Alzheimer’s Dementia Tied to Frailty

Frailty appeared to modify the association between Alzheimer’s disease pathology and Alzheimer’s dementia in older adults, a post-mortem analysis showed.

Both Alzheimer’s disease 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, Canada, 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.”

Frailty is a crucial 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.

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.”

The third approach, the editorialists stated, is based on the biopsychosocial model and mixes physical and psychosocial domains.

The study led by Rockwood 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 analysis 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. Participants were followed 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 Alzheimer’s dementia at their last annual clinical assessment; the remainder had no dementia. Alzheimer’s dementia 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 Alzheimer’s disease-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 Alzheimer’s disease 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, 3.31–7.01; P<0.0001) were 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 (P<0.0001).

There was a significant interaction between frailty and Alzheimer’s disease pathology (OR 0.73, 95% CI 0.57–0.94; P for interaction=0.015), 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).

Understanding frailty may help predict and prevent dementia, Panza and co-authors observed. But the vulnerability of old adults at risk of developing dementia is not completely captured by deficit-accumulation measurements. While the biopsychosocial model might help assess and target frail patients better, “at present, this model is not fully operationalized,” the editorial stated.

Still, in light of what is known about the cognitive frailty phenotype, secondary preventive strategies for cognitive impairment and physical frailty are possible, Panza et al. 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.”

Rockwood and co-authors noted several limitations to their research: the data were cross-sectional and 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.