Important risk factors for dementia have been increasing rapidly

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To the medical community’s surprise, several studies from the US, Canada, and Europe suggest a promising downward trend in the incidence and prevalence of dementia.

Important risk factors for dementia, such as mid-life obesity and mid-life diabetes, have been increasing rapidly, so the decline in dementia incidence is particularly perplexing.

A new hypothesis by University of Toronto Professor Esme Fuller-Thomson, recently published in the Journal of Alzheimer’s Disease, suggests that the declining dementia rates may be a result of generational differences in lifetime exposure to lead. U of T pharmacy student ZhiDi (Judy) Deng, co-authored the article.

“While the negative impact of lead exposure on the IQ of children is well-known, less attention has been paid to the cumulative effects of a lifetime of exposure on older adults’ cognition and dementia,” says Fuller Thomson, director of the Institute of Life Course and Aging and professor at the Factor-Inwentash Faculty of Social Work.

“Given previous levels of lead exposure, we believe further exploration of the of this hypothesis is warranted.”

Leaded gasoline was a ubiquitous source of air pollution between the 1920s and 1970s. As it was phased out, beginning in 1973, levels of lead in citizens’ blood plummeted.

Research from the 1990s indicates that Americans born before 1925 had approximately twice the lifetime lead exposure as 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 U of T’s Faculty of Medicine. “Back then, 88 percent of us had blood lead levels above 10 micrograms per deciliter.

To put this numbers in perspective, during the Flint Michigan water crisis of 2014, one percent of the children had blood lead levels above 10 micrograms per deciliter.”

Lead is a known neurotoxin that crosses the blood-brain barrier.

Animal studies and research on individuals occupationally exposed to lead suggest a link between lead exposure and dementia.

Other studies have shown a higher incidence of dementia among older adults living closer to major roads and among those with a greater exposure to traffic-related pollution.

Fuller-Thomson and Deng are particularly interested in a potential link between lifetime lead exposure and a recently identified subtype of dementia: Limbic-predominant Age-related TDP-43 Encephalopathy (LATE), whose pathological features have been identified in 20 percent of dementia patients over the age of 80.

Research from the 1990s indicates that Americans born before 1925 had approximately twice the lifetime lead exposure as those born between 1936 and 1945.

Other plausible explanations for the improving trends in dementia incidence include higher levels of educational attainment, lower prevalence of smoking, and better control of hypertension among older adults today compared to previous generations.

However, even when these factors are statistically accounted for, many studies still find incidences of dementia declining.

The authors suggest that next steps to assess the validity of this hypothesis could include: comparing 1990s assessment of blood lead levels to current Medicare records, assessing lead levels in teeth and tibia bones (which serve as proxies for life-time exposure) when conducting post-mortems of brains for dementia, and examining the association between particular gene variants associated with higher lead uptake and dementia incidence.

“If lifetime lead exposure is found to be a major contributor to dementia, we can expect continued improvements in the incidence of dementia for many more decades as each succeeding generation had fewer years of exposure to the neurotoxin,” says Deng.


Association between risk factors and cognitive outcomes and/or dementia

Study findings showed remarkable similarity with the majority reporting a relationship between exposure to increased risk factor load and subsequent poorer cognitive function or dementia (table 3). No clear differences of results were observed by baseline age group, that is, cohorts in midlife or late-life at baseline, or for length of follow-up, although the varied presentation of study results meant that formal statistical testing could not be performed.

Eleven articles reported a relationship between risk factors and cognitive outcomes88 89 92 93 96 98–103; three between unhealthy behaviours105–107 and poorer cognitive outcomes; three reported a relationship between protective factors97 104 109 and two between ideal health behaviours90 91 and better cognitive outcomes at follow-up.

For the remaining studies, that is, those that reported a more mixed relationship between risk factor exposure and increased risk, the Personality and Total Health study found that only reaction time showed a relationship between risk factors and cognitive outcomes108; for the Schneider et al analyses of the Washington Heights study, risk factors were only associated with a small attenuation in decline in memory measures in black participants94 and in the Cache Country study, the unhealthy behaviours plus religious belief cluster showed an increased risk of dementia, while the unhealthy behaviour, non-religious group and the healthy behaviour groups did not.95 

In addition to the Cache County study, two further studies examined the relationship between groups of co-occurring risk factors. The Supplementation en vitamines et mineraux antioxy dants study study reported that their unhealthy lifestyle latent factor was associated with poorer memory but not with executive function and that the main drivers for this association were low fruit and vegetable consumption and low physical activity.105 

The Betula Study found that varying clusters of health components (metabolic, glycaemic, lipid, thyroid, inflammatory and nutritional clusters) had varying relationships with differing cognitive abilities with the metabolic component showing the strongest relationships99 (table 3).

Finally, results were essentially consistent across the studies with more than one publication. The Whitehall study found a relationship between increased risk factor exposure and different measures of cognitive decline using both latent growth curve106 and logistic regression analyses107; the Washington Heights study reported an increased risk of incident AD89 with greater numbers of risk factors and a lower risk of incident AD with greater health behaviours (diet and physical activity).97

Six studies provided various risk ratios for the impact of one, two or three or more risk factors; five for incident dementia88 93 98 100 101 (figure 2 and online supplementary text 2 show results of each meta-analysis) and three for AD (online supplementary figure 1).89 98 100 Forest plots of these showed a clear dose response such that higher numbers of risk factors were associated with an increased risk.

Based on the rare disease assumption,110 RRs, ORs and HRs were combined in two separate meta-analyses, one for dementia and the other for AD, yielding pooled ratios for presence of one, two and three or more risk factors compared with no risk factors.

A fixed effects meta-analysis was used because the number of studies was small preventing a good estimate of the between study variance, however for comparability results are also reported for a random effects model. See online supplementary text 2 for details of the meta-analyses. For dementia outcomes fixed effect pooled risk ratios for one risk factor were 1.2 (95% CI 1.0 to 1.4), for two risk factors 1.7 (95% CI 1.4 to 1.9) and for three or more risk factors 2.2 (95% CI 1.8 to 2.7).88 93 98 100 101 

Results for the random effects model did not differ. Heterogeneity was low and there was no evidence of publication bias (online supplementary text 2). For AD,89 98 100 fixed effect pooled risk ratios for one risk factor were 1.2 (95% CI 0.9 to 1.5), for two risk factors 1.8 (95% CI 1.4 to 2.3) and for three or more risk factors 1.2 (95% CI 0.2 to 6.1). The results for the random effects model were 1.2 (95% CI 0.9 to 1.6) for one risk factor, 1.8 (95% CI 1.2 to 2.8) for two risk factors and 1.5 (95% CI 0.9 to 2.5) for three or more risk factors. For AD, the heterogeneity was high and the number of constituent studies was low, restricting analysis of publication bias (online supplementary text 2).

Visual examination of the plotted results per incremental risk factor for the studies included in the meta-analysis showed no clear pattern by study baseline age, population sex distribution, length of follow-up or study covariates; however, the small numbers precluded meta-regression or other formal statistical testing-

Figure 2
Figure 2
Forest plots showing dose response for exposure to increasing numbers of risk factors and risk of incident dementia for individual studies Follow-up 27 years for the Honolulu Asia Ageing Study (HAAS) cohort, 20 years for the Uppsala cohort, ~5 years for the Kungsholmen cohort, 26.7 for the Kaiser Permanente cohort and 21 years for the Cardiovascular Risk factors Ageing and Dementia (CAIDE) cohort. RF, risk factor; RR, relative risk.

Study quality

Of the 22 articles, 14 were assessed as having an overall medium risk of bias88 92 93 95 96 98 99 101 102 104–107 109; 7 as having a low risk89 90 94 97 100 103 108 and 1 as having high risk.91 Risk of bias was assessed with regard to recruitment, exposure (eg, assessments of risk factor exposure), outcome (eg, assessment tools, use of blinded assessors) and follow-up (eg, attrition, length of follow-up) (online supplementary table 2).

Several studies analysed population-based cohorts,89 92–97 99–103 108 109 some specifying that their analyses were based on selective populations.90 91 95 96 98 101 102 105 Two studies were specifically designed to recruit selective populations; the Honolulu Asia Ageing Study which only included Japanese American men living in Honolulu88 and the Whitehall study which recruited exclusively from a civil servant population.106 107 

Two further studies recruited from previously existing healthcare provider or insurance databases.93 104 All studies used recognised and standard measures to characterise baseline risk factors, although variation in the evidence base, current guidelines and recommendations at the time of study data collection and analysis inevitably resulted in diverse risk factor definitions.

Regarding outcome measurement and length of follow-up, two studies reported follow-up likely to be <5 years, putting them at risk of reverse causality92 109; however, five studies reported long (ie, >20 years) follow-up88 90 93 96 101 and three of these reported incident dementia outcomes.88 93 101 Two studies used dementia outcomes taken from medical databases,93 104 which may have underestimated the number of cases, but all other studies used standard diagnostic criteria or standard neuropsychological tests.

The majority of studies reported on incident dementia or on change in cognitive function assessed using neuropsychological tests; however, five studies reported cognitive function only at follow-up, potentially including prevalent, rather than incident, cases of poor function.90 96 102 105 107 

The majority of studies adjusted for age, sex and education, although some carried out further adjustment for wider covariates. Finally, details of how researchers had accounted for missing data and attrition were not consistently reported with information provided in around half the articles.90 92 94 96 97 99 100 105–108

Discussion

This systematic review of the evidence base relating to intraindividual co-occurring modifiable risk factors for dementia and cognitive decline found a clear relationship between the presence of/exposure to greater numbers of baseline risk factors and an increased risk of later cognitive decline or incident dementia. The converse was also seen in identifying a relationship between greater numbers of protective factors or healthy behaviours and a reduced risk of cognitive decline or dementia.

Studies reporting risk ratios for all-cause dementia per incremental risk factor consistently demonstrated a clear dose-response relationship. When combined in a meta-analysis, a 20% increase in dementia risk with the presence of one risk factor (combined risk ratio 1.2 (95% CI 1.0 to 1.4)) was observed rising to 65% for two risk factors (1.7 (95% CI 1.4 to 1.9)). Presence of three risk factors doubled the risk of dementia with a combined risk ratio of 2.2 (95% CI 1.8 to 2.7). Fewer studies and incident cases were identified for a similar meta-analysis of AD with the dose response only being evident for the presence of one and two risk factors.

Although data relating to summed risk or protective factors showed clear relationships with cognitive outcomes, limited data were available on clustering of specific risk factors and subsequent cognitive outcomes. Only three studies used statistical clustering techniques and the methods are too diverse and the results too varied to allow conclusions to be drawn.

To our knowledge, this is the first review to examine the impact of intraindividual co-occurring modifiable risk factors and risk of dementia and cognitive decline. As such, comparison to prior similar work in this area is difficult, however, scoring systems involving the sum, or weighted sum of individual risk factors, including both modifiable and non-modifiable risk factors, have been widely used in other areas such as cancer,111 all-cause mortality112 and, especially, cardiovascular disease.113 

A recent systematic review reported on 363 such cardiovascular disease risk scores or models114 and several such cardiovascular and other scores have also been used to predict dementia outcomes.46 

Our findings are congruent with such scoring systems and are biologically plausible with higher numbers of vascular risk factors in midlife associated with elevated amyloid deposition in addition to vascular damage.115 What our findings add is the first quantifiable estimation of the impact of risk factor accrual. What we were unable to add is evidence related to particular risk factor clusters.

In fact, data on the impact of modifiable risk factor clusters are rare, although recent work on all-cause mortality found that combinations of specific risk factors, for example, physical inactivity, prolonged sitting and short or long sleep duration are associated with higher levels of mortality risk.112


Source:
University of Toronto
Media Contacts:
Esme Fuller-Thomson – University of Toronto
Image Source:
The image is in the public domain.

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

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