Rare variants protect from Alzheimer’s – Could you have them?

Alzheimer’s disease (AD) is a debilitating condition affecting the brain, memory, and behavioral skills. While it is most common in older adults, not everyone will develop AD and the condition is not a normal part of aging. Eventually, the degenerative disease causes patients to lose the ability to lead a normal life. Currently, AD affects more than 5 million individuals in the United States. 

Abnormal accumulation of protein pieces and beta amyloid plaque and tangles around brain cells is the leading cause of AD. These abnormal additions suffocate tissue and damage brain cells, leading to the progressive worsening of the condition.

Did you know that there are certain rare variants that can offer protection from AD? The majority of the population does not have them, which is normal. However, for the very few cases that do, those folks get some extra protection.

You can use the Nebula Genome Browser to search for these variants in your genome. Keep reading to learn what these newly discovered mutations are and how you can check your status.

What causes Alzheimer’s?

Causes of AD are not fully understood. In addition to lifestyle and environment, many experts believe that genetics play a role, especially the APOE gene. In some cases, pathogenic alleles increase the risk of developing the disease. Furthermore, you may have heard of a variant known to definitely cause the condition, which occurs in only 1% of cases

On the other hand, researchers at Stanford have recently discovered rare APOE variants that are protective against AD. Although rare, having these variants decreases one’s chance of developing AD by about three-fold.

Brain tangles
Brain tangles. Gerd Altmann via PublicDomainPictures.net

The Study

The authors in this 2022 study published in JAMA Neurology performed meta-analyzes on a large (544,384) cohort of participants from multiple publicly available genome wide association studies. These included people with AD, those with proxy-AD, and healthy controls. The participants were 57.4% female with a mean age of 64.9 years.  

Their initial analysis revealed two missense variants that they retained for future analysis: V236E (nomenclature that describes a change in amino acid sequence of the APOE protein from a Valine to Glutamate at position 236) and R251G (nomenclature that describes a change in amino acid sequence of the APOE protein from a Arginine to Glycine at position 251). Interestingly, V236E is always co-inherited with APOE ε3 and R251G is always co-inherited with APOEε4. The rsIDs, rs199768005 and rs267606661, describe genome locations that encode the corresponding amino acid in the protein.

While L28P was not associated with AD risk, the authors found significant risk decrease associated with V236E and R251G when adjusted for APOE ε2 and APOE ε4 dosages (these are common alleles associated with AD risk). Notably, both variants showed a 4-fold to 5-fold decreased AD risk. 

In a complementary analysis, when these two alleles were stratified by their associated common APOE allele genotype (ε3 for V236E and ε4 for R251G), V236E showed a 3-fold decrease and R251G showed a 5-fold decrease in risk. The group used multiple replication cohorts and confirmed both the unstratified and stratified results, confirming a 2-fold to 3-fold decreased AD risk.


The study notes several limitations including the V236E association not being genome-wide significant and assessing the variants only in European ancestry.

This study represents the largest available sample of the V236E and R251G variants to date. It validates the protective effect of V236E and reveals a new candidate for protection in R251G.

Overall, these results indicate that V236E and R251G are associated with a greater than 2-fold mitigation in the risk of developing Alzheimer’s disease. The frequency of having one of these alleles is less than 0.1%, making them rare in the general population. This means that it’s normal to not have either of these protective alleles.

Examine your Genome!

Did you know you can use the Nebula Genome Browser (available with Deep and Ultra Deep WGS) to check whether you have this protective variant?
  1. Go to the Genome Browser. In the top left corner of the genome browser, you can find a search bar.
  2. The rsIDs for V236E and R251G are rs199768005 and rs267606661, respectively. Using the dbSNP database, you can find the the genome coordinates in the format [chromosome number][chromosome location]. These are 19:44909057 and 19:44909101 (GRCh38 reference genome). 
  3. Copy-paste one of these two locations into the search bar and press enter. 
  4. The genome browser will now zoom in to these locations. 
  5. Activate the “Center Line” in the bar at the top to better see the location that you are looking at.
  6. You should see stacked, gray stripes. Those are your personal DNA sequencing reads that are aligned to a reference genome sequence (colored letters above). If your DNA sequence matches the reference, then the stripes are gray. If the sequence is somehow different from the reference, then you will see various letters and symbols in different colors.
  7. For the variant rs199768005, you have a protective allele if you see an A (instead of the reference T allele indicated by gray stripes). For the variant rs267606661, you have a protective allele if you see an G (instead of the reference C allele indicated by gray stripes). Remember that the protective alleles are very rare and >99.9% of people don’t have them!


Le Guen Y, Belloy ME, Grenier-Boley B, de Rojas I, Castillo-Morales A, Jansen I, Nicolas A, Bellenguez C, Dalmasso C, Küçükali F, Eger SJ, Rasmussen KL, Thomassen JQ, Deleuze JF, He Z, Napolioni V, Amouyel P, Jessen F, Kehoe PG, van Duijn C, Tsolaki M, Sánchez-Juan P, Sleegers K, Ingelsson M, Rossi G, Hiltunen M, Sims R, van der Flier WM, Ramirez A, Andreassen OA, Frikke-Schmidt R, Williams J, Ruiz A, Lambert JC, Greicius MD; Members of the EADB, GR@ACE, DEGESCO, DemGene, GERAD, and EADI Groups; Arosio B, Benussi L, Boland A, Borroni B, Caffarra P, Daian D, Daniele A, Debette S, Dufouil C, Düzel E, Galimberti D, Giedraitis V, Grimmer T, Graff C, Grünblatt E, Hanon O, Hausner L, Heilmann-Heimbach S, Holstege H, Hort J, Jürgen D, Kuulasmaa T, van der Lugt A, Masullo C, Mecocci P, Mehrabian S, de Mendonça A, Moebus S, Nacmias B, Nicolas G,

Olaso R, Papenberg G, Parnetti L, Pasquier F, Peters O, Pijnenburg YAL, Popp J, Rainero I, Ramakers I, Riedel-Heller S, Scarmeas N, Scheltens P, Scherbaum N, Schneider A, Seripa D, Soininen H, Solfrizzi V, Spalletta G, Squassina A, van Swieten J, Tegos TJ, Tremolizzo L, Verhey F, Vyhnalek M, Wiltfang J, Boada M, García-González P, Puerta R, Real LM, Álvarez V, Bullido MJ, Clarimon J, García-Alberca JM, Mir P, Moreno F, Pastor P, Piñol-Ripoll G, Molina-Porcel L, Pérez-Tur J, Rodríguez-Rodríguez E, Royo JL, Sánchez-Valle R, Dichgans M, Rujescu D.

Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease. JAMA Neurol. 2022 Jul 1;79(7):652-663. doi: 10.1001/jamaneurol.2022.1166. PMID: 35639372; PMCID: PMC9157381.

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