Alzheimer’s and Comorbidities: Implications for Patient Care

Alzheimer’s disease (AD), the most common cause of dementia, is the fifth leading cause of death in the United States. An estimated 6.9 million Americans aged 65 years or older have AD. Comorbid conditions in AD may exacerbate the progression of dementia and negatively affect overall health.
Although the exact mechanisms remain unclear, systemic inflammation is thought to play a significant role in the development of many common comorbidities associated with AD. Among the most frequently observed comorbid conditions are hypertension, diabetes, and depression. The presence of these comorbidities affects the treatment and management of AD, underscoring the need to understand the mechanisms of their interrelationship and develop effective management strategies. 
Hypertension is a well-established risk factor for numerous health conditions, including AD. A comprehensive review of five meta-analyses and 52 primary studies revealed that elevated systolic blood pressure (SBP) correlates with an 11 % increased risk of developing AD, raising the question of whether early intervention and control of blood pressure would mitigate the risk for AD later in life. 
Findings from the Northern Manhattan Study suggest that although elevated SBP contributes to cognitive decline in older patients, the use of antihypertensive medications can neutralize the effects of high SBP on certain cognitive functions. Furthermore, a systematic review and meta-analysis comprising 12 trials (92,135 participants) demonstrated a significant reduction in the risk for dementia and cognitive impairment with antihypertensive treatment.
Notably, a retrospective cohort study involving 69,081 participants treated with beta-blockers for hypertension found that beta-blockers with high blood-brain barrier permeability were associated with a reduced risk for AD compared with those with low blood-brain barrier permeability. Additionally, a secondary analysis of the SPRINT trial found antihypertensive medications that stimulate vs inhibit type 2 and 4 angiotensin II receptors were associated with a lower incidence of cognitive impairment. Although further clinical trials are necessary to directly assess specific medications, these findings emphasize the potential of antihypertensive treatment as a strategic approach to reduce the risk for AD.
The connection between AD and type 2 diabetes is such that AD is sometimes referred to as “type 3 diabetes.” Both diseases share some of the same underlying pathophysiologic mechanisms, particularly the development of insulin resistance and oxidative stress. A prospective cohort study of 10,095 participants showed that diabetes was significantly associated with a higher risk of developing dementia; this risk is even greater in patients who develop diabetes at an earlier age.
In an interview with Medscape, Alvaro Pascual-Leone, MD, PhD, a professor of neurology at Harvard Medical School, commented, “In addition to being a comorbidity factor, diabetes appears to be a predisposing risk factor for AD.” This is supported by a comprehensive literature review showing an increased progression from mild cognitive impairment (MCI) to dementia in patients with diabetes, prediabetes, or metabolic syndrome, with a pooled odds ratio for dementia progression in individuals with diabetes of 1.53.
Owing to the overlapping pathophysiologic mechanisms in AD and diabetes, treating one condition may have beneficial effects on the other. A systematic umbrella review and meta-analysis that included 10 meta-analyses across nine classes of diabetes drugs found a protective effect against dementia with the use of metformin, thiazolidinediones (including pioglitazone), glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors. Moreover, a cohort study of 12,220 patients who discontinued metformin early (ie, stopped using metformin without a prior history of abnormal kidney function) and 29,126 patients considered routine users found an increased risk for dementia in the early terminator group. Although further research is warranted, the concurrent treatment of AD and diabetes with antidiabetic agents holds considerable promise.
Anxiety and depression are significant risk factors for AD, and conversely, AD increases the likelihood of developing these psychiatric conditions. A systematic review of 14,760 studies showed dysthymia often emerges during the early stages of AD as an emotional response to cognitive decline. 
Data from the Australian Imaging Biomarkers and Lifestyle study showed a markedly elevated risk for AD and MCI among individuals with preexisting anxiety or depression. This study also found that age, sex, and marital status are important determinants, with men and single individuals with depression being particularly susceptible to developing AD. Conversely, a cohort study of 129,410 AD patients with AD, 390,088 patients with all-cause dementia, and 3,900,880 age-matched controls without a history of depression showed a cumulative incidence of depression of 13% in the AD group vs 3% in the control group, suggesting a heightened risk for depression following an AD diagnosis. 
These findings underscore the importance of targeted screening and assessment for patients with anxiety and depression who may be at risk for AD or those diagnosed with AD who are at risk for subsequent depression and anxiety. Although antidepressants are effective in treating depression in general, their efficacy in AD-related depression is of variable quality, probably owing to differing pathophysiologic mechanisms of the disease. Further research is necessary to explore both pharmacologic and nonpharmacologic interventions for treating depression in AD patients. Some studies have found that cognitive behavioral-therapy can be effective in improving depression in patients with AD.
Research has shown a strong correlation between AD and sleep disorders, particularly obstructive sleep apnea, insomnia, and circadian rhythm disruptions. Additionally, studies suggest that insomnia and sleep deprivation contribute to increased amyloid beta production and tau pathology, hallmark features of AD. A scoping review of 70 studies proposed that this relationship is mediated by the glymphatic system (glial-dependent waste clearance pathway in the central nervous system), and that sleep deprivation disrupts its function, leading to protein accumulation and subsequent neurologic symptoms of AD. Another study showed that sleep deprivation triggers glial cell activation, initiating an inflammatory cascade that accelerates AD progression.
Given that the gold standard treatment for obstructive sleep apnea is continuous positive airway pressure (CPAP), it has been hypothesized that CPAP could also alleviate AD symptoms owing to shared pathophysiologic mechanisms of these conditions. A large systemic review found that CPAP use improved AD symptoms in patients with mild AD or MCI, though other sleep interventions, such as cognitive-behavioral therapy and melatonin supplementation, have yielded mixed outcomes. However, most studies in this area are small in scale, and there remains a paucity of research on treating sleep disorders in AD patients, indicating a need for further investigation.
Although no direct causative link has been established, research indicates an association between osteoarthritis (OA) and dementia, likely because of similar pathophysiologic mechanisms, including systemic inflammation. Longitudinal analyses of data from the Alzheimer’s Disease Neuroimaging Initiative study found cognitively normal older individuals with OA experience more rapid declines in hippocampal volumes compared to those without OA, suggesting that OA may elevate the risk of cognitive impairment. Current treatments for OA, such as nonsteroidal anti-inflammatory drugs, glucocorticoids, and disease-modifying OA drugs, might also help alleviate AD symptoms related to inflammation, though the research in this area is limited.
AD has also been linked to osteoporosis. In a longitudinal follow-up study involving 78,994 patients with osteoporosis and 78,994 controls, AD developed in 5856 patients with osteoporosis compared with 3761 patients in the control group. These findings represent a 1.27-fold higher incidence of AD in patients with osteoporosis than in the control group, suggesting that osteoporosis might be a risk factor for AD.
Additionally, research has identified a relationship between AD and increased fracture risk and decreased bone mineral density , with AD patients exhibiting a significantly higher likelihood of bone fractures compared with those without AD. “Falls and fractures, aside from the risk they pose in all geriatric patients, in individuals with cognitive impairment — whether due to AD or another cause — have higher risk to cause delirium and that can result in greater morbidity and mortality and a lasting increase in cognitive disability,” stated Dr Pascual-Leone. Current recommendations emphasize exercise and fall prevention strategies to reduce fracture risk in patients with AD, but there is a lack of comprehensive research on the safety and efficacy of osteoporosis medications in this population.
The intricate interplay between AD and its comorbidities highlights the need for a comprehensive and integrated approach to patient care. The overlapping pathophysiologic mechanisms suggest that these comorbidities can contribute to the evolution and progression of AD. Likewise, AD can exacerbate comorbid conditions. As such, a holistic assessment strategy that prioritizes early detection and management of comorbid conditions to mitigate their impact on AD progression would be beneficial. Dr Pascual-Leone adds, “The presence of any of these comorbidities suggests a need to screen for MCI earlier than might otherwise be indicated or as part of the treatment for the comorbid condition. In many cases, patients can make lifestyle modifications that improve not only the comorbid condition but also reduce its effect on dementia.” In doing so, healthcare providers can help improve patient outcomes and enhance the overall quality of life for individuals living with AD.