New Hypothesis: Declining Dementia Rates May Reflect Reduced Lifetime Lead Exposure

Summary: Researchers propose that falling dementia incidence could be linked to generational reductions in lifetime lead exposure.

Source: University of Toronto

Overview: Several large studies from the United States, Canada and Europe have reported a surprising trend: the incidence and prevalence of dementia appear to be decreasing in recent decades. This is unexpected because many established dementia risk factors—such as mid-life obesity and type 2 diabetes—have risen rapidly over the same period. A new hypothesis from University of Toronto researchers offers a possible environmental explanation.

Professor Esme Fuller-Thomson of the University of Toronto, together with pharmacy student ZhiDi (Judy) Deng, has published a paper in the Journal of Alzheimer’s Disease proposing that generational differences in lifetime lead exposure could partly explain the falling rates of dementia. Their theory links historical patterns of lead pollution—especially from leaded gasoline—to later-life cognitive decline and a particular form of dementia called LATE (Limbic-predominant Age-related TDP-43 Encephalopathy).

Lead was an abundant air pollutant from the widespread use of leaded gasoline between the 1920s and the 1970s. After phased removal of lead from gasoline beginning in the 1970s, blood lead levels in the population fell sharply. Historical measurements indicate that people born before 1925 had roughly twice the lifetime lead exposure of those born between 1936 and 1945.

“The levels of lead exposure when I was a child in 1976 were 15 times what they are today,” says Fuller-Thomson, who is also cross-appointed with the University of Toronto Faculty of Medicine. “Back then, 88 percent of us had blood lead levels above 10 micrograms per deciliter. By contrast, during the Flint, Michigan water crisis of 2014, roughly one percent of children had blood lead above that level.”

Lead is a well-known neurotoxin that crosses the blood-brain barrier. Animal experiments and studies of workers with occupational lead exposure have linked lead to cognitive decline and dementia-like pathology. Epidemiological work has also found higher dementia rates among older adults living near major roads and in areas with greater traffic-related pollution—consistent with leaded gasoline as an earlier source of airborne lead.

Fuller-Thomson and Deng draw particular attention to LATE, a recently characterized form of late-life cognitive disorder that can resemble Alzheimer’s disease clinically. LATE is defined by abnormal accumulation of TDP-43 protein in limbic brain regions and has been identified in roughly 20 percent of autopsies of adults over 80. Laboratory evidence suggests that heavy metals such as lead can disrupt TDP-43 homeostasis and promote its accumulation, raising the possibility of a causal connection between lead exposure and LATE pathology.

Other factors likely contributed to improvements in dementia incidence, including higher educational attainment, reduced smoking, and better management of hypertension. However, the authors note that many studies still observe declines in dementia even after adjusting statistically for those factors, pointing to the potential role of environmental exposures such as lead.

Suggested Research Directions

To test the hypothesis that lifetime lead exposure influences dementia and LATE prevalence, the authors recommend several research approaches:

• Compare historical blood lead data from earlier decades (for example, 1990s surveys) with current clinical records for dementia diagnoses in similar birth cohorts.
• Measure long-term lead burden directly in autopsy studies by assessing lead concentration in tibia bone or teeth, which reflect cumulative exposure over many decades, and correlate those measures with brain pathology including TDP-43 accumulation.
• Examine gene–environment interactions by studying whether individuals with genetic variants that increase lead uptake show greater TDP-43 pathology or higher dementia rates.

“If lifetime lead exposure proves to be a major contributor to dementia risk, we should expect continued reductions in dementia incidence over coming decades as each successive generation has experienced lower cumulative exposure to this neurotoxin,” says ZhiDi (Judy) Deng.

Source:
University of Toronto

Media contacts:
Esme Fuller-Thomson – University of Toronto

Image source:
The image is in the public domain.

Original research:
“Could Lifetime Lead Exposure Play a Role in Limbic-predominant Age-related TDP-43 Encephalopathy (LATE)?” Fuller-Thomson, Esme; Deng, ZhiD. Published in Journal of Alzheimer’s Disease. DOI: 10.3233/JAD-190943 (closed access).

Abstract (Condensed)

LATE is a late-life condition that clinically resembles Alzheimer’s disease and is characterized by TDP-43 proteinopathy in limbic brain regions. TDP-43 pathology is found in a substantial proportion of autopsies from adults over 80 and may underlie many tau-negative dementia cases. Experimental evidence links heavy metals such as lead to disruption of TDP-43 homeostasis and accumulation. Because blood lead levels were dramatically higher before leaded gasoline was phased out, successive birth cohorts have experienced progressively lower lifetime lead exposure. Tibia bone lead levels can serve as a long-term biomarker of cumulative exposure. The authors hypothesize that lower lifetime lead exposure contributes to the observed decline in dementia incidence and specifically to lower prevalence of LATE across more recent cohorts. They propose autopsy-based comparisons of tibia lead and TDP-43 pathology across birth cohorts and investigation of genetic variants that affect lead absorption to explore gene–environment interactions relevant to LATE.