An intriguing case of “exceptional resilience” against dementia

This is the story of a man who has escaped his genetic fate, and of the tantalizing possibility that we might be able to share some of his remarkable cognitive resilience.

Most Alzheimer’s disease (AD) is driven by primary aging processes and is not genetically determined in the sense that a single gene dictates whether you will develop it, though genetics still plays a substantial role in shaping risk.

Take APOEε4, the most common genetic variant with a high impact on a person’s risk of AD. Recall that you get two copies of every gene in your genome: one from each biological parent. If you’re 55, having a single copy of APOEε4 triples your risk of developing AD by the age of 85 compared to someone who has two copies of the more common APOEε3 variant.¹ And if you have two copies, different studies report that you are 8.7 times² to as high as 11.2 times³ as likely to slide into AD as is a double-ε3, depending on the population and the time horizon the studies look at.

To look at the proportions another way, about 30% of the European and North American populations have at least one ε4 allele (most of them only one; ε4/ε4 is about 3%),^2,4 but roughly 60% of AD cases in these same countries are carriers.^5*

Thus, having copies of APOEε4 in your genome causes a large and intimidating increase in your relative risk of AD—yet “only” about 35-40% of APOEε4/ε4 double carriers will go on to develop either so-called “mild” cognitive impairment (MCI) or dementia by the age of 85.⁶ (Despite the name, there is nothing “mild” about MCI, which is a substantial level of cognitive impairment but short of dementia).

The converse side of this coin is, of course, that up to two-thirds of APOEε4/ε4 people will never develop AD—or at least be free of it until sometime after their 85th birthday.

Some of what determines whether an APOEε4 carrier will ultimately succumb to AD is other genes that interact with an APOEε4 genotype, such as KLOTHO, which we discussed in detail on The Drive with Dena Dubal. But much of that variation is due to a person’s lifestyle and environment, much of which is in your control, as we discussed in detail in two AMA episodes of The Drive and as will be the subject of an upcoming episode.

But a very small number of people inherit much scarier genes: mutations with near-complete penetrance that almost inevitably lead to Alzheimer’s disease, and often at a shockingly young age. All such genes are involved in the production or  processing of beta-amyloid, the signature form of molecular aging damage that accumulates in the brains of people with AD. And while many gene variants that have the potential to cause disease either don’t manifest any phenotype if they’re “overpowered” by the second, “dominant” gene variant with which they are paired, and other genes only have a partial effect if paired with a healthy second gene version (as happens with APOEε4), these severe AD risk genes are themselves dominant. This means that inheriting a single copy of the gene from one parent will virtually doom you to AD dementia if you live into middle age, even if your other copy is perfectly healthy. This condition is accordingly called dominantly-inherited AD (DIAD).

“Exceptional resilience”

Rare as such dominant, determinative AD genes are (they account for about 1% of all cases of AD), there are even rarer cases in which even people who carry such genes somehow manage to escape their terrible inheritance. A recent paper⁷ reports one such “exceptional resilience” case.

Doug Whitney is a 75-year-old man with a dominant, determinative AD mutation in the PSEN2 gene, which is involved in processing the precursor protein to beta-amyloid. This mutation is highly penetrant: his mother and 11 of her 13 siblings developed AD at an average age of 49.3 years, which is similar to the age of onset for other carriers of his mutation.^† Yet at age 75, Whitney’s cognitive function is normal or above normal for his age.

Given the age of onset in his family (49.3 years) and of other carriers of his mutation (53.7, with a range of 39–58 years), surviving cognitively intact to age 75 places Whitney more than two decades beyond the expected clinical onset for carriers of this mutation, making him one of the most extreme outliers ever reported among PSEN2 mutation carriers.

What might be responsible for Whitney’s “exceptional resilience” against his genetic fate? The investigators quickly ruled out the explanation for previous such cases: he lacks either of the two also-rare gene variants that are known to counteract a similar mutation.^8,9 They then looked to see if Whitney had somehow escaped the overproduction of beta-amyloid that usually results from his mutation. That wasn’t it either: at his last test, at age 71, Whitney’s brain had the burden of beta-amyloid that is typical of a person five years after the onset of dementia.

Similarly, the investigators looked at the volume of Whitney’s hippocampus, an area central to converting short-term memories into long-term memories that atrophies in AD, and also at the integrity of his white matter (the insulation surrounding brain neurons, which is often full of lesions in people with various neurodegenerative diseases). Both of these brain structures are typical for people his age, not for people with AD. And when they did a spinal tap to look at proteins in his cerebrospinal fluid (CSF—the fluid that bathes the brain and spinal nerves), they found that most of the AD-related proteins in his CSF are (wait for it!) typical for a cognitively-intact 70-something gentleman, while others are intermediate between the values of people undergoing “normal” cognitive aging and those of DIAD patients.

But they saw something very unusual when they looked at scans for abnormal forms of the protein tau. The majority of people over age 60 develop deposits of aberrant tau in and around their hippocampus, whether or not they have beta-amyloid deposits in their brains,¹⁰ and some studies find that essentially everyone over age 70 has such damage, regardless of cognitive status.¹¹

AD usually manifests after beta-amyloid accumulation appears to facilitate the spread of aberrant tau to spread beyond the hippocampal region to the frontal cortex, the center for decision-making and planning.^10,12 Notably, the pattern of tau pathology in previous “exceptionally resilient” DIAD mutation carriers had looked more like that of cognitively-intact older people than that of AD or DIAD, with their tau pathology confined to areas in and around the hippocampus despite their extensive beta-amyloid pathology.^8,9

But Whitney’s pattern of tau pathology doesn’t look like any of these groups: despite his rampant burden of beta-amyloid, the aberrant tau in his brain is confined almost entirely to his occipital lobe, a region primarily responsible for visual processing that is not typically a major site of neuropathology in AD. Now, it’s not that the molecular damage in Whitney’s occipital lobe is benign: the afflicted area is metabolically sluggish, as shown by low uptake of a glucose tracer, which is typical of affected areas in the AD brain. But the rest of his brain is burning fuel like a “normal” 75-year-old‘s would, and (again) his cognitive function is as good as or better than that of other men his age.

The investigators also performed whole-exome sequencing on Whitney, looking for novel protective gene variants that might explain his “exceptional resilience,” and identified multiple genes carried by Whitney that have never been reported in people with dementia due to DIAD. Most of these variants were previously unknown, although a few have also been reported in other exceptional resilience cases. One such variant is Whitney’s version of MAPT, the gene for tau. Additionally, Whitney has several other genetic variants that are unique to him that are located near MAPT in the genome and might affect its function.

If these variants were validated as being responsible for Whitney’s exceptional resilience, they could become targets for novel AD drugs. But as it stands today, none of the identified genes provides a clear genetic explanation for his escaping the genetic odds: for that, scientists would need to find other patients with DIAD mutations (ideally, with his DIAD mutation) who do and do not have some of his candidate protective variants, and see if any of them were consistently associated with freedom from dementia.

A hot prospect

An intriguing alternative explanation for Whitney’s exceptional resilience turned up in his CSF, which has exceptionally high levels of heat-shock proteins (HSPs). The investigators measured four major HSPs in Whitney’s CSF: his level for each of them is roughly one and a half to two times the median level of three groups of controls (similar-aged cognitively intact people without a DIAD mutation; people with sporadic age-related AD; and DIAD mutation carriers). This puts him at the extreme upper end of the distribution for the former two groups.

Why might this be important? HSPs are molecular Origami artists that help fold proteins into their proper, biologically functional shapes, and also help refold damaged proteins back into their right conformation if they get warped when the cell is under stress. So the remarkably high level of HSPs in the fluid bathing Whitney’s brain might have protected his native, properly-folded tau protein from aggregating, or blocked the toxicity of such aggregates,¹³ which in turn might prevent it from spreading, virus-like, throughout his brain via synaptic networks.¹²

One HSP whose levels were not reported by the investigators, Hsp27, binds to tau when the protein undergoes early pathological changes and prevents it from forming mature aggregates.¹⁴ To test its effects on aberrant tau in a living organism, researchers in China turned to transgenic flies that express a mutated tau protein that causes a form of dementia in humans. These flies accumulate high levels of aberrant tau, which leads to progressive atrophy of their brain tissue. In response to this pathology, the flies naturally increased production of the protective chaperone Hsp27, but this endogenous response was clearly insufficient to prevent severe neural damage. But when the researchers overexpressed Hsp27 in these same animals’ brains, several forms of aberrant tau were nearly eliminated, and their nervous tissue remained more or less normal.¹⁴

Why were HSPs cranked up so high in Whitney’s brain? It can’t just be the brain’s normal response to the damaged proteins: if that were it, we’d see much higher levels of HSPs in AD and DIAD brains than in those of cognitively-intact people, which we don’t. And in any case, Whitney’s HSP levels are at the extreme high end of the distribution seen in other AD patients. And while his high CSF HSP level could itself be the result of an unidentified genetic factor, no obvious genetic candidate turned up.

But there’s an intriguing alternative explanation. As the investigators report, Whitney underwent “high exposure to high heat for years while working as a mechanic in a diesel engine in a naval ship for many hours a day, requiring him to be hosed down with water to prevent overheating”.⁷ So his high CSF HSPs could be a long-term adaptive response to that extreme environment that has kept his tau pathology in check, allowing him to beat his genetic destiny.

What makes this hypothesis so enticing is that if Whitney’s high CSF HSPs are indeed the result of his occupational exposure to extreme heat, and the HSPs are an important factor in his exceptional resilience, then they offer a possible mechanistic explanation for the epidemiological association of frequent sauna use with greatly reduced risk of AD.^15,16 It is important to emphasize that this hypothesis remains speculative: elevated HSPs could be a marker of another protective process rather than the cause of Whitney’s resilience.

Sauna does upregulate HSP expression, with larger effects in sedentary rather than active people.^17,18,19 This is presumably because exercise itself boosts HSPs in part via heat stress, and people adapt to regular heat stress with less robust responses,²⁰ and because regular exercise improves thermoregulation (such as sweating).²¹ And like sauna, having high cardiorespiratory fitness is also associated with a profound reduction in your risk of dementia.²²

So it’s reasonable to speculate that frequent sauna use might elevate a person’s CSF HSPs, thereby conferring lower risk of AD, especially in people at risk for the slow-acting, more purely age-related form of AD.

Listeners of The Drive will know that I was initially skeptical of the literature on sauna, in part because of the many layers of confounding to which observational data are subject. In particular, I thought there was too much potential for healthy user bias in the studies—that is, the idea that people who are actively engaged with any given practice that is thought to be healthy (in this case, sauna) are likely to also engage in many other health practices (such as exercise or a healthy diet). On top of that, you have to have a certain level of health just to be able to tolerate a hot sauna most days of the week. So frequent sauna users have a potential double advantage, being healthier people who choose to do healthier things.

This kind of confounding makes it hard to tease out whether an association between (in this case) sauna and some positive health outcome (in this case, dementia) is due to that practice (sauna), or whether sauna instead is acting as a proxy marker for the robust health that allows sauna users to keep up with the practice, and/or for the other health practices in which users are engaged that are actually protecting them.

But over the last 5 years, as I’ve looked more closely at the data, I’ve found it increasingly hard to believe that there isn’t a fire underneath the sauna steam, at least in terms of cardiovascular disease and dementia. For example, skeptics of the sauna epidemiology often suggest that these associations are due to confounding with socioeconomic status (SES). Frequent sauna users, they argue, would likely be of higher SES, since people of higher SES would have greater access to a sauna room and more free time and/or flexibility to take advantage of it. And since higher SES is itself associated with reduced risk of dementia and other diseases of aging, the multiple protective effects attributed to sauna could actually be just signposts of sauna users’ greater wealth and education.

However, this does not seem to be true in Finland, where these epidemiological studies were performed. Sauna is so embedded in the culture that it’s almost like running water: a separate observational study, also from Finland, found only minor differences in annual salary or a composite score of SES among people with high versus low sauna use.²³

Throw the cold water

Enticing as this possible link may be, it’s important to point out its limitations. First, what we are sketching here is a chain of hypotheticals: if Whitney’s exceptional resilience is largely driven by his high HSPs; if his high HSPs are due to his heat exposure, and not due to some genetic or unknown lifestyle factor; if a mechanism that is protective against Whitney’s rare DIAD mutation is also protective effect against garden-variety age-related dementia; and if the association of sauna use with reduced dementia risk is causal and not an artifact of confounding. A flaw in any link in this chain of reasoning could cause it to break under stress.

Second, it seems unlikely that the magnitude of the effect on HSPs that one is likely to get from “chilling out” for half an hour a day in the sauna would approach the effect that Whitney would have obtained from spending hours every weekday doing hard physical work in heat so high as to require a hosing down for safety. Relatedly, Whitney has high HSPs where you’d expect it to count (the fluid bathing his brain and spinal cord), whereas our only evidence for the effect of sauna on HSPs in humans is in white blood cells in the circulation. The body works very hard to avoid overheating the brain, so just because the heat in the sauna seems fierce doesn’t guarantee that your brain is subjected to the kind of heat that would trigger an increase in HSPs in your CSF.

That said, repeated high-level heat exposure both causes the brain to ramp up HSP production in animal models and establishes a new baseline level of expression of unknown persistence^24,25 that can “prime” the brain to increase HSP production in response to unrelated stressors.²⁵ Speculatively, Whitney’s heat exposure could have provided the initial stimulus to maintain a higher basal HSP level in his brain, and the damaged proteins driven by his mutation might have constituted a follow-on stimulus.

Also, as we’ve already mentioned, the HSP response to sauna appears to be more weaker in people who get regular exercise than in sedentary persons.^17,18,19 Similarly, sauna acutely lowers blood pressure and arterial stiffness²⁶ but it only lowered 24-hour ambulatory blood pressure when combined with exercise.²⁷ (We do not have information on Whitney’s blood pressure or other cardiovascular risk factors). So if you’re already getting regular exercise—a much higher-priority intervention for increasing your healthy life expectancy than sauna—then the additional protection you might expect from upping your sauna game may be marginal.

The less-than-additive effect on HSPs of adding sauna to exercise seems consistent with an epidemiological study looking at the individual and joint associations of sauna use and cardiorespiratory fitness with the risk of death from cardiovascular diseases and from all causes combined.²⁸ The study followed 2,277 Finnish men who underwent VO2max testing at the beginning of the study, along with bloodwork and a questionnaire about how often they took a sauna.

Compared to men with a low VO2max who reported using sauna twice a week or less, men with a low VO2max who said they used sauna every day were a bit more than one quarter less likely to die from cardiovascular diseases over the following 26 years (HR 0.72 (0.54–0.97)), while those with high VO2max who used sauna much less frequently were only half as likely to do so (HR 0.50 (0.39–0.63)). The combination of daily sauna use with a high VO2max was only associated with a modest further improvement over having a high VO2max alone, but compared to daily sauna use alone, also having a high VO2max was associated with almost a further halving of risk (HR 0.42 (0.28–0.62)). Having a  high VO2max was similarly the dominant factor in associations with all-cause mortality.²⁸

Don’t leave it to lucky genes

Doug Whitney is a unicorn: he was born with a rare gene that almost guarantees an early descent into AD dementia, typically when most people are in the prime of their lives, yet some combination of exceptional influences has allowed him to escape that fate well into what is currently considered old age. By contrast, the overwhelming majority of people who develop dementia do so late in our current life expectancies, and while genes (especially APOE variants) play a role, there is strong evidence that we each have a good deal of control over our cognitive future.

None of us can bank on being gifted with whatever combination of other, also-rare genes and extreme, decades-long occupational exposure that has kept Whitney’s brain sharp for decades beyond his genetically-predicted date with destiny. Instead, we must work with the tools available to us to keep our brains healthy. Some of those tools have reached the point of medical consensus, including treating hearing loss, diabetes, and hypertension; maintaining a lean body composition and a low level of atherogenic lipoproteins; and being socially and cognitively engaged and cultivating mental health.²⁹ Others that are still emerging were discussed in two AMA episodes of The Drive and will be the subject of an upcoming episode.

So enjoy your sauna if you have access, but take it as a reward at the end of a day when you’ve done your exercise and taken all other steps to keep the Third Horseman at bay. Cases like Whitney’s remind us that even when Alzheimer’s appears genetically predetermined, the biology of resilience still exists and may ultimately prove more informative than the biology of risk.

^* Far fewer cases in Asian countries appear to bear one,⁵ but there are well-known historical difficulties in diagnosing AD in South Asian populations.

^† We don’t know what happened to Whitney’s mother’s other two siblings, but it is already statistically surprising that so many of them inherited the mutation in the first place, when we expect only one grandparent to have carried a single copy of the gene. Unfortunately, we don’t actually know the genetics of the grandparents or those of the mother’s siblings—just their dementia status. It’s of course possible to flip heads 12 out of 14 times, but alternatively (all my speculations) perhaps the affected grandparent was homozygous, or perhaps the unaffected grandparent was a DIAD carrier but had an ‘exceptional resilience’ gene that she passed on to the unaffected siblings (though apparently not Whitney’s mother), or perhaps his mother’s unaffected siblings died before a fated diagnosis

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References

1. Neu SC, Pa J, Kukull W, et al. Apolipoprotein E genotype and sex risk factors for Alzheimer disease: A meta-analysis: A meta-analysis. JAMA Neurol. 2017;74(10):1178-1189.
2. Rasmussen KL, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Absolute 10-year risk of dementia by age, sex and APOE genotype: a population-based cohort study. CMAJ. 2018;190(35):E1033-E1041.
3. Slooter AJ, Cruts M, Kalmijn S, et al. Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam Study. Arch Neurol. 1998;55(7):964-968.
4. Williams DM, Heikkinen S, Hiltunen M, FinnGen, Davies NM, Anderson EL. The proportion of Alzheimer’s disease attributable to apolipoprotein E. NPJ Dement. 2026;2(1):1.
5. Arrighi HM, Crean SM, Ward A, et al. P3‐067: A systematic literature review and meta‐analysis of apolipoprotein E ∊4 prevalence in Alzheimer patients. Alzheimers Dement. 2010;6(4S_Part_15):S468-S469.
6. Qian J, Wolters FJ, Beiser A, et al. APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts. PLoS Med. 2017;14(3):e1002254.
7. Llibre-Guerra JJ, Fernandez MV, Joseph-Mathurin N, et al. Longitudinal analysis of a dominantly inherited Alzheimer disease mutation carrier protected from dementia. Nat Med. 2025;31(4):1267-1275.
8. Arboleda-Velasquez JF, Lopera F, O’Hare M, et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019;25(11):1680-1683.
9. Lopera F, Marino C, Chandrahas AS, et al. Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man. Nat Med. 2023;29(5):1243-1252.
10. Maass A, Lockhart SN, Harrison TM, et al. Entorhinal tau pathology, episodic memory decline, and neurodegeneration in aging. J Neurosci. 2018;38(3):530-543.
11. Bouras C, Hof PR, Giannakopoulos P, Michel JP, Morrison JH. Regional distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of elderly patients: a quantitative evaluation of a one-year autopsy population from a geriatric hospital. Cereb Cortex. 1994;4(2):138-150.
12. Xiao Y, Spotorno N, An L, et al. Brain network dynamics determine tau presence while regional vulnerability governs tau load in Alzheimer’s disease. Neuroscience. Published online April 23, 2025. https://www.biorxiv.org/content/10.1101/2025.04.17.648358v4
13. Kundel F, De S, Flagmeier P, et al. Hsp70 inhibits the nucleation and elongation of tau and sequesters tau aggregates with high affinity. ACS Chem Biol. 2018;13(3):636-646.
14. Zhang S, Zhu Y, Lu J, et al. Specific binding of Hsp27 and phosphorylated Tau mitigates abnormal Tau aggregation-induced pathology. Elife. 2022;11(e79898):e79898.
15. Knekt P, Järvinen R, Rissanen H, Heliövaara M, Aromaa A. Does sauna bathing protect against dementia? Prev Med Rep. 2020;20(101221):101221.
16. Laukkanen T, Kunutsor S, Kauhanen J, Laukkanen JA. Sauna bathing is inversely associated with dementia and Alzheimer’s disease in middle-aged Finnish men. Age Ageing. 2017;46(2):245-249.
17. Żychowska M, Półrola P, Chruściński G, Zielińska J, Góral-Półrola J. Effects of sauna bathing on stress-related genes expression in athletes and non-athletes. Ann Agric Environ Med. 2017;24(1):104-107.
18. Żychowska M. Changes in expression of selected cellular stress response genes after passive body overheating in sauna and moderate exercise in judo athletes and untrained people. March 26, 2025. Accessed March 10, 2026. https://www.archbudo.eu/index.php/latest-publication/2017-volume-13/changes-in-expression-of-selected-cellular-stress-response-genes-after-passive-body-overheating-in-sauna-and-moderate-exercise-in-judo-athletes-and-untrained-people
19. Pilch W, Szarek M, Olga CL, et al. The effects of a single and a series of Finnish sauna sessions on the immune response and HSP-70 levels in trained and untrained men. International Journal of Hyperthermia. 2023;40(1). doi:10.1080/02656736.2023.2179672
20. Yang FL, Lee CC, Subeq YM, Lee CJ, Ke CY, Lee RP. Heat adaptation from regular hot water immersion decreases proinflammatory responses, HSP70 expression, and physical heat stress. J Therm Biol. 2017;69:95-103.
21. Reilly T, Drust B, Gregson W. Thermoregulation in elite athletes. Curr Opin Clin Nutr Metab Care. 2006;9(6):666-671.
22. Lee J. Influence of cardiorespiratory fitness on risk of dementia and dementia mortality: A systematic review and meta-analysis of prospective cohort studies. J Aging Phys Act. 2021;29(5):878-885.
23. Laukkanen T, Kunutsor SK, Khan H, Willeit P, Zaccardi F, Laukkanen JA. Sauna bathing is associated with reduced cardiovascular mortality and improves risk prediction in men and women: a prospective cohort study. BMC Med. 2018;16(1):219.
24. Sareh H, Tulapurkar ME, Shah NG, Singh IS, Hasday JD. Response of mice to continuous 5-day passive hyperthermia resembles human heat acclimation. Cell Stress Chaperones. 2011;16(3):297-307.
25. Eynan M, Ertracht O, Gancz H, Kashi Y, Arieli Y. Prolonged latency to CNS-O2 toxicity induced by heat acclimation in rats is associated with increased antioxidative defenses and metabolic energy preservation. J Appl Physiol. 2012;113(4):595-601.
26. Laukkanen T, Kunutsor SK, Zaccardi F, et al. Acute effects of sauna bathing on cardiovascular function. J Hum Hypertens. 2018;32(2):129-138.
27. Gayda M, Paillard F, Sosner P, et al. Effects of sauna alone and postexercise sauna baths on blood pressure and hemodynamic variables in patients with untreated hypertension: Hemodynamic effects of sauna in hypertensive patients. J Clin Hypertens (Greenwich). 2012;14(8):553-560.
28. Kunutsor SK, Khan H, Laukkanen T, Laukkanen JA. Joint associations of sauna bathing and cardiorespiratory fitness on cardiovascular and all-cause mortality risk: a long-term prospective cohort study. Ann Med. 2018;50(2):139-146.
29. Livingston G, Huntley J, Liu KY, et al. Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. Lancet. 2024;404(10452):572-628.