How is it that some people can have a brain full of plaques and tangles, yet somehow fend off dementia? By way of explanation, the concept of cognitive reserve tends to come up and now, two new postmortem studies suggest that physical fitness plays a role. In the February Lancet Neurology, researchers led by Kenneth Rockwood of Dalhousie University in Halifax, Nova Scotia, reported that people with plaques and tangles were more likely to have had dementia if they had also been frail. On January 16 in Neurology, researchers led by Aron Buchman at Rush University Medical Center in Chicago reported that being physically active correlated with better cognition, even in people with neurodegenerative pathology.

  • Frail elderly are more likely to have AD pathology and dementia.
  • They are less able to tolerate plaques and tangles.
  • Levels of physical activity correlated with cognition, regardless of neuropathology.

Alzheimer’s disease develops amidst the complex backdrop of aging. People with multiple age-related morbidities, such as diabetes, heart disease, muscle weakness, fatigue, and lack of mobility, are considered frail. They are more vulnerable to further illness than their healthier counterparts. They are also at greater risk for AD pathology, cognitive decline, and dementia (Buchman et al., 2008Song et al., 2014; Buchman et al., 2014). However, studies have not teased apart whether frailty alters the relationship between AD pathology and its cognitive consequences. This is the question Rockwell and colleagues investigated.

Rockwell, first author Lindsay Wallace, and colleagues analyzed postmortem data from 456 participants in the Rush Memory and Aging Project (MAP). At their last visit before death, 242 had a diagnosis of possible or probable AD. Using information gathered from past clinical visits, the researchers calculated a frailty index for each based on a 41-item questionnaire that assessed age-related symptoms, morbidities, and functional deficits. The final score represented a fraction of the total possible deficits. For this cohort, who averaged 89.7 years of age at death, the mean frailty index was 0.42, right at the threshold between moderately and severely frail.

Compared with people who were less frail, those whose frailty was above average were older, likelier to have been diagnosed with AD dementia, and had a higher burden of Aβ plaques and tau tangles at autopsy. Thirty-five participants who had not been diagnosed with dementia, but who had a high burden of plaques and tangles, turned out to have low frailty scores. On the other side of the spectrum, 50 who had been diagnosed with dementia but had little AD pathology had the highest frailty indexes. Overall, the findings tied frailty to dementia, and suggested that less frail people are better able to withstand a given amount of AD pathology than their more fragile counterparts.

Could dementia have caused the frailty? The researchers could not rule out reverse causality with their cross-sectional data. However, they did find that the relationship among frailty, pathology, and dementia remained even when they corrected the frailty index for functional deficits that can be caused by dementia, or when they controlled for known dementia risk factors, including stroke and hypertension.

According to Rockwood, the findings suggest that the clinical manifestation of AD depends not just on its neuropathology, but also on the extent of the aging process. People age at different rates, and those who do so more rapidly will not only be more likely to develop AD pathology, but also be more sensitive to it, he said. On a positive note, Rockwood said the findings suggest that slowing the broader process of aging—via changes in lifestyle and/or anti-aging therapeutics—might also prevent dementia.

In their Neurology paper, Buchman and colleagues investigated the relationship between physical activity, cognition, and neuropathology in the same study cohort. Previous studies have correlated physical activity with cognitive function, but its relationship with neuropathology has been less certain (Mar 2016 news; Sep 2018 news). The researchers analyzed 454 MAP participants who, around two years before death, wore an accelerometer for a 10-day stint to take stock of their levels of daily activity. The meters tallied up every movement, whether a wave from the couch or a step up the stairs. The researchers also assessed the participants’ motor abilities, and found a modest correlation between those and physical activity. However, because of the all-inclusive counts, even people whose range of range of motor abilities was narrow scored all along the spectrum of daily activity levels.

Higher physical activity scores and better motor abilities independently associated with global cognitive score. The correlations were independent of neuropathology. About 85 percent of participants had evidence of two or more of either plaques, tangles, Lewy bodies, TDP-43 inclusions, nigral neuronal loss, hippocampal sclerosis, and cerebral amyloid angiopathy, any of which independently correlated with cognitive deficits. However, no combination of these affected the relationships between physical activity/motor ability and cognition. For every standard deviation increase in physical activity or motor abilities, participants had a 31 percent and 55 percent reduction, respectively, in dementia diagnosis.

Could reverse causality explain these correlations? Here, that seems unlikely, too. The correlations held even when the researchers removed from the analysis people with the lowest cognitive scores and those who were diagnosed with dementia

Buchman considers the findings empowering, especially for people who are no longer able to exercise in the classic sense. “Even if you can’t get out to the gym, you might still buffer against the consequences of neuropathology by moving around the house,” he told Alzforum.

In an accompanying editorial, James Mortimer of the University of South Florida in Tampa and Yaakov Stern of Columbia University in New York pointed out unknowns, including whether mid-life exercise correlates with late-life physical activity and dementia risk. “Although important questions remain, currently available data suggest that promotion of an active lifestyle in late as well as early life that includes regular physical activity and exercise may be beneficial in reducing the risk of dementia, both through increases in reserve and reduction of Alzheimer neuropathology,” they wrote.

Eric Larson of the Kaiser Permanente Washington Health Research Institute in Seattle thinks the studies add an important neuropathological element to decades of research linking physical activity, dementia, and frailty. “In old age when people are at risk for dementia and frailty, the extent of risk and decline are potentially modifiable through increased levels of physical activity,” he wrote.

Bruno Vellas of the University of Toulouse in France commented that frailty is a known risk factor for functional decline with aging, hence Rockwood’s findings linking frailty with cognitive decline, including in people with AD pathology, are unsurprising. He added that exercise might stave off both frailty and cognitive decline. Data from the Multidomain Alzheimer’s Preventive Trial (MAPT) suggests that frailty is a risk factor for Aβ plaques, and that multidomain interventions, including exercise, might help prevent those as well (Maltais et al., 2019).—Jessica Shugart


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News Citations

  1. Midlife Pep Does Not Curtail Alzheimer’s Biomarkers
  2. Exercise Linked to Less Pathology, Better Function in Familial AD

Paper Citations

  1. . Physical frailty in older persons is associated with Alzheimer disease pathology. Neurology. 2008 Aug 12;71(7):499-504. PubMed.
  2. . Age-related deficit accumulation and the risk of late-life dementia. Alzheimers Res Ther. 2014;6(5-8):54. Epub 2014 Sep 18 PubMed.
  3. . Brain pathology contributes to simultaneous change in physical frailty and cognition in old age. J Gerontol A Biol Sci Med Sci. 2014 Dec;69(12):1536-44. Epub 2014 Aug 18 PubMed.
  4. . Association between brain -amyloid and frailty in older adults. J Gerontol A Biol Sci Med Sci. 2019 Jan 9; PubMed.

Further Reading


  1. . Frailty is associated with incident Alzheimer's disease and cognitive decline in the elderly. Psychosom Med. 2007 Jun;69(5):483-9. PubMed.

Primary Papers

  1. . Investigation of frailty as a moderator of the relationship between neuropathology and dementia in Alzheimer's disease: a cross-sectional analysis of data from the Rush Memory and Aging Project. Lancet Neurol. 2019 Feb;18(2):177-184. PubMed.
  2. . Physical activity, common brain pathologies, and cognition in community-dwelling older adults. Neurology. 2019 Feb 19;92(8):e811-e822. Epub 2019 Jan 16 PubMed.