A large prospective study of middle-aged and older women found no convincing evidence that using proton pump inhibitors increased their risk of dementia, investigators reported.

However, using H2 receptor antagonists for at least 9 years was associated with a slight decrease in scores of learning and working memory (mean decrease, –0.2; 95% confidence interval, –0.3 to –0.08; P less than .001), Paul Lochhead, MBChB, PhD , and his associates wrote in the October issue of Gastroenterology ( doi: 10.1053/j.gastro.2017.06.061 ). “Since our primary hypothesis related to PPI [proton pump inhibitor] use, our findings for [H2 receptor antagonists] should be interpreted with caution,” they said.

In a recent German study of a medical claims database, use of PPIs was associated with a 44% increase in the likelihood of incident dementia ( JAMA Neurol. 2016;73:410-6 ). “The existence of a causal mechanism linking PPI use to dementia is suggested by observations from cellular and animal models of Alzheimer’s disease, where PPI exposure appears to influence amyloid-beta metabolism,” Dr. Lochhead and his associates wrote. “However, other preclinical data on PPIs and Alzheimer’s disease are conflicting.” Noting that cognitive function predicts dementia later in life, they analyzed prospective data on medications and other potential risk factors from 13,864 participants in the Nurses’ Health Study II who had completed Cogstate , a computerized, self-administered neuropsychological battery.

Study participants averaged 61 years old when they underwent cognitive testing, ranging in age from 50 to 70 years. Users of PPIs tended to be older, had more comorbidities, were less physically active, had higher body mass indexes, had less education, and ate a lower-quality diet than women who did not use PPIs. After adjusting for such confounders, using PPIs for 9-14 years was associated with a modest decrease in scores for psychomotor speed and attention (mean score difference, compared with never users, –0.06; 95% CI, –0.11 to 0.00; P = .03). “For comparison, in multivariable models, a 1-year increase in age was associated with mean score decreases of 0.03 for psychomotor speed and attention, 0.02 for learning and working memory, and 0.03 for overall cognition,” the researchers wrote.

Next, they examined links between use of H2 receptor antagonists and cognitive scores among 10,778 study participants who had used PPIs for 2 years or less. Use of H2 receptor antagonists for 9-14 years predicted poorer scores on learning, working memory, and overall cognition, even after controlling for potential confounders (P less than or equal to .002). “The magnitudes of mean score differences were larger than those observed in the analysis of PPI use, particularly for learning and working memory,” the researchers noted. Additionally, PPI use did not predict lower cognitive scores among individuals who had never used H2 receptor antagonists.

On the other hand, using PPIs for 9-14 years was associated with the equivalent of about 2 years of age-related cognitive decline, and controlling for exposure to H2 receptor antagonists weakened even this modest effect, the investigators said. Users and nonusers of PPIs tend to differ on many measures, and analyses of claims data, such as the German study above, are less able to account for these potential confounders, they noted. “Nonjudicious PPI prescribing is especially frequent among the elderly and those with cognitive impairment,” they added. “Therefore, elderly individuals who have frequent contact with health providers are at increased risk of both PPI prescription and dementia diagnosis. This bias may not be completely mitigated by adjustment for comorbidities or polypharmacy.”

The findings regarding H2 receptor antagonists reflect those of three smaller cohort studies, and these medications are known to cause central nervous system effects in the elderly, including delirium, the researchers said. Ranitidine and cimetidine have anticholinergic effects that also could “pose a risk for adverse cognitive effects with long-term use.”

Dr. Lochhead reported having no conflicts. Two coinvestigators disclosed ties to Bayer Healthcare, Pfizer, Aralez Pharmaceuticals, AbbVie, Samsung Bioepis, and Takeda.