Late-Life Low BP, Weight Loss, High Blood Sugar Precede Dementia

Batya Swift Yasgur, MA, LSW

July 30, 2018

Individuals with elevated blood glucose level, low blood pressure (BP), and weight loss in late life are at higher risk for dementia, new research suggests.

Investigators studied almost 4000 people, including individuals with dementia and healthy control persons, over a 14-year period.

They found that compared to control persons, body mass index (BMI) declined and BP rose more slowly in those with prodromal dementia, whereas blood glucose levels increased in those who developed dementia.

"This study showed that demented persons presented a BMI decline and lower blood pressure — specifically, systolic blood pressure [SBP] — several years before dementia diagnosis that might be a consequence of underlying disease," lead author Maude Wagner, MPH, a PhD candidate at the University of Bordeaux and the Bordeaux Population Health Research Center, France, told Medscape Medical News.

"In contrast, [dementia patients] presented consistently higher blood glucose levels up to 14 years before dementia, suggesting that high glycemia is a strong risk factor for dementia," she said.

The study was published online July 24 in JAMA Psychiatry.

Midlife vs Late Life

Several cardiometabolic risk factors have been identified as being associated with increased dementia risk, including overweight/obesity, hypertension, hypercholesterolemia, and diabetes at midlife, the authors write.

Previous studies of the trajectories of risk factors during the long period preceding dementia diagnosis have been limited, and no large cohort study examined the trajectories of all main cardiovascular risk factors concurrently during those years.

"Many studies have shown associations between cardiometabolic health and dementia in midlife, but associations later in life remain inconclusive," Wagner remarked.

"This study aimed to model concurrently and to compare the trajectories of major cardiometabolic risk factors in the 14 years before diagnosis among cases of dementia and controls," she said.

The researchers used a case-control approach to contrast trajectories between individuals who developed dementia and control persons and to identify time lags when their trajectories differed significantly.

Participants were drawn from the Three-City study, an ongoing prospective study that started in 1999 and includes 9294 noninstitutionalized participants (aged 18 years and older) from three French cities.

Participants were interviewed at baseline and at follow-up visits every 2 to 3 years until 2014.

The researchers matched each dementia patient to four control persons at the diagnosis visit.

Inclusion in the control sample required that the individual be free of dementia at the matching visit, be from the same cohort center as the case patient, and be of similar sex, age (±3 years), and educational level.

Among the 841 incident cases that were identified in the initial sample, 783 patients were successfully matched to four control persons, "leading to a nested, case-control study sample of 3925 individuals," the authors report.

Trajectories of cardiometabolic variables were investigated through repeated measure of BMI, SBP, diastolic BP (DBP), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and blood glucose levels.

After excluding from the initial cohort those who missed follow-up visits or failed to undergo cardiometabolic measurement, the final sample consisted of 785 patients with incident cases of dementia (68.4% with Alzheimer's disease, and 20.6% with vascular dementia) and 3140 control persons (65% women; mean age, 76 years; SD, 5 years).

Key Components

At baseline, the incident case patients were more often carriers of the ε4 allele of the APOE gene, had slightly lower scores on the Mini–Mental State Examination, and had similar smoking status in comparison with control persons.

Although the two groups were similar with respect to most cardiometabolic risk factors and medication use at baseline, more of the case patients had diabetes or had undergone treatment for diabetes.

In the case patients as well as the control persons, mean BMI declined significantly over time, although the decline was more pronounced among the case patients (P < .001 for group-by-time interaction).

The BMI of case patients was initially slightly higher than the predicted level of the control persons 14 years prior to the matching visit but dropped below the BMI of the control persons about 7 years before diagnosis. The values were significantly different 2.4 years before the matching visit (BMI, 25.1 for case patients vs 25.5 for control persons; P = .05).

Mean BMI values 14 years before diagnosis (-14 years) and at diagnosis (year 0) for case patients were 26.1 (95% confidence interval [CI], 25.6 - 26.5) and 24.8 (95% CI, 24.5 - 25.1), respectively, vs 25.7 (95% CI, 25.4 - 26.1) and 25.3 (95% CI, 25.0 - 25.5) for control patients.

In both groups, the SBP increased significantly over time (P < .001 for time and time2 parameters).

For case patients, mean SBP at -14 years and at year 0 was 135.2 mm Hg (95% CI, 131.8 - 138.7) and 142.1 mm Hg (95% CI, 140.3 - 143.9), respectively; for control persons, mean SBP at -14 years and at year 0 was 135.8 mm Hg (95% CI, 132.9 -138.6) and 144.9 mm Hg (95% CI, 143.7 - 146.1), respectively.

There was also a significant group-by-time interaction (P = .049); however, the increase was slower for case patients than for control persons and showed a significant divergence 3.4 years prior to diagnosis.

Unlike SBP, DBP trajectories decreased for both groups (P = .02 for time and time2 parameters).

Although the shape of the DBP decline did not differ significantly overall between groups (P = .58 for group-by-time interaction), a significant difference was found between case patients and control persons up to 8.7 years before diagnosis.

On the other hand, glycemia level was higher among case patients (mean fasting glucose values at -14 years and year 0: 89.4 mg/dL [95% CI, 86.9 - 92.1] and 96.4 mg/dL [95% CI, 93.7 - 99.3], respectively, for case patients and 87.1 mg/dL [95% CI, 85.1 - 89.2] and 95.3 mg/dL [95% CI, 93.5 - 97.1] mg/dL, respectively, for control persons.

Predicted glucose levels were consistently higher among case patients vs control persons during the study period, with significant differences in a large window spanning 1.6 years to 14.0 years before the matching visit.

There were no significant case-control differences in trajectories of blood lipid levels.

Neither polypharmacy at baseline nor factor-specific medication during follow-up were differentially associated with the trajectories of biological factors, "suggesting that medication had little association with the differential trajectories between cases and controls," the authors commented.

"BMI declined in prodromal dementia, possibly reflecting early preclinical changes," they suggest.

"Lower BP prior to dementia may reflect both a consequence and a contributing factor for the disease, whereas higher blood glucose levels may constitute a risk factor for dementia in the older age range," they noted.

"These findings emphasize that blood glucose control, low blood pressure, and weight loss could be key components of cardiovascular health management for primary and secondary prevention of dementia in older persons," Wagner commented.

She noted that although hypertension and obesity are generally considered to be risk factors for dementia, "these factors are causal risk factors in midlife, but at the approach of diagnosis, the underlying disease can impact metabolism and therefore decrease BMI and BP."

At the same time, "for BP — specifically, SBP — low levels can also generate, for example, hypoperfusion that can increase the risk of dementia," she said.

Trajectory of Change

Commenting on the study for Medscape Medical News, Ruth Peters, PhD, the University of New South Wales, Sydney, Australia, and Neuroscience Research Australia, who was not involved with the study, said that it "adds to a growing evidence base which points to the importance of taking trajectory of change into account."

She cautioned that, as stated by the authors, "the commonly observed fall in BP and BMI in the years preceding a diagnosis of dementia is likely, for the most part, to represent reverse causality."

Nevertheless, the study has important implications for practicing clinicians because "it reinforces the importance of understanding risk factor history," she said.

Wagner added that future research will focus on life-course epidemiology and seek to "extend these trajectories to midlife or even before" and will also seek to "evaluate the combined effects of these factors."

The Three-City Study is conducted under a partnership agreement between the Institut National de la Sant. et de la Recherche M.dicale and is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l’Education Nationale, Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research-INSERM Programme Cohortes et collections de données biologiques, French National Research Agency Cognition, Anti-Oxydants, Acides Gras: Approche Interdisciplinaire de le Nutrition dans le Vieillissement Cérébral the Fondation Plan Alzheimer, and the Caisse Nationale pour la Solidarit. et l’Autonomie. The authors of the study and Dr Peters have disclosed no relevant financial relationships.

JAMA Psychiatry. Published online July 24, 2018. Full text

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