Hot News: DIAN Participant Defies Presenilin 2 Mutation

Only a few individuals with autosomal-dominant Alzheimer's mutations have staved off their near-total odds of cognitive decline. They somehow do it despite having high amyloid plaque loads. Previous examples of this phenomenon were attributed to protective variants in apolipoprotein and reelin genes, but now comes Doug Whitney, who carries neither. In the February 10 Nature Medicine, scientists led by Jorge Llibre-Guerra and Randall Bateman at Washington University, St. Louis, reported that Whitney, 75, who has the presenilin 2 Volga mutation, remains cognitively healthy 18 years past his predicted age of symptom onset. PET imaging shows a high plaque load, but almost no tangles. 

  • A Volga mutation carrier remains cognitively healthy 18 years past expected age of onset.
  • He has extensive plaques, but tangles only in the occipital cortex.
  • Potential protective factors include several rare genetic variants
  • Could high levels of heat shock proteins play a part, too?

Whitney is a volunteer in the Dominantly Inherited Alzheimer Network (DIAN). Genetic analysis and extensive clinical profiling point toward some possible protective factors, including variants in his CD33 and tau genes, but Llibre-Guerra and colleagues have not pinpointed a reason for his resilience. Intriguingly, environmental exposures may play a role, too. Whitney worked as a ship mechanic in very hot rooms for years, and his cerebrospinal fluid boasts an abundance of heat shock proteins. 

“This man underscores the continuing need for therapeutic approaches to AD beyond amyloid, especially those addressing tau, TDP43, and even heat shock proteins,” Thomas Bird at the University of Washington, Seattle, wrote to Alzforum. Ekaterina Rogaeva at the University of Toronto called the data set comprehensive. “This study sets a high standard for in-depth analyses of family members at clinical, genetic, biomarker, and imaging levels,” she wrote (comments below).

Where's the Tau? On flortaucipir PET scans, the resilient PS1 mutation carrier (left) has much fewer tangles than do symptomatic carriers (right). [Courtesy of Llibre-Guerra et al., Nature Medicine.]

The first reported case of extraordinary resilience to autosomal-dominant AD was a Colombian woman who carried the E280A Paisa presenilin mutation (Nov 2019 news). A homozygous Christchurch mutation in APOE3 emerged as a protective factor, spurring research into the mechanisms and therapeutic potential (Oct 2023 news; Feb 2025 news). In a second instance, a protective mutation in the extracellular matrix protein reelin was deemed responsible for resilience in two siblings carrying the Paisa mutation (May 2023 news).

Whitney carries the N141I mutation in presenilin 2, also known as the Volga mutation, which normally leads to symptom onset around the age of 53. He is a member of the extended Reiswig family, who lost 10 of 13 siblings of one generation to the disease and have become  foundational contributors to autosomal-dominant Alzheimer's research (see 2010 book review of 'The Thousand Mile Stare'). Whitney, as well as several of his relatives, have advocated publicly for the plight of familial Alzheimer's for some years, and this most recent paper was widely reported (WashU release, NPR story).

Whitney was cognitively healthy when he enrolled in DIAN in 2011 at age 61, and remained so at his most recent evaluation in 2021. This puts him 18 years past the estimated age at onset (AAO) for this mutation. The estimate may be conservative because, in his immediate family, the average AAO is 49.

Detailed clinical and cognitive testing determined the extent of this resilience. In 2021, at age 71, Whitney scored a perfect 0 on the CDR; 30 on the MMSE. On most other cognitive and behavioral measures in DIAN's extensive test battery, such as delayed story recall and the Neuropsychiatric Inventory Questionnaire, he was within the norm for his age. His only deficit was on four tests of executive function: the Digit Symbol Substitution Test, Trails A and B, and animal fluency.

PiB PET revealed a high amyloid burden of 3.6 SUVR, which would be expected for a N141I mutation carrier of his age. However, a flortaucipir PET scan showed tangles only in the occipital lobe (image above). An FDG PET scan found hypometabolism in this area, but not elsewhere. There was only age-related shrinkage of the hippocampus, not the accelerated rate that marks AD.

Biomarkers: A Split. On many measures (top), values for a resilient mutation carrier (yellow diamond) were within non-carrier norms (blue). On a few measures (middle), his scores were intermediate between non-carriers and symptomatic carriers (red), while on others (bottom), he resembled symptomatic carriers. [Courtesy of Llibre-Guerra et al., Nature Medicine].

CSF biomarkers reflected this split pathology. The Aβ42/40 ratio was as expected for his plaque load, while p-Tau181, p-Tau217, and p-Tau205, which track both plaques and tangles, were intermediate between control and ADAD levels. CSF p-Tau202 and total tau were within the normal range for his age.

What explains this resilience? Whole-genome sequencing offered hints. The authors found rare loss-of-function variants in nine genes that have not been associated with AD before: ANKRD36C, CEP290, CHST15, FAM151B, GPCPD1, MROH9, MRPL15P1, MUC3A, and PRICKLE3. None of these variants suggest any obvious protective mechanisms. However, upregulation of GPCPD1, an enzyme that helps make choline, was recently reported to be protective in AD (Jul 2024 news).

As for known AD genes, Whitney carries the G304R CD33 variant and the Y441H MAPT variant, both of which have been reported to be protective, as well as a TREM2 variant of unknown effect (Poorkaj et al., 1998; Guerreiro et al., 2013). He is homozygous for APOE3.

Looking beyond genetics, the authors searched for environmental factors that might explain resilience. On most measures, including exercise, smoking, and exposure to toxins, Whitney was within population norms, but one unusual aspect of his history stood out. For many years, he worked as a ship mechanic in diesel engine rooms. Temperatures in these enclosed spaces were so high that he frequently had to be hosed down to prevent overheating. Proteomic analysis of his CSF found elevated levels of multiple heat shock proteins and other protein folding chaperones. Meanwhile, a metabolomic CSF analysis found elevations in glutathione metabolism, an antioxidant pathway, and in nicotinamide metabolism, which is involved in cellular energy production and DNA repair. The combined proteomic and metabolomic data point toward changes in pathways that have anti-aging, anti-oxidant, and protein synthesis effects, the authors noted.

The authors emphasize that more work is needed to narrow down which of these genetic variants or environmental exposures explain Whitney's ability to dodge the consequences of amyloid pathology. With these new clues, however, the Reiswig family has given Alzheimer's research another gift.—Madolyn Bowman Rogers

Comments

  1. Llibre-Guerra et al. have reported on a fascinating man who showed clinical resilience to a pathogenic variant in the PSEN2 gene. I am personally familiar with him because he is a member of a Volga German pedigree with early onset AD that we described 37 years ago, and identified by Robert Cook-Degan prior to that. In 1995, our group reported the PSEN2 mutation in this family (Levy-Lahad et al., 1995, although not cited by Llibre-Guerra et al.). In 2020, we also noted that this man did not have the Christchurch variant in APOE (Yu et al., 2020). Llibre-Guerra et al. now show that when tested at age 71 (and now age 75) he had only mild signs of MCI and not dementia, although he is more than 22 years beyond the average age of onset of dementia in his family (49 years).

    Although he obviously represents an “n of 1,” the authors found he carries several interesting variants in a number of relevant genes, including TREM2, MAPT, and CD33. He also has “a unique proteomic profile rich in heat shock proteins.” Furthermore, although his PiB PET shows considerable amyloid accumulation, tau PET reveals only a small accumulation in one occipital lobe. This fits with the observation that tau accumulation is an important contributor to dementia in AD, and it correlates with the findings of Latimer et al. that lack of cortical tau and TDP43 is associated with resilience (Latimer et al., 2019). This man underscores the continuing need for therapeutic approaches to AD beyond amyloid, especially those addressing tau, TDP43, and even heat shock proteins.

    References:

    Levy-Lahad E, Wijsman EM, Nemens E, Anderson L, Goddard KA, Weber JL, Bird TD, Schellenberg GD. A familial Alzheimer's disease locus on chromosome 1. Science. 1995 Aug 18;269(5226):970-3. PubMed.

    Yu CE, Chen S, Jayadev S, Bird T. Lack of APOE Christchurch variant in five age of onset outliers with PSEN1, PSEN2 Alzheimer's disease and MAPT frontotemporal dementia. J Neurol Sci. 2020 Nov 15;418:117143. Epub 2020 Sep 18 PubMed.

    Latimer CS, Burke BT, Liachko NF, Currey HN, Kilgore MD, Gibbons LE, Henriksen J, Darvas M, Domoto-Reilly K, Jayadev S, Grabowski TJ, Crane PK, Larson EB, Kraemer BC, Bird TD, Keene CD. Resistance and resilience to Alzheimer's disease pathology are associated with reduced cortical pTau and absence of limbic-predominant age-related TDP-43 encephalopathy in a community-based cohort. Acta Neuropathol Commun. 2019 Jun 7;7(1):91. PubMed.

    View all comments by Thomas Bird

  2. Recent studies are increasingly focused on the search for protective factors in Alzheimer’s disease, with the understanding that both risk and resilience to AD are influenced by an interplay of genetic, environmental, and lifestyle factors.

    The paper by Llibre-Guerra et al. is a nice example of comprehensive longitudinal study conducted by the Dominantly Inherited Alzheimer Network. It focused on the largest PSEN2 family affected by the Volga German p.Asn141Ile mutation, with one carrier remaining unaffected for 15 years beyond the expected AD onset. This individual exhibited high amyloid deposition but atypical tau pathology, without evidence of spreading.

    The authors noted that investigating a single case requires careful interpretation. Nonetheless, this study set a high standard for in-depth analyses of family members at clinical, genetic, biomarker, and imaging levels. For instance, genetic evaluation included several models and revealed nine genes with potential protective variants. Future studies may validate these loci in cases with similar brain pathology. Additionally, such studies could assess the contribution of copy number variations, as well as polygenic risk/hazard scores and the polygenic burden of expanded short tandem repeats (Guo et al., 2025; Feb 2025 news).

    In general, AD age at onset is highly variable, even among identical twins or triplets, suggesting the existence of modifiers beyond genetic factors (Zhang et al., 2019). The value of the study by Llibre-Guerra et al. lies in its careful collection of information on family members. Notably, the medications used by the resilient case included daily atorvastatin to lower cholesterol, as well as nonsteroidal anti-inflammatory drugs (aspirin and ibuprofen).

    References:

    Guo MH, Lee WP, Vardarajan B, Schellenberg GD, Phillips-Cremins JE. Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer's disease. Nat Commun. 2025 Jan 28;16(1):1126. PubMed.

    Zhang M, Dilliott AA, Khallaf R, Robinson JF, Hegele RA, Comishen M, Sato C, Tosto G, Reitz C, Mayeux R, George-Hyslop PS, Freedman M, Rogaeva E. Genetic and epigenetic study of an Alzheimer's disease family with monozygotic triplets. Brain. 2019 Nov 1;142(11):3375-3381. PubMed.

    View all comments by Ekaterina Rogaeva

  3. … and now there are three cases with extreme protection against the most aggressive form of Alzheimer’s disease—all with high amyloid levels in their brains. These include: The DIAN-reported case, the APOE3 Christchurch homozygote and the Reelin-COLBOS case. 

    These cases challenge conventional assumptions and offer critical insights into resistance and resilience mechanisms against Alzheimer’s. As we work to replicate these effects with novel therapeutics, it's crucial to ask: What are these cases telling us?

    Discussions on this topic often get bogged down by causality debates, which, at this point, may be moot, especially given that we now have approved amyloid-targeting drugs. But the need for new therapies remains. And they don’t have to focus on amyloid—they should target the genetic pathways conferring 20–30 years of protection.

    There appears to be a protective genetic pathway against Alzheimer’s, distinct from the known disease mechanisms. Understanding this pathway could unlock entirely new therapeutic strategies beyond conventional targets.

    View all comments by Joseph Arboleda-Velasquez
    • User Profile Image Yakeel T. Quiroz
      Massachusetts General Hospital, Harvard Medical School
    • Posted:

    This case report stands out for its comprehensive longitudinal data and detailed phenotypic assessment, as well as its thought-provoking findings. Here, the relationship between Aβ and tau pathology is disrupted, implying that widespread tau deposition may be a critical factor driving neurodegenerative processes and cognitive impairment—an observation that aligns well with our findings in other ADAD-protected cases, including individuals with the APOE3 Christchurch variant.

    This case invites further exploration into the underlying mechanisms of the individual's observed cognitive resilience, particularly regarding the contributions of tau pathology, neuroinflammation, and vascular factors. Moreover, as noted by the authors, further research is needed to narrow down the list of candidate genetic variants. Specifically, experimental investigations into the variants identified in TREM2, MAPT, and CD33 are needed to deepen our understanding of their contributions.

    View all comments by Yakeel T. Quiroz

  5. In this exciting case study, Llibre-Guerra et al. present a detailed analysis of a PSEN2 mutation carrier who demonstrates remarkable cognitive resiliency to Alzheimer's disease. Intriguingly, this individual had obtained a remarkable amount of heat exposure during his career as a mechanic on a naval ship, and had a profound increase in heat shock protein levels. Although the individual did not express any known resilience-associated mutations in either RELN or APOE, the researchers identified several candidate resilience-associated mutations, including one in the gene GPCPD1, a phospholipid-cleaving enzyme, which we previously found was associated with cognitive resilience in a single-nuclear RNA-Seq study (Mathys et al, 2024). Understanding the mechanisms by which changes to phospholipid metabolism impact cognitive resilience to Alzheimer's disease represents a very exciting direction of study.

    References:

    Mathys H, Boix CA, Akay LA, Xia Z, Davila-Velderrain J, Ng AP, Jiang X, Abdelhady G, Galani K, Mantero J, Band N, James BT, Babu S, Galiana-Melendez F, Louderback K, Prokopenko D, Tanzi RE, Bennett DA, Tsai LH, Kellis M. Single-cell multiregion dissection of Alzheimer's disease. Nature. 2024 Aug;632(8026):858-868. Epub 2024 Jul 24 PubMed.

    View all comments by Li-Huei Tsai View all comments by Leyla A Akay

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References

Mutations Citations

  1. PSEN1 E280A (Paisa)
  2. PSEN2 N141I (Volga)

News Citations

  1. Can an ApoE Mutation Halt Alzheimer’s Disease?
  2. New Therapeutic Strategy—Mimic the ApoE Christchurch Mutation?
  3. ApoE3 Christchurch Clings Tightly to Tau, Averting Tangles
  4. Reelin Variant Wards Off Dementia in Colombian Kindred Siblings
  5. ARF Notable Book: The Thousand Mile Stare, by Gary Reiswig
  6. Transcriptomics Paint Astrocytes as Source of Cognitive Resilience

Paper Citations

  1. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 1998 Jun;43(6):815-25. PubMed.
  2. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St George-Hyslop P, Singleton A, Hardy J, Alzheimer Genetic Analysis Group. TREM2 variants in Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):117-27. Epub 2012 Nov 14 PubMed.

External Citations

  1. WashU release
  2. NPR story

Further Reading

Primary Papers

  1. Llibre-Guerra JJ, Fernandez MV, Joseph-Mathurin N, Bian S, Carter K, Li Y, Aschenbrenner AJ, Pottier C, Sigurdson W, McDade E, Gordon BA, Renton AE, Benzinger TL, Ibañez L, Barthelemy N, Johnson M, Hassenstab J, Wang G, Goate AM, Western D, Wang C, Hobbs D, Daniels A, Karch C, Morris JC, Cruchaga C, Johnson EC, Bateman RJ, Dominantly Inherited Alzheimer Network. Longitudinal analysis of a dominantly inherited Alzheimer disease mutation carrier protected from dementia. Nat Med. 2025 Feb 10; Epub 2025 Feb 10 PubMed.

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