies (GWAS) have collectively identified 86 single nucleotide polymorphisms (SNPs) that are associated with a slight modification of the risk of AD.^{10, 11}

Intriguingly, the reverse is also true, as ≈ 60% of the chance to survive to 100 years in good cognitive health depends on inheriting favorable genetic factors,¹² comprising a relative depletion of risk-increasing variants and an enrichment of advantageous genetic variants that associate with a prolonged (brain) health.^13-15 In fact, in 2018 we reported that the effect size of 29 SNPs that were associated with AD risk was increased on average 2-fold when using cognitively healthy centenarians as controls rather than controls age-matched with the AD cases.¹⁶ Consequently, cognitively healthy centenarians had a significantly lower polygenic risk score (PRS), compared to AD cases and age-matched controls.

In the current study, we aimed to further expand on these findings by investigating the prevalence in cognitively healthy centenarians of the 86 SNPs that are currently associated with AD risk, based on the most recent GWAS for AD.¹⁰ We studied the effect of individual AD-associated SNPs as well as their combined effect (PRS) on prolonged cognitive health. Furthermore, we identified risk-increasing and protective SNPs that were, respectively, most depleted or enriched in a cohort of cognitively healthy centenarians, which allowed us to highlight the biological mechanisms most strongly involved with resilience against AD.

 

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