02 Mar 2022

Scientists increasingly recognize limbic predominant age-related TDP-43 encephalopathy—aka, LATE—as a highly prevalent neuropathology lurking in the brains of people in their 80s and 90s. While neuropathologists have long observed TDP-43 inclusions crowding the limbic regions among people with memory complaints, the christening of this neuropathological entity nearly three years ago has prompted them to re-examine autopsy cohorts, and decipher how much this pathology contributes to cognitive impairment. At LATE 2022—a virtual workshop hosted by the National Institute on Aging on February 11—researchers reported that not only was LATE neuropathology highly prevalent in older people, but it also mattered. People who had LATE pathology at death were likelier to have suffered from cognitive impairment or dementia during life, and they had a similar, albeit less severe, amnestic syndrome as that caused by AD. When lurking together in the same brain, LATE and AD pathology dramatically stepped up risk for dementia, suggesting a synergism between these neuropathological scourges of aging.

LATE Decline
As people age into their 80s and 90s, mixed proteopathy increasingly becomes the name of the game and brains dotted with pure neuropathologies become less common. LATE arises during this period of aging. At the NIA workshop, researchers questioned how much LATE neuropathological change (LATE-NC) contributes to cognitive decline, especially if it occurs in the company of other protein deposits.

Patricia Boyle of Rush University Medical Center in Chicago addressed this in the Religious Orders and Memory and Aging Project (ROS-MAP), a community cohort of some 3,000 people who had no dementia at baseline and submitted to lifelong cognitive testing and an autopsy after death. Focusing on participants who had undergone at least three cognitive examinations, Boyle asked to what extent different pathologies had contributed to a person’s deviation from the average pace of cognitive decline. She noted that in past studies, a combination of 11 brain pathologies, including amyloid plaques, neurofibrillary tangles, α-synuclein aggregates, limbic TDP-43 inclusions, hippocampal sclerosis, and various vascular pathologies accounted for 43 percent of that variance (Boyle et al., 2021). Myriad other factors, including lifestyle, cognitive resilience, education, and socioeconomic status, also steer cognitive trajectories (Jan 2017 news; Oct 2018 news; Oct 2019 news; Jan 2019 news).

In her previous study, Boyle had assumed a linear course of cognitive decline. At LATE2022, she presented findings from an updated statistical model, called functional mixed effects, that accounts for ups and downs of cognitive decline. Boyle said that flexibility built into this model allows it to more closely track how a person’s cognitive function fades. Among 1,147 ROS-MAP participants, global AD pathology accelerated decline by 26 percent, TDP-43 pathology by 8.3 percent, and hippocampal sclerosis by 6.6 percent. Cerebral amyloid angiopathy explained 5.7 percent of the change, while all other vascular pathologies combined explained less than 3 percent. Boyle found that, in toto, the measured pathologies accounted for half the cohort’s variance in cognitive decline. She said this finding implicates LATE-NC as a driver of late-life cognitive decline.

To be clear, this is not to say that half of ROS-MAP participants lacked a neuropathological explanation for their cognitive impairment. Rather, the remaining variance could stem from myriad nonpathological factors or unknown pathologies that were not measured by the study, said co-author Julie Schneider from Rush.

Do LATE-NC and AD harm the mind in the same way? Boyle investigated this by examining individual cognitive domains. Both LATE-NC and AD associated with a dip in episodic memory about 10 years prior to death, and with semantic memory loss appearing five years later. Working memory started to falter a few years earlier in people with plaques and tangles than in people with LATE-NC, and visuospatial abilities were more severely degraded in cases with AD pathology than LATE-NC.

“In terms of cognitive domains, there are more similarities than differences between LATE-NC and AD,” Nelson said. “Pure AD is more severe than pure LATE-NC, but the two pathologies are more likely to occur in combination than alone,” he added.

Mixed Pathologies
Indeed, Nelson and colleagues previously reported that among 375 participants in the University of Kentucky ADRC autopsy cohort who died at an average age of 87, around 13 percent had not one but four neurodegenerative proteinopathies: amyloid plaques, neurofibrillary tangles, TDP-43 inclusions, and α-synuclein Lewy bodies. This is in keeping with a large number of studies documenting mixed pathology in AD (Karanth et al., 2020; Schneider et al., 2007; James et al., 2016). 

Correlating that ADRC neuropath data with cognition, U. Kentucky’s Erin Abner reported that people with those same four misfolded proteinopathies deteriorated faster through mild cognitive impairment and into dementia than did people with fewer proteinopathies. Among those in the cohort who died with dementia, 19 percent had all four, 27 percent had plaques, tangles, and TDP-43 inclusions, while 5 percent had tangles and TDP-43. Notably, all participants included in this analysis had at least some tangle pathology consistent with primary age-related tauopathy. Abner said her findings place TDP-43 among the heavy hitters on cognition in this age bracket.

Yet more support for LATE-NC as a cognitive menace came from the population-based Adult Changes in Thought study. Caitlin Latimer of the University of Washington in Seattle presented preliminary findings from ACT, which enrolls cognitively normal people over the age of 65 in brain imaging, cognitive testing, and, ultimately, neuropathology. ACT researchers recently finished LATE-NC staging across the entire autopsy cohort, which currently includes brain samples from more than 800 people. Latimer investigated how their LATE-NC relates to their plaques/tangles, and dementia. In agreement with findings in other cohorts, Latimer saw both LATE and AD neuropathology as strongly linked to dementia. Compared to 271 people who had neither, 61 people with LATE-NC alone were twice as likely to have died with dementia, while 216 people with AD pathology alone had nearly quadruple the risk. The 127 people with both LATE-NC and AD pathology were 18 times likelier to have had dementia at death. Latimer said her findings were controlled for sex and age, ruling out the possibility that people with LATE-NC were likelier to have had dementia merely because they tended to be older than other members of the cohort.

Latimer noted that nearly everyone with both LATE-NC and AD had died with dementia, suggesting the combination of the two pathological entities potently drives decline. Is this relationship merely additive, Latimer wondered? Her preliminary findings hinted at potential synergism between LATE-NC and tangles, though not amyloid. The presence of stage 2-3 LATE-NC correlated with a higher burden of tangles, particularly in the midfrontal gyrus, Latimer reported, suggesting that neocortical tangles and limbic TDP-43 deliver a one-two punch on cognition.

In the Oldest Old
How does LATE-NC affect cognition in the oldest old? Maria Corrada of the University of California, Irvine, investigated this in the 90+ study, a cohort of nona- and centenarians based in Orange County, California. So far, the study has banked brain samples from 401 people who died at an average of 98 years of age, 44 percent of them with dementia. A little more than a third had had LATE-NC, most of them stage 2. After age 100, the prevalence of LATE-NC rose to 44 percent, from 33 percent in nonagenarians. In contrast to data from other younger cohorts, Corrada found that even stage 1 LATE-NC—in which TDP-43 inclusions are only in the amygdala—boosted the person’s dementia risk. In fact, LATE-NC of any stage more than tripled risk of dementia in this cohort.

There were cases of hippocampal sclerosis in this cohort, as well (see also Part 1 of this series). Two-thirds of them cropped up in people with limbic TDP-43 pathology, supporting the idea that most of this hippocampal pathology is associated with LATE-NC.

Corrada also probed how LATE-NC fits in with the burden of AD pathology, finding that LATE-NC correlated with Braak stage as well as the CERAD score of neuritic amyloid plaques. Although these two pathologies correlated, Corrada emphasized that it was not uncommon to see LATE-NC in people without substantial AD pathology, and that LATE-NC appeared to exert an independent effect on cognition.

The majority of people in this cohort died with more than one type of pathology in their brain, and Corrada used a statistical model to estimate how each may have contributed to dementia. She reported that vascular pathology posed by far the greatest risk, accounting for 40 percent of dementia. AD was next at 25 percent, and LATE-NC, Lewy bodies, and hippocampal sclerosis accounted for 19, 5.5, and 2.7 percent, respectively.

In discussion during the meeting, Carol Brayne, Cambridge University, England, picked up on the apparent differences in how much vascular pathology contributes to dementia across cohorts. While Abner had attributed 3 percent contribution to vascular problems in the University of Kentucky ADRC cohort, Corrada reported that it accounted for 40 percent of dementia risk in the oldest old. Corrada said that in addition to LATE-NC, vascular pathology, in particular small microvascular lesions, contributes substantially to the rising dementia rates as people live to be very old. She lamented that these oldest age groups are excluded from most clinical trials (see Part 3 of this series for more about LATE clinical trials and emerging biomarkers). “We’re neglecting a very high proportion of people who are actually affected by this condition,” she said.—Jessica Shugart

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References

News Citations

1. Dementia Risk Ticks Up Near Major Roadways 11 Jan 2017
2. Intelligence Matters More for Brain Reserve, but Education Helps 12 Oct 2018
3. Does Your Personality in High School Foretell Your Dementia Risk? 24 Oct 2019
4. Dementia: Frailty Hastens It, Physical Activity Wards It Off 25 Jan 2019
5. Virtual Workshop Tackles LATE, a Cause of Late-life Dementia 25 Feb 2022
6. Does LATE Subvert Alzheimer's Trials? Biomarkers, Please! 4 Mar 2022

Paper Citations

1. Boyle PA, Wang T, Yu L, Wilson RS, Dawe R, Arfanakis K, Schneider JA, Bennett DA. To what degree is late life cognitive decline driven by age-related neuropathologies?. Brain. 2021 Aug 17;144(7):2166-2175. PubMed.
2. Karanth S, Nelson PT, Katsumata Y, Kryscio RJ, Schmitt FA, Fardo DW, Cykowski MD, Jicha GA, Van Eldik LJ, Abner EL. Prevalence and Clinical Phenotype of Quadruple Misfolded Proteins in Older Adults. JAMA Neurol. 2020 Jun 22; PubMed.
3. Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007 Dec 11;69(24):2197-204. PubMed.
4. James BD, Wilson RS, Boyle PA, Trojanowski JQ, Bennett DA, Schneider JA. TDP-43 stage, mixed pathologies, and clinical Alzheimer's-type dementia. Brain. 2016 Sep 30; PubMed.

Further Reading

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