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Frailty Moderates Link Between Alzheimer Pathology and Dementia (CME/CE)

Action Points

  • Frailty is a moderator of neuropathology and dementia in Alzheimer’s disease.
  • Understand that frailty is associated with less tolerance for a given burden of Alzheimer’s dementia.

CME Author: Vicki Brower

Study Authors: Lindsay M.K. Wallace, Olga Theou, et al.; Franceso Panza, Madia Lozupone, et al.

Target Audience and Goal Statement:

Neuropsychiatrists, neuropsychologists, psychiatrists, psychologists, gerontologists, internists, and family medicine specialists

The goal was to determine whether frailty, which is associated with age and dementia, moderates the relationship between Alzheimer’s disease (AD) and severe cognitive impairment.

Questions Addressed:

  • Does frailty, which is associated with age and dementia, moderate the relationship between AD pathology and dementia?
  • Is AD a single disease marked by genetic risk or the deposition of a particular protein, or a complex disease of aging?

Study Synopsis and Perspective:

Older individuals in this cross-sectional analysis had a higher risk of AD and disease expression when they were frail, defined via comorbidities such as joint, heart, and mobility problems, in contrast to those who were not frail. AD pathology and frailty were independently associated with Alzheimer’s dementia, but as frailty increased, the relationship between pathology and dementia weakened — suggesting that the frailer people are, the less likely they could tolerate a given burden of Alzheimer’s disease pathology, wrote Kenneth Rockwood, MD, of Dalhousie University in Halifax, Nova Scotia, and colleagues in The Lancet Neurology.

“By reducing an individual’s physiological reserve, frailty could trigger the clinical expression of dementia when it might remain asymptomatic in someone who is not frail,” Rockwood said in a statement. “This indicates that a ‘frail brain’ might be more susceptible to neurological problems like dementia as it is less able to cope with the pathological burden.”

Rockwood and colleagues used a deficit accumulation-based frailty index, incorporating 41 components of health including fatigue, joint and heart problems, osteoporosis, and mobility, with higher values indicating poorer health.

The study included 456 participants drawn from the Rush Memory and Aging Project, a community-based cohort study of older adults who agreed to annual detailed clinical examination and brain donation at the time of death. Researchers followed participants for up to 21 years until the study cutoff date of January 2017. Mean age at death was about 90, and 69% of the participants were women. Postmortem brain tissue analysis included quantitative assessments of neuritic plaques, diffuse plaques, and neurofibrillary tangles.

Just over half the sample (242 participants, or 53%) had a clinical diagnosis of possible or probable AD at their last annual clinical assessment; the remainder had no dementia. AD diagnoses were based on criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association joint working group.

Overall, 35 participants (8%) had substantial AD-related brain changes without having been diagnosed with dementia, and 50 (11%) had Alzheimer’s dementia but had little disease-related brain changes. Among people with a low burden of AD pathology, the prevalence of Alzheimer’s dementia was higher in those who had high frailty than those with low frailty (69% vs 5%).

Frailty (OR 1.76, 95% CI 1.54–2.02; P<0.0001) and Alzheimer's pathology (OR 4.81, 95% CI 3.31–7.01; P<0.0001) were each independently associated with Alzheimer's dementia, after adjusting for age, sex, and education. When frailty was added to the model for the relationship between Alzheimer's pathology and dementia status, the model fit improved.

There was a significant interaction between frailty and Alzheimer’s disease pathology (OR 0.73, 95% CI 0.57–0.94; P=0.015 for interaction), the researchers found. The frailty–pathology interaction remained significant after excluding activities of daily living (such as shopping, handling finances, and meal preparation) from the frailty index variables and controlling for the effects of risk factors linked to both frailty and Alzheimer’s disease pathology (like history of stroke, hypertension, diabetes, congestive heart failure, or depression).

Rockwood and colleagues concluded that “frailty plays a key role in the natural history of Alzheimer’s disease,” based in part on the observation that not everyone who has neuropathological evidence of AD is diagnosed with the disease at autopsy (or before), and conversely, that individuals who receive an AD diagnosis do not necessarily have the neuropathological evidence of the disease. Therefore, there must be a mediating factor or factors which push individuals toward the expression of the disease, rather than one necessary and sufficient cause. This team of researchers concluded that the comorbidities underlying frailty may function precisely in that role. Their AD concept is that AD dementia is a complex disease of aging, rather than a single disease entity characterized by plaques and tangles, and that there may be ways to moderate risk in elderly people.

They note that their hypothesis follows an emerging concept in which multiple factors work together to give rise to dementia.

Source References: The Lancet Neurology 2019; 18:177-184

Editorial: The Lancet Neurology 2019; 18:133-134

Study Highlights: Explanation of Findings

Researchers found that individuals with AD but a low burden of AD pathology had the highest frailty scores, “suggesting that Alzheimer’s disease pathology is implicated in dementia expression in this group.” Frailty might reduce the threshold of AD pathology needed to cause clinical disease, or it could be a marker of impaired repair processes that might otherwise allow for AD pathology to be better tolerated, they wrote. Frailty levels were no higher than average in those without AD but with a high burden of AD pathology. “Taken together, these results suggest that the frailer an individual is, the less likely they are to tolerate a given burden of AD pathology.” the authors wrote. Thus, they conclude that frailty is a substantial moderator in the relationship between AD pathology and dementia status; increasing frailty weakens the relationship between Alzheimer’s disease pathology and dementia.

“Frailty is a crucial intermediate state of the aging process, characterized by an increased risk of negative health-related events,” noted Francesco Panza, MD, PhD, of the University of Bari Aldo Moro, in Bari, Italy, and co-authors in an accompanying editorial. It is the accumulation of these events, such as stroke, hypertension, diabetes, congestive heart failure, and history of depression, which pushes an individual toward expression of AD.

They explained that three main approaches to defining frailty are commonly used: “The first approach is based on the notion of a physical and biological frailty phenotype, for which the operational definition assumes that there is a state of negative energy balance, sarcopenia, diminished muscle strength, and low tolerance for exertion. An alternative, and potentially complementary, definition of frailty is provided by the so-called deficit accumulation model, which incorporates several factors ranging from disease states, symptoms, and signs, to abnormal laboratory values.”

Understanding frailty may help predict and prevent dementia, Panza and co-authors observed. But the vulnerability of older adults at risk of developing dementia is not completely captured by deficit-accumulation measurements.

The third approach, the editorialists stated, is based on the biopsychosocial model and mixes physical and psychosocial domains. This model may best help assess individuals and target interventions in patients with frailty, although the editorialists write that “this model is not fully operationalised.”

In light of what is known about the cognitive frailty phenotype, secondary preventive strategies for cognitive impairment and physical frailty are possible, Panza and colleagues added. “For instance, individualized multi-domain interventions can target physical, nutritional, cognitive, and psychological domains that might delay the progression to overt dementia and secondary occurrence of adverse health-related outcomes, such as disability, hospitalization, and mortality.” For example, a 24-month structured, moderate intensity physical activity program was shown to reduce the severity of “cognitive frailty” when compared to a health education program for sedentary seniors.

Rockwood and co-authors noted several limitations to their research: the data were cross-sectional, and as such, causal inferences cannot be drawn. Since frailty measurements at the participants’ last assessment were taken within a year of death, frailty states may reflect terminal decline. Competing risks are also a potential limitation — i.e., if participants died of causes other than those related to dementia before developing dementia, the results might be confounded. The researchers also noted that they did not have access to cause of death and thus could not control for this factor.

  • Reviewed by
    Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco
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