Could Lifetime Lead Exposure Play a Role in Limbic-predominant Age-related TDP-43 Encephalopathy (LATE)?

INTRODUCTION

An international panel of experts recently published a consensus report on Limbic-predominant Age-related TDP-43 Encephalopathy or LATE [1]. TDP-43 (Transactive response DNA binding protein of 43 kDa) is an RNA binding protein that regulates RNA transcription, splicing, transport, and stress granule formation [2, 3]. Alterations in normal TDP-43 activity will thus disrupt RNA metabolic pathways, interfere with neuronal function, and may lead to neuronal cell death [3]. TDP-43 proteinopathy, including formation of aberrant cytoplasmic and nuclear inclusions, has been previously linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [1, 2], and more recently, Alzheimer’s disease (AD) as well as LATE [1]. LATE pathology, caused by TDP-43 proteinopathy in older adults, has been associated with cognitive impairment that appears clinically similar to AD [1]. Neuropathological changes of LATE are present in more than 20% of autopsies of community-dwelling adults over age 80 years, and approximately one-sixth of clinically diagnosed AD is attributable to neuropathological change associated with TDP-43 encephalopathy [1]. LATE may be a main contributor of tau-negative dementia [1], but it is important to note that Josephs and a large group of collaborators suggest it is unclear whether the concept of LATE improves diagnostic accuracy or communication among researchers in the field [4]. They “urge researchers to focus on defining the pathological processes and their biochemical differences underlying TDP immunoreactive lesions in FTLD [Frontotemporal Lobar Degeneration] and non-FTLD disorders” [4].

Recent research has suggested that TDP-43 proteinopathy may be strongly influenced by heavy metals [2]. In particular, animal studies have shown that exposure to lead induces accumulation of TDP-43 in neuronal nuclei and alters splicing regulation within neuronal cells [2]. Some neurodegenerative conditions, such as AD and Parkinson’s disease, have been linked to the disruption of TDP-43 homeostasis [2, 6].

ALS is another neurological disease that has been associated with TDP-43 proteinopathy [1]. A study of a small Italian population has indicated that ALS patients have higher concentrations of lead in their blood in comparison to healthy subjects [7]. A separate study of veterans with ALS compared to healthy peers yielded similar results [8]. The latter study also found that there was a dose-response relationship between blood lead levels (BLL) and the odds of ALS [8]. Additionally, ALS patients were also found to have higher lead levels in their hair [9]. Cumulatively, these studies suggest that there may be a correlation between lead exposure and development of ALS.

Beyond neurodegenerative diseases, TDP-43 pathology has also been connected with dysregulation of the thyroid hormone [1]. Interestingly, other studies have found that lead exposure can affect the hypothalamic–pituitary–thyroid axis [10], thus suggesting another potential link between TDP-43 pathology and lead exposure.

We therefore hypothesize that exposure to historically high environmental levels of lead in air pollution before the phase-out of leaded gasoline may play a role in TDP-43 pathology and, thus, LATE in older adults. We propose several potential ways to explore the validity of this hypothesis.

DISCUSSION

Recent research has linked lifetime lead exposure to cognitive decline (it must be noted that previous research did not differentiate between LATE and other forms of cognitive decline). A 2004 prospective study evaluated the Mini-Mental State Examination (MMSE) scores of elderly community-dwelling American men over time and identified that higher patella bone lead level was linked to a steeper decrease in the scores of the cognitive test over time [11]. Another study of community-dwelling older Americans showed that one interquartile range increase in tibia lead concentration was associated with the equivalent of 2–6 years older age in cognitive function tests [12]. Several explanations have been proposed to explain the link between an individual’s cumulative lifetime exposure to lead and a faster decline in cognitive function. For instance, animal studies have identified that early life lead exposure results in decreased DNA methyltransferase activity and altered epigenetic modifications of genes involved in AD pathways, thus suggesting that lead contributes to cognitive decline via epigenetic mechanisms [13]. Additionally, lead is also a neurotoxin that can induce neuronal cell death and thus affect cognitive abilities [14].

Other studies have indicated that the odds of dementia were elevated among those living closer to major roads [15], and among older adults having greater exposure to traffic-related air pollution [16]. Even though many of these studies were conducted after the phase-out of leaded gasoline, the long latency of dementia and the low residential mobility among older adults, the majority of whom have owned their homes for many decades [17], suggests that much earlier lead exposure may plausibly have played a role.

The phasing out of leaded gasoline, which began in 1973 in the United States resulted in a dramatic reduction in mean BLL. In 1976-1980, the mean BLL was 12.8 μg/dL, this decreased sharply to 2.8 μg/dL in 1988-1991 [18], and dropped further to 0.84 μg/dL in 2013-2014 [19]. One-quarter of all 1-5-year-old children in the late 1970s had BLL greater than 20 μg/dL, and African American children had an average BLL of 20.2 μg/dL during that era [18]. The percentage of 1-5-year-old children with the current Center for Disease Control (CDC) actionable BLL > 5 μg/dL was 99.8% in 1976-1980, dropping to 33.2% in 1988-1991 [18], 9.9% by 1999-2000, and 0.5% in 2013-14 [19]. To put the magnitude of these numbers into perspective, during the Flint Michigan water crisis in 2014, 5% of the children had BLL > 5 μg/dL [20].

BLL reflect current and recent exposure to lead, with a half-life of only 28–36 days [21]. A better measure of cumulative lifetime exposure is bone lead. Lead can be absorbed through inhalation of airborne lead particulates or diet [22]. Once in the body, it is rapidly distributed to various compartments including blood, soft tissues (e.g., kidneys) and mineralizing tissues (e.g., bones) [22]. Bones are the major depository for lead as lead can replace the calcium in hydroxyapatite, which are abundant in bones [21, 23]. More than 90% of adults’ lead burden is in their bones and teeth [21, 24]. Absorbed lead is primarily eliminated in the urine or feces; however, once sequestered in bone or other bodily compartment, lead becomes difficult to eliminate [22, 25]. Lead sequestered in bone becomes an endogenous source of lead exposure. Estimates suggest that for each 10 μg/g increase of lead in the tibia bone, there is an increase of 0.8 μg/dl in BLL [26].

Research has indicated that the half-life of lead in the tibia is several decades with one estimate suggesting 49 years [27]. Lead in the tibia therefore provides a helpful proxy for lifetime lead exposure. Younger birth cohorts had cumulatively fewer years of exposure to high lead content in air pollution and this is clearly reflected in cohort differences in lead levels in the tibia. As we have discussed elsewhere, measures of tibia bone lead levels in Americans in the early 1990s indicated older adults born before 1925 had at least five-fold higher tibia bone lead levels (25 μg/g-28 μg/g) compared to individuals born between 1965-1982 (4-5 μg/g). Also, in comparison to those born in the post-baby boomer cohort, individuals born between 1926-1935 (18–22 μg/g) and between 1936-1945 (13 μg/g) had, approximately four-fold and a three-fold higher tibia bone lead levels [28].

If lead plays a major role in the development of LATE, the higher cumulative exposure to lead of earlier birth cohorts, as measured by tibia bone lead level, should correlate to birth cohort differences in the prevalence of LATE in those aged 80 and older. If our hypothesis is correct, the prevalence of LATE should be higher in earlier cohorts than in later birth cohorts. This should be evident using existing autopsy studies if re-analyzed by birth cohort, holding age constant (e.g., only looking at those 80 and older in the 1990s, in the 2000s, and in the 2010s). We hypothesize that there should be a downward trend over time in the prevalence of LATE among older adults and this temporal trend should continue for the next five decades until all older adults will have been born after the phase-out of leaded gasoline. The prevalence of LATE might also be higher among those who lived in the 1970s and before in inner city areas and near major roads in comparison to those who lived in areas with less traffic-related air pollution. Additionally, the role of lead in the development of other neurological diseases such as ALS and tau-positive dementia would be interesting to explore. For instance, correlation between levels of tibia lead and phosphorylated tau, which can be used as a diagnostic marker in AD [29], may be examined and birth cohort differences identified.

Future research would greatly benefit if tibia bones, and possibly permanent teeth, are also harvested when brains are donated. This will allow investigation of the extent to which cumulative lifetime lead exposure and childhood exposure [30], respectively, are associated with level of LATE pathology.

We also hypothesize that individuals with genetic polymorphisms that predispose them toward greater metal absorption will have a higher prevalence of LATE. For instance, DMT1 is involved in the intestinal absorption of lead [31]. A study of a Turkish cohort showed that individuals homozygous for the DMT1 IVS4 + 44C allele have higher BLL than those with a different genotype [31]. In addition, in a study from Mexico before the phase out of leaded gasoline, subjects with certain variants of the HFE gene (i.e., H63D or C282Y) or the TF gene (i.e., P570S) had approximately 10% higher BLL and those with both these alleles had 50% higher BLL in comparison to the wild type subjects [32].

If LATE is indeed more prevalent in those with alleles that confer greater lead absorption phenotype (such as DMT1 IVS4 + 44C and HFE, C282Y), then it would be promising to look at the association between the presence of these alleles and the degree of TDP-43 accumulation shown in autopsies.

Iron supplementation has been demonstrated to lower brain lead levels in rats [33]. Thus, the potential of iron supplementation therapy in reducing lead deposition in neurons of patients with high lead burden is a promising area of future research.

As indicated in the review by Nelson and colleagues, there are several genes (e.g., ABCC9 and APOE) with alleles that are associated with LATE [1]. Interestingly, APOE isoforms are known to be able to bind to metals such as copper and zinc, with APOE4 displaying lower metal chelating activity compared to isoforms such as APOE2 [34]. Recent research on older men indicate that, in general, higher bone lead levels are associated with cognitive decline, but individuals homozygous for the APOE ɛ4 allele have significantly greater cognitive decline related to lead exposure [35].

It is important to note that other environmental factors may impact LATE risks. For instance, the rates of smoking, a known risk factor for neurological diseases, have declined significantly in United States since the 1960s [36, 37]. This decline is in parallel to the phasing out of leaded gasoline and thus may confound the relationship between lead exposure and LATE development. In addition to smoking history, other possible environmental risk factors such as exposure to toxins (e.g., organophosphates), other heavy metals (e.g., mercury, selenium), and aryl hydrocarbon receptor agonists (e.g., dioxin) must be taken into account when investigating the relationship between tibia lead level and LATE risks [2].

In summary, although highly speculative, the potential role of lead exposure in the development of LATE is plausible and worthy of further study.