Late-onset Alzheimer's disease (AD) is the most prevalent cause of dementia among older adults, yet more than a century of research has not determined why this disease develops. One prevailing hypothesis is that late-onset AD is caused by infectious pathogens, an idea widely studied in both humans and experimental animal models. This review examines the infectious AD etiology hypothesis and summarizes existing evidence associating infectious agents with AD in humans. The various mechanisms through which different clinical and subclinical infections could cause or promote the progression of AD are considered, as is the concordance between putative infectious agents and the epidemiology of AD. We searched the PubMed, Web of Science, and EBSCO databases for research articles pertaining to infections and AD and systematically reviewed the evidence linking specific infectious pathogens to AD. The evidence compiled from the literature linking AD to an infectious cause is inconclusive, but the amount of evidence suggestive of an association is too substantial to ignore. Epidemiologic, clinical, and basic science studies that could improve on current understanding of the associations between AD and infections and possibly uncover ways to control this highly prevalent and debilitating disease are suggested.

PTSD diagnosis is associated with an increased risk for dementia diagnosis that varied with receipt of psychotropic medications. Further research would help to delineate if these findings are due to differences in PTSD severity, psychiatric comorbidity, or independent effects of psychotropic medications on cognitive decline.

IntroductionEmerging evidence indicates associations between extra-central nervous system (CNS) bacterial infections and an increased risk for dementia; however, epidemiological evidence is still very limited.MethodsThis study involved a retrospective cohort of a national sample of US veterans (N = 417,172) aged ≥56 years. Extended Cox proportional hazard models adjusted for demographic characteristics and medical and psychiatric comorbidities determined the associations between systemic and localized extra-CNS bacterial infections occurring >2 years before the initial dementia diagnosis and the risk for dementia.ResultsExposure to any extra-CNS bacterial infection was associated with a significantly increased risk for dementia (hazard ratio [HR] = 1.20 [95% confidence interval = 1.16–1.24]). Independently, septicemia (HR = 1.39 [1.16–1.66]), bacteremia (HR = 1.22 [1.00–1.49]), osteomyelitis (HR = 1.20 [1.06–1.37]), pneumonia (HR = 1.10 [1.02–1.19]), urinary tract infections (HR = 1.13 [1.08–1.18]), and cellulitis (HR = 1.14 [1.09–1.20]) were associated with a significantly increased risk for dementia.DiscussionBoth systemic and localized extra-CNS bacterial infections are associated with an increased risk for developing dementia.

Background Comparator selection is an important consideration in the design of observational research studies that evaluate potential associations between drug therapies and adverse event risks. It can affect the validity of observational study results, and potentially impact data interpretation, regulatory decision making, and patient medication access. Objective The aim of this study was to assess the impact of comparator selection bias using two real-world case studies evaluating an increased rate of acute myocardial infarction (AMI). Methods Data from the Truven Health Analytics MarketScan ® electronic medical claims database were used to conduct two retrospective observational cohort studies, utilizing a cohort new-user design, comparing AMI risk between testosterone replacement therapy (TRT) and phosphodiesterase-5 inhibitors (PDE5is) in men treated for hypogonadism, and triptans versus other prescribed acute treatments for migraine in adults. All patients were enrolled continuously in a health plan (no enrollment gap > 31 consecutive days) for ≥ 1 year before index. Baseline period was defined as 365 days prior to index. Exposure was defined by prescription and outcome of interest was defined as occurrence of AMI. Using Cox proportional hazard models, primary analysis for the TRT cohort compared AMI risk between propensity score (PS)-matched TRT-treated and untreated patients; secondary analysis evaluated risk between PS-matched TRT-treated and PDE5i-treated patients. For the triptan cohort, primary analysis compared AMI/ischemic stroke risk between PS-matched triptan-treated and opiatetreated patients; secondary analysis evaluated risk between PS-matched triptan-treated and nonsteroidal anti-inflammatory drug (NSAID)-treated patients and PS-matched non-prescription-treated migraine patients and general patients. Results No significant association between TRT and AMI was observed among TRT-treated (N = 198,528, mean age 52.4 ± 11.4 years) versus PDE5i-treated men (N = 198,528, mean age 52.3 ± 11.5 years) overall (adjusted hazard ratio [aHR] 1.01; 95% CI 0.95-1.07; p = 0.80). Among patients with prior cardiovascular disease (CVD), risk of AMI was significantly increased for TRT-treated versus PDE5i-treated patients (aHR 1.13; 95% CI 1.03-1.25). The triptan study included three comparisons (triptans [N = 436,642] vs prescription NSAIDs [N = 334,152], opiates [N = 55,234], and untreated migraine [N = 1,168,212]), and a positive control (untreated vs general non-migraine patients [N = 11,735,009]). Analyses of MI risk in migraine patients prescribed triptans versus NSAIDs/opiates had mixed results: the point estimate ranged from 0.33 to 0.84 depending on chosen study window. Conclusions Cardiovascular outcomes were not worse in hypogonadism patients with TRT versus PDE5i; however, a potential association with AMI was found in patients with prior CVD receiving TRT versus PDE5i. Findings pointed to a pseudoprotective effect of triptans versus untreated migraine patients or those potentially older and less health...

Analysis of the associations between PTSD and psychotropic PTSD medication use with the risk for dementia showed a significant association between PTSD and the risk for dementia (HR=1.35; 95%CI=1.27-1.43) after adjustment for demographic characteristics, medical and psychiatric comorbidity, and health care utilization. Analysis of the impact of psychotropic PTSD medications including selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), benzodiazepines (BZA), novel antidepressants (NA) and atypical antipsychotics (AA) on the association between PTSD and the risk for dementia showed significant interactions between PTSD and use of SSRIs (p<.0001), NAs (p=.0016), and AAs (p<.0001). Multivariate analysis showed a significant association between PTSD and an increased risk for dementia among individuals not using any psychotropic PTSD medications at baseline (HR=1.70; 95%CI=1.58-1.82). PTSD patients using SSRIs (HR=2.10; 95%CI=1.82-2.41), NAs (2.19; 95%CI=1.94-2.48) or AAs (4.56; 95%CI=4.04-5.15) were significantly more likely to develop dementia compared to those without PTSD and not using any psychotropic PTSD medications. PTSD patients using SSRIs (HR=1.24; 95%CI=1.08-1.42), NAs (HR=1.29; 95% CI=1.14-1.46) or AAs (HR=2.69; 95%CI=2.38-3.04) were also significantly more likely to develop dementia compared to those with PTSD and not using any psychotropic PTSD medications. SNRI (HR=1.35; 95%CI=1.26-1.46) and BZA drug use (HR=1.40; 95%CI=1.35-1.45) at baseline was associated with an increased risk for dementia regardless of PTSD diagnosis. These findings indicate; 1) evidence for an infectious AD etiology hypothesis in inconclusive, 2) both severe (e.g. sepsis), and less severe (e.g. cellulitis) systemic bacterial infections are collectively and independently associated with an increased risk of dementia among older U.S. veterans hence prevention of systemic bacterial infections could positively influence the risk for dementia among older adults, and 3) PTSD and psychotropic medication use are associated with an increased risk for dementia among U.S. veterans. Further epidemiologic, clinical, and basic science research is required to elucidate the mechanisms and the associations between infections and the risk for vi dementia and to determine if the independent and effect modifying impacts of psychotropic PTSD medication use on the risk for dementia are related to differences in PTSD severity, other psychiatric comorbidity, or whether psychotropic PTSD medication use is an independent risk factor for dementia. vii