Dementia Prevention: Pipe Dream vs Possibility

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Case Vignette 

“Janet” is a 72-year-old married woman and a retired high school counselor. She has treated hypertension and dyslipidemia, mild hearing loss, and is sedentary and 20 lb overweight. Her mother and maternal grandmother died of dementia in their early 80s. She has noticed short-term memory loss (forgetting some recent events, slower word finding) and wants to know whether she should be concerned now and, going forward, what her risk of dementia is and what she can do to reduce that risk.

Understanding Dementia

TABLE 1. Differential Diagnosis of Dementia Subtypes

The cognitive domains affected by dementia include memory, learning, executive function, language, orientation, attention, and visuospatial function. The most common underlying etiologies of dementia are Alzheimer disease (AD), which accounts for 60% of all cases; vascular dementia (VaD); and mixed AD and VaD; followed by dementia with Lewy bodies and cognitive impairment associated with Parkinson disease (Table 1). Dementia is typically preceded by the transitional clinical syndrome, mild cognitive impairment (MCI), which is characterized by a loss of cognitive abilities that is not sufficient to cause significant functional impairment, differentiating it from dementia. About 10 million Americans have MCI, and approximately 5% to 10% of individuals with MCI progress to dementia annually.¹

Relatively rare autosomal dominant, fully penetrant genetic mutations cause AD dementia before the age of 60, accounting for less than 5% of all AD cases. Age is one of the greatest risk factors for the more common form of sporadic or late-onset AD dementia. About 5% of individuals aged 60 to 64 years are affected, increasing to more than 45% of those over age 85.² Carriage of 1 copy of the APOE e4 allele increases the risk of AD dementia by about 3-fold; carriage of 2 copies increases the risk over 10-fold.³ Other risk factors include gender, cerebrovascular disease, diabetes, obesity, sleep, and physical, cognitive, and social activity levels.^4-6 For clinical assessment of suspected cognitive impairment, see the review articles summarized in the Figure.^7,8

FIGURE. Work-Up for Suspected Cognitive Impairment^7,8

Issues in Prevention

Are there medical treatments to prevent dementia? About 10 trials have been completed in cognitively unimpaired individuals at risk for both autosomal dominant AD and sporadic AD; however, none have succeeded. There are 3 active prevention trials for late-onset AD, with readouts expected beginning in 2027.^9,10 If any of these trials are positive, it could be a game-changer. This will not help Janet, but it could be a resource down the road.

Are there other ways to prevent dementia? Based on the 2024 Lancet Commission Report on Dementia Prevention, Table 2 summarizes other major risk factors for dementia in general and the percent reduction in dementia prevalence if a risk factor could be eliminated.¹¹ Some of these factors (eg, education, air pollution) are relevant at a societal level; the others mainly at an individual level. If all risk factors were fully addressed, about 45% risk reduction could be achieved—a remarkable figure. Some of these factors have been addressed in clinical trials. For example, the SPRINT-MIND trial showed that assertive treatment of hypertension reduced incident cognitive impairment in older individuals by nearly 20% in just 3 years.¹²

TABLE 2. 2024 Lancet Commission Report on Dementia Prevention: Risk Factors¹¹

Exploring the Case Vignette

Janet expressed cognitive concerns, so a medical evaluation was warranted (see Figure for a schematic summary). As part of the evaluation, the clinician took a careful history, addressing whether she had developed any cognitive, functional, and/or neuropsychiatric features such as depression, even if subtle, as well as a focused neurocognitive review of systems addressing issues such as abnormal movements, focal motor or sensory features, head trauma, and toxin exposure. A neurological examination was recommended to address focal findings such as abnormal tone, gait, sensation, or reflexes.¹³ Similarly, without routine laboratory studies in the past year, one was needed to ensure she did not have an emerging medical problem such as hypothyroidism or B₁₂ deficiency. An office-based standardized cognitive test (eg, Montreal Cognitive Assessment [MoCA], Mini Mental Status Exam [MMSE], or St Louis University Mental Status Exam) was essential to quantify the cognitive deficits. (The most commonly used assessments are the MMSE and MoCA. The MoCA is more sensitive and comprehensive in identifying cognitive decline than the MMSE.¹⁴)

The evaluation results. Janet had no other cognitive concerns beyond worry about her short-term memory. She had no decline in her ability to function on a daily basis, including complex activities such as managing her financial and legal affairs. She did not report the presence of any neuropsychiatric features. Medical history and family history were confirmed. She took olmesartan 40 mg/d and atorvastatin 20 mg/d. The pertinent review of systems was unrevealing except for mild hearing loss and nearsightedness. Her general physical exam was normal except for a blood pressure of 140/80 mm Hg, reduced high-frequency hearing, a body mass index of 30, and a waist circumference of 36 inches. Her neurological exam was normal. Mental status exam was normal except for mild anxiety about her cognitive status. Her MoCA total score was 28, with 1 error in short-term recall and 1 error in cube drawing. Routine labs were negative or normal except for a fasting glucose of 108, hemoglobin A_1C of 6.0, and triglycerides of 170. She underwent a formal neuropsychological assessment, which did not reveal significant cognitive impairment.

Determining the diagnoses. Based on these findings, the diagnosis was subjective cognitive impairment (ICD 10 code R41.81), partially treated hypertension, partially treated dyslipidemia, obesity, borderline diabetes, mild vision impairment, and mild high-frequency hearing loss. She did not meet the criteria for MCI, as her detailed objective testing was normal.

Exploring Next Steps

In a case like this, the next step would be to educate the patient about other diagnostic options. Structural neuroimaging, such as brain MRI, may be useful in identifying potentially treatable causes of cognitive impairment, such as an operable tumor or normal pressure hydrocephalus, and in identifying specific patterns observed in different neurocognitive disorders. We did not recommend a brain MRI in this case, as she lacked objective evidence of cognitive impairment. This decision could be debated, and some clinicians might have ordered an MRI. We noted that repeat formal neuropsychological evaluation in the future could be considered if she showed subsequent evidence of decline.

Patients like Janet may eventually want to learn about the pros and cons of undergoing APOE genotyping. This is not to be undertaken lightly. Expert guidance notes that this requires an assessment of psychological readiness, potential insurability issues, family risk implications, and so on.¹⁵ We typically do not perform such testing clinically except for someone with known AD who is being evaluated for treatment with newly approved biologic therapies for AD, where risk is influenced by APOE4 carriage. Although we would not recommend current US Food and Drug Administration (FDA)–approved biomarker testing for AD pathology (with PET scan or spinal fluid testing, which is relevant chiefly for individuals with symptoms due to AD), she may wish to know about these options and know that FDA- approved blood biomarker tests may become available in the next 1 to 3 years. These tests would not likely be relevant for her in the absence of objective cognitive impairment; however, if one of the AD prevention therapies currently under investigation proves safe and effective and is approved by the FDA, she might consider one of these diagnostic options later on.

There are FDA-approved therapies for memory loss, including the cholinesterase inhibitors and memantine, which are FDA approved for the treatment of AD dementia, as well as 2 different monoclonal antibodies against amyloid (lecanemab and donanemab) that are FDA approved for MCI or mild dementia due to AD (and require proof of elevated brain amyloid). Janet is not a candidate for these because she lacks objective evidence of cognitive impairment.

Discussion: Reducing Risk

At present, no approved preventive therapies exist for a patient like Janet. She could consider participating in clinical research, such as natural history studies or, if available, prevention trials. Beyond that, Table 2 provides a good road map for education and counseling.¹¹

We would recommend a few follow-up assessments and interventions in such a case. Janet should work with her doctor to ensure that her blood pressure and lipids are controlled properly. Since both hearing and vision impairment are risk factors for future dementia, we would urge her to have an audiology and updated vision evaluations. Nutritional counseling and an exercise program would be ideal to help her achieve gradual weight loss and optimize brain health. Finally, Janet might look for ways to optimize social stimulation, for which evidence also suggests protection against future cognitive decline. Although not flagged by the Lancet Commission as known modifiable risk factors, other guidelines point to the importance of intellectual stimulation and sleep hygiene.^16-19

Concluding Thoughts

Janet met the criteria for subjective cognitive impairment, which is not related to progressive cognitive deterioration in most individuals but could be an early indicator of future cognitive decline.²⁰ She was counseled on several known contributors to impaired brain health: blood pressure, dyslipidemia, excess weight, lack of exercise, hearing loss, and possibly impaired vision. If addressed, this could potentially help protect against future MCI or dementia. Janet was advised about dementia prevention research options near her. She wanted to be informed if new AD prevention therapies became approved so that she could be evaluated for eligibility.

MCI and dementia are common, and their incidence and prevalence are rising sharply. Psychiatrists and other mental health professionals are on the front lines for recognizing who may be at risk for these conditions, facilitating evaluations for those with known concerns, offering education and counseling about emerging diagnostic technologies and therapies, and providing evidence-based counseling regarding nonmedication risk-reduction strategies. Lastly, we may be a few short years from having FDA-approved blood tests to diagnose AD changes in the brain, even before patients develop symptoms, and FDA-approved preventive therapies. Dementia prevention is indeed a possibility.

Dr Joshi is a geriatric psychiatrist at Banner Alzheimer’s Institute and an assistant clinical professor at University of Arizona, College of Medicine-Phoenix. Dr Tariot is the director at Banner Alzheimer’s Institute and has served in this position since its inception in 2006, in addition to his roles as a clinician, researcher, and leader. He serves as codirector of the international Alzheimer’s Prevention Initiative.

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