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Geriatric Cognitive Decline and Polypharmacy

Editor: Kamalika Roy Updated: 4/16/2023 4:21:16 PM


With age, health-related comorbidities increase. Aging contributes to significant functional changes in organ systems and results in decreased homeostatic capacity. Aging also affects body composition, increased volume of distribution for fat-soluble drugs, reduced clearance of multiple medications. The ongoing changes in the body's physiology with aging are associated with an increased risk of adverse reactions to commonly used medications. The definition of polypharmacy is the simultaneous use of 5 or more drugs.

Mild cognitive impairment (MCI) is defined as cognitive decline more than expected for an individual's age and level of education but interfering notably with daily life activities. On the other hand, dementia is more severe and widespread with a significant effect on daily function. Multiple long-term follow-up studies have shown that most mild cognitive impairment progress to dementia or Alzheimer's dementia. People with MCI are 3 to 4 times more likely to develop dementia when compared to those with normal cognition.[1]

Polypharmacy can be appropriate and inappropriate. Inappropriate polypharmacy primarily refers to over-the-counter medications, supplements lacking evidence-based indications, and interacting with other medicines, thus doing more risks than benefits. Clinical consequences of polypharmacy in older adults are adverse drug reactions, depression, disability, falls, frailty, increased healthcare use, postoperative complications, mortality, and caregiver burden.[2]

Multiple drug-drug and drug-disease interactions are associated with polypharmacy in the elderly. Over a long time, the continued use of polypharmacy can also create new comorbidities, requiring more medications.[4] This vicious cycle makes the elderly weaker, resulting in decreased strength, falls, increased dependence on others, increased morbidity, and mortality. An Italian multicenter cohort study conducted by Trevisan C et al. studied adults with MCI for one year. About 50% of study participants took >3 drugs per day; at the end of one year, the odds of dementia were sixfold higher in this group compared with similar adults taking < 3 drugs/day.

The odds of developing dementia were eightfold higher in people with > one drug-drug interaction and a five-fold high in the anticholinergic risk scale greater than or equal to 1. Drug-drug interactions contributed to the most association (70%) between the number of medications and MCI progression to dementia. About 4% of patients with MCI progressed to dementia. Anticholinergic drugs and other drugs categorized as potentially inappropriate medications are strongly associated with cognitive impairment. Older adults using anticholinergic drugs had a more significant decline in memory, psychomotor speed, and cognitive flexibility when compared to non-users. This effect was worse in apolipoprotein ε4 carriers (at-risk population for dementia).[1]

The current evidence shows that physical frailty and cognitive impairment are very closely related. A prospective cohort study conducted by Dogrul et al. studied the association between physical frailty and cognitive function in older adults without dementia and depression and found that physically frail adults have poor MMSE and 3-word recall test scores. There is limited evidence to suggest a physiologic link between physical frailty and cognitive decline.

Based on observation studies, chronic inflammation, changes in energy metabolism, oxidative stress, and mitochondrial dysfunction in stress response contribute to cognitive decline in physically frail people. The combined physical frailty and cognitive impairment are called mental frailty associated with increased mortality. Frailty and cognitive decline are associated with increased incidence of falls and further physical injuries.[3]


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The risk factors for polypharmacy-related mild cognitive impairment are age over 65, multiple comorbidities including hypertension, diabetes, obesity, Apo ε4 carriers, cerebrovascular accidents, low socio-economic status, and lower education. Any increase in the number of medications prescribed to individuals raises the risk of unexpected drug interactions and their side effects, leading to impaired cognitive or physical capability. Over time, the cumulative exposure of multiple drugs with changes in body homeostasis with age makes the elderly vulnerable to pronounced mental and physical decline.[4]

The elderly with multiple comorbidities are at increased risk for adverse drug reactions and drug interactions because of age-related physiological changes in the body. Many patients see numerous specialists and may fill medications at various pharmacies. The complex and rapid changes in older adult's care in multiple settings by multiple providers contribute to polypharmacy and their undesirable outcomes.

Potentially inappropriate medications (PIM) like benzodiazepines, anticholinergics, antipsychotics, antidepressants, and opioids can affect cognition and frailty in the geriatric population.[5] Effective and constant communication between healthcare providers and patients and their families can help identify potentially inappropriate medications, essential in reducing polypharmacy and its complications.[6]


The US population older than 65 who take five or more prescription medications increased from 24% to 39% between 1999 and 2012. Studies estimate that nursing home patients take eight different medications on average, and medication errors occur in two-thirds of such patients. Geriatric polypharmacy is associated with increased health care utilization, costs, medication nonadherence, and functional decline.[4]

 In the US alone, there would be 72.1 million individuals aged more than 65 by 2030, which is more than double the number of older people in 2000. Older adults comprise about 15% of the total US population, but they account for 30 to 35% of prescription and nonprescription medication use. According to the published data, by 2030, the population age 65 and older will represent 20% of the US population and about 50% of healthcare costs. The current prevalence of polypharmacy is between 8 to 78% in Age group more than 65. Older adults in the US are the largest consumers of medications, making polypharmacy a significant public health problem.[7]


With age, the number of health-related comorbidities also increases. As the number of comorbidities increases, so does the number of medications. This complex relation leads to polypharmacy, a geriatric syndrome. With age elderly become frail, characterized by diminished strength and endurance, falls, increased functional dependence. Increased interleukin-6, low vitamin D levels, anemia, and abnormal brain imaging are associated with cognitive decline in the elderly. With age, people become physiologically and functionally very different due to their underlying comorbid conditions. These changes lead to varied life expectancies in older adults.[4]

The risk factors mentioned above, along with the use of multiple medications, make cognitive impairment more severe and pronounced when compared to healthy adults who are not taking any medicines.

History and Physical

A detailed history focusing on the baseline function, specifically physical and cognitive ability, should be obtained from multiple sources. Getting the list of all medications and their frequency, duration, dose titrations, if any, over-the-counter medications, including herbal supplements, should be obtained in detail. A detailed evaluation of symptoms, including fatigue, difficulty with ambulation, recent weight loss, should be obtained as a part of the geriatric evaluation. Always use the Charlson comorbidity index to assess the severity of comorbidities. Evaluating nutrition status, including self-care, feeding, good sleep, ability to take medications, maintain weight, is crucial and requires frequent evaluation. Further history should be obtained from family members if available.[8]

A general examination should include vitals, skin, head, and neck for thyroid, oral cavity. Organ system-specific examination should include a respiratory, cardiovascular, genitourinary, musculoskeletal, neurologic, and mental status examination. A detailed vision and hearing assessment should also be performed in all older adults.

There are multiple tools to evaluate cognition and physical frailty in the elderly. Cognitive impairment in older adults has multiple causes, and the most common is Alzheimer dementia. The other reasons for cognitive impairment are metabolic, endocrine, medication side effects, delirium due to infections, and depression. Identifying the cause of cognitive decline can help treat the underlying cause, comorbid conditions, utilize community support services, and create advanced directives and long-term care planning. Identifying cognitive decline during the early stages can help inappropriate referral to behavioral health specialists who can provide tools to help manage and organize memory loss. Educating caregivers with appropriate information is an integral part of evaluating cognitive decline in older adults.

The United States preventative task force does not necessarily recommend for or against the cognitive screening impairment in older adults age 65 and above, but clinicians should be vigilant to identify early signs and symptoms of cognitive impairment. Dementia screening indicators can help geriatricians and primary care providers screen for cognitive impairment in office setup. Tools like AD8, Quick Dementia Rating System (QDRS), and Mini cog (three-word registration, clock drawing, and three-word recall) can be used for dementia screening followed by a detailed evaluation.[9] 

The most commonly used cognitive performance evaluation tests are Mini-Mental score evaluation, word-learning task, verbal search speed task, Addenbrooke's cognitive examination, Frontal assessment battery, digit span backward test, and word list recall test.[10] The most commonly used physical capability tests are the chair rise test (measures number of stands per minute), walking speed (measures distance walked in meters per second), standing balance time(measured in seconds), and grip strength.[11]

The health care provider should have a clear understanding of all medications and their indications. Any change in cognition and a decrease in baseline function should raise concern for new or adjusted medication.


The geriatric assessment is multidisciplinary and multidimensional. Older adult's functional ability, cognition, mental, physical health, and social and environmental factors should be a part of complete geriatric assessment. For example, a complete geriatric assessment should be performed when a caregiver mentions changes in cognition and memory or the provider identifies a potential cognitive deficit. The focus of geriatric assessment should include appropriate diagnosis, workup, development of treatment plan, and follow-up.

Along with evaluating functional abilities like bathing, dressing, toileting, feeding, walking, shopping, doing regular household work, taking daily medications, and managing money, focus should also be on screening for age-appropriate diseases, nutrition, vision, hearing, depression, and polypharmacy. Age-appropriate screening for vision and hearing impairment and osteoporosis should be done. The benefits and harms of routine screening for cancers should be discussed with patients and care providers. Nutrition should be evaluated by history, usual food intake pattern, specific examination for signs of inadequate nutrition, and appropriate laboratory testing. Multiple studies have shown that vitamin A, B12, C, D are often deficient in older adults. Mineral elements like iron, calcium, and zinc are also deficient in older adults.[12]

The United states preventive services task force (USPSTF) recommends screening for depression in older adults. The most commonly used screening tests are the geriatric depression scale and the Hamilton depression scale. The positive screening test should be followed by a detailed evaluation of the severity and nature of depression. Polypharmacy is common in older adults, and about 30% of hospital admissions are related to polypharmacy and can be preventable.

Various laboratory tests are available to help diagnose cognitive decline and rule out other causes like vitamin deficiency and hormonal imbalance. The commonly ordered tests are complete blood count, blood glucose, comprehensive metabolic panel, urinalysis, toxicology screen, CSF to rule out specific infections, thyroid function test. In high-risk populations testing for nutritional deficiencies like B12 levels, HIV and syphilis should be performed. Brain imaging like CT of the head, MRI brain, electroencephalography can also be used in specific cases to rule out underlying stroke, brain mass, and seizures (epileptic and nonepileptic).[13]

To advance the dialogue on Wasteful or unnecessary medical tests, treatments, and procedures American Board of internal medicine foundation called for a 'choosing wisely' initiative. In 2013 American Geriatric Society released a choosing wisely list of '10 things clinicians and patients should question,' 7 of 10 choosing wisely recommendations are related to medication use. The challenges in medication management in older adults are multimorbidity, polypharmacy, potentially inappropriate medications(PIMS), multiple specialists, frequent hospitalizations and transitions of care, lack of high-quality evidence to guide prescribing for older adults as evidence-based guidelines rely on clinical trials that typically exclude frail and older adults. 

A core principle of management of polypharmacy in older adults is avoidance of potentially inappropriate medication use. Unfortunately, the determination of whether a medication is inappropriate is highly individualized and circumstantial. Inappropriate medicines, in general, can be found in two resources that serve as guidance on PIMS in adults. They are the BEERS criteria and the START and STOP criteria. A comprehensive medical reconciliation and medication management should be a part of office visits, hospital admission, and discharge planning at every transition point.[8]

Medication appropriateness index can be used to consider the indication for the drug, effectiveness for a specific condition, appropriate dose, and directions, clinically significant drug-drug interactions, and acceptable therapy duration. It serves as a valuable tool for measuring potentially inappropriate prescribing in older adults.

The beers criteria(initially developed by Mark H. Beers in 1991) for potentially inappropriate medication use in older adults from the American Geriatric Society list problematic medications for elderly patients. It also gives recommendations regarding drug interactions to avoid. The list of medicines keeps changing. The most recent 2019 update uses the five criteria from 2015. They are

  1. The medications should typically be avoided by the elderly.
  2. Medications should be avoided in the elderly with certain conditions.
  3. Medications with caution because of benefits that may offset risks.
  4. Medication interactions.
  5. Changes in dosing based on kidney function.

Beers criteria can be used in all out-patient, acute care, and hospital settings, and it is not used in palliative care and hospice services. In addition, the Beers criteria in the geriatrics app of the American Geriatric Society can be integrated into electronic health records to identify when an inappropriate medication is ordered.

Screening tools for older people's prescriptions( STOPP) and a screening tool to alert them to proper treatment (START) criteria were first published in 2008. Both of these two tools outline criteria for stopping and starting medications in patients older than 65. There are many categories of drugs-cardiovascular, anticoagulation, CNS and psychiatric, Etc. It has similar recommendations to the beer's criteria list, but they are more specific and explicit. The most recent update was in 2015.[14]

Treatment / Management

Once other causes of cognitive decline are ruled out, polypharmacy triggering a mild cognitive decline in the elderly should be the working diagnosis. After a thorough discussion with the patient and family, the patient's other providers' focus on adjusting medications should be an integral part of managing geriatric cognitive decline related to polypharmacy.

A clear understanding of polypharmacy and its relation to cognitive decline is essential in managing this complex geriatric syndrome. There is no specific treatment for polypharmacy-related cognitive decline.[15] The starting point is to obtain a detailed history, medical records from the hospital, pharmacy, and controlled substance refill reporting. The brown bag assessment is the gold standard for medication reconciliation where patient brings everything they are taking in a brown bag to the appointment including hospital visits.[16]

Deprescribing - Total number of medications taken by patients is the single most important predictor of inappropriate medication use. Deprescribing has been demonstrated as a helpful tool in the optimization of medication management. The goal is to target one drug at a time. First, look for medications that have no valid reason for being used, assess risk versus benefit, and prioritize removing medicines with the lowest help with high risk. Avoid prescribing cascade (when medications are used to treat the side effects of other medications) and new to market medications. If the patient takes over-the-counter herbal or supplement products, assess their efficacy and safety. Always run patients' prescription and over-the-counter medicines, herbal products, and accessories through a point of care interaction checker in an app or online.[16] 

Studies have demonstrated that deprescribing is feasible in the clinical setting, especially when it incorporates patient preferences, shared decision making, and an interdisciplinary team. Medication-specific algorithms can facilitate deprescribing in the clinical environment.[17]

Creating a systematic method to address polypharmacy in older patients by properly performing medical reconciliation during every visit, minimizing the use of potentially inappropriate medications, and ensuring appropriate monitoring can help improve long-term outcomes and avoid medication-related adverse events and cognitive decline. Polypharmacy contributes to significant medical and economic burdens on patients and their families, and providers should use patient-focused approaches. Discussing alternative nonpharmacologic methods to treat simple symptoms should be a priority. The goal in managing polypharmacy is to improve and optimize patients' overall function and quality of life.[18]

Differential Diagnosis

The relation between polypharmacy and mild cognitive impairment is a challenging diagnosis. It requires thorough evaluation to rule out other organic causes, including depression, hypothyroidism, B12 deficiency, chronic alcoholism, Parkinson's disease. Once the diagnoses mentioned earlier are excluded, polypharmacy should be considered a cause of mild cognitive impairment.[19]


The prognosis of mild cognitive impairment in the context of polypharmacy, in general, is favorable. Identifying the appropriate drug and risk factors and managing the underlying organic cause with alternative medications when feasible should be strongly considered. Isolated polypharmacy as a sole cause of mild cognitive impairment without other risk factors should recover well once the offending agent is identified and removed. The natural aging process, presence of diabetes, hypertension, and cerebrovascular disease might contribute to cognitive decline over time.[4]


Polypharmacy, old age, underlying frailty pose multi-level challenges in the management of complications. Complications of polypharmacy include adverse drug reactions(ADRs), falls resulting in head injury, mild cognitive impairment with and without behavioral changes, and dementia.

Polypharmacy can lead to ADRs from multiple drug interactions, herbal supplements, and over-the-counter medications. The most predominant risk factor for ADRs is the number of drugs taken, i.e., more the medicines, the risk of ADRs increases exponentially. Other adverse events from polypharmacy include decreased medication compliance resulting in worsening of underlying medical problems, poor quality of life, increased office visits, unnecessary drug costs, excessive healthcare expenses, hospital admissions, and even death.[20]


Geriatricians and pharmacists should always be consulted by primary care physicians when in doubt about older adults' medications and drug interactions.

Deterrence and Patient Education

Management of polypharmacy and mild cognitive impairment requires a team approach. Involving patient, family, home-care nurse, primary care physician, geriatrician, pharmacist should be a part of the team in managing this complex health situation. Every drug should be assessed for indication, interactions with other medications. All short and long-term adverse events should be thoroughly discussed and then be prescribed appropriately. A close follow-up on daily living and cognition should be assessed periodically and communicated with the care providers.

Pearls and Other Issues

The elderly taking at least five medications are at increased risk of mild cognitive impairment and dementia. Polypharmacy is associated with adverse drug reactions leading to falls, cognitive dysfunction, and death. Age, polypharmacy, head injury, and cerebrovascular accidents are associated with a decline in cognitive capacity. Every attempt should be made to reduce medication over-prescription. Identifying and avoiding polypharmacy has better outcomes in elderly patients and helps improve their quality of life. Thorough medication review plays an essential part in management to prevent adverse effects caused by polypharmacy in older adults.[21]

Enhancing Healthcare Team Outcomes

In the current medical practice, providers, patients, and their family members must clearly understand the risk and benefits of each drug the patient is taking. Unfortunately elderly have multiple comorbidities requiring multiple medications given by multiple practitioners at numerous times. Proper coordination and communication between providers, pharmacists, patient's and their family members are crucial in avoiding any unwanted complications from polypharmacy.



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