14 Sep 2023

Physical activity staves off dementia, but does that mean being sedentary makes cognitive decline more likely? Yes, according to David Raichlen, University of Southern California, Los Angeles, and colleagues. In the September 12 JAMA, the scientists reported that, among almost 50,000 people, being inactive for 15 hours per day tripled dementia risk over seven years compared to the group’s average of nine hours of sitting a day.

“Sitting all day long deteriorates pretty much all biological systems in the body, including the brain,” wrote Borja del Pozo Cruz, University of Southern Denmark in Odense, to Alzforum (comment below).

The study implies that exercise benefits the brain. “Moving and engaging in physical activities as much as possible is very important for physical and cognitive health in old age,” wrote Kumar Rajan, Rush University, Chicago.

Exactly how might exercise protect the brain? On this separate but related research question, scientists led by Rudolph Tanzi and Se Hoon Choi at Massachusetts General Hospital, Charlestown, offered a molecular mechanism pointing to protection from the effects of brain amyloid deposition. In the September 8 Neuron, they reported that the exercise-induced hormone irisin reduces soluble Aβ in vitro by binding to integrin receptors on astrocytes, which prompted release of the Aβ protease neprilysin.

Previously, Raichlen and others had found that certain self-reported sedentary behaviors, such as watching TV, raised the risk of future dementia (Raichlen et al., 2022; Bakrania et al., 2018). However, a more recent study led by Steve Nguyen, University of California San Diego, La Jolla, of almost 1,300 women who wore accelerometers to track their activity reported no such link (Nguyen et al., 2023).

To conduct a larger data-driven study that goes beyond self-reporting by collecting physical activity data, first author Raichlen analyzed accelerometer and clinical data from 49,841 cognitively normal U.K. Biobank participants aged 60 and older. Fifty-four percent were women; 97 percent were white. Participants wore an activity tracker on their wrists 24 hours a day for three days to a week, then were followed for an average of seven years to see who developed all-cause dementia; 414 did.

The scientists used a previously developed machine-learning algorithm to decipher when people were sedentary or active. They had trained the algorithm to identify 30-second bouts as active or not based on annotated accelerometer data from 152 U.K. Biobank participants who also donned a wearable camera and kept a time diary (Walmsley et al., 2021). 

The new study showed that people sat for about nine hours a day, on average. Sitting for 12 hours per day increased all-cause dementia risk by 63 percent, while sitting for 15 hours came with a whopping 3.2-fold higher risk.

“The size of the study, the mean length of follow-up, and the careful statistical analyses covarying for usual demographic factors make the findings plausible,” wrote Henry Brodaty, University of New South Wales, Sydney. Nguyen agreed. “Higher sedentary behavior is associated with higher risk of cardiovascular disease, which, in turn, is associated with higher dementia risk,” he wrote (comments below).

This study suggests that getting off the couch helps maintain a sharp mind, adding to a growing body of evidence (Sep 2022 news; Aug 2021 news; Sep 2019 news).

Some research even suggests that physical activity may protect the brain from amyloid accumulation and its effects (Jul 2019 conference news). How could that be?

In their new paper, Tanzi and Choi implicate the Aβ endopeptidase neprilysin and the hormone irisin, both of which rise in the brain after exercise in mouse models of amyloidosis (Maesako et al., 2012; Moore et al., 2016; Oct 2013 news). Irisin protected the mice from synaptic and memory deficits (Jan 2019 news).

To see if irisin and neprilysin interact, first author Eunhee Kim and colleagues used three-dimensional co-cultures of human neurons, astrocytes, and oligodendrocytes, all carrying APP Swedish, APP London, and presenilin 1 ΔE9 mutations, that the group had previously developed (Oct 2014 news; Sep 2023 news). These cultures make copious amounts of Aβ and hyperphosphorylated tau. After treating 3.5-week-old three-dimensional cultures with irisin for 10 days, Kim saw fewer dystrophic neurites, measured less Aβ40, Aβ42, and phospho-tau in the media, and detected twice as much soluble neprilysin.

Co-treating with the neprilysin inhibitor sacubitril, a vasodilator used in clinical practice, ramped up soluble Aβ42 levels, suggesting that the enzyme is crucial to irisin’s amyloid-lowering ability. Sacubitril is a component of the heart failure drug Entresto, and has been shown to change patients’ plasma Aβ42/40 ratio (Dec 2022 conference news).

Since astrocytes make neprilysin, might irisin prompt them to pump out the enzyme? Indeed, when Kim tested this hunch by applying irisin to human iPSC-derived astrocytes, they released neprilysin. In the three-dimensional cultures, Kim spotted astrocytes highly expressing integrin β5, an irisin receptor in bone and fat cells, suggesting this may be how the hormone acts on these brain cells too (Kim et al., 2018). 

In the cultures, irisin activated this integrin receptor, as evidenced by increased phosphorylation of its downstream signaling proteins. Blocking integrin β5, either by treating with an inhibitor or knocking down its gene, prevented irisin from lowering soluble Aβ42 and raising neprilysin expression.

To the authors, these results mean that irisin binds the integrin receptor on astrocytes, stirring them to release neprilysin and degrade Aβ (see image above). “This beautiful study adds insight into the neuroprotective mechanisms of irisin in Alzheimer’s experimental models,” wrote Fernanda De Felice of Queen’s University, Ontario, Canada (comment below).—Chelsea Weidman Burke

News Citations

1. Can 10,000 Steps a Day Keep Dementia at Bay? 23 Sep 2022
2. Can Exercise Protect People Whose Plasma Tau Is Up? 27 Aug 2021
3. “Runner Plasma” Jogs Neurogenesis, Quells Neuroinflammation in Mice 27 Sep 2019
4. Physical Activity May Shield the Brain from the Onslaught of Aβ 25 Jul 2019
5. Does Peripheral Hormone Control Expression of Brain Trophic Factor? 11 Oct 2013
6. Could the Purported Muscle Exercise Hormone, Irisin, Jog Memory? 16 Jan 2019
7. Alzheimer’s in a Dish? Aβ Stokes Tau Pathology in Third Dimension 10 Oct 2014
8. In 3D Cell Model of AD, Microglia and CD8+ T Cells Gang Up on Neurons 1 Sep 2023
9. Blood Amyloid Test May Help Diagnose Alzheimer’s, but Questions Remain 29 Dec 2022

Mutations Citations

1. APP K670_M671delinsNL (Swedish)
2. APP V717I (London)
3. PSEN1 c.869-22_869-23ins18 (ΔE9)

Paper Citations

1. Raichlen DA, Klimentidis YC, Sayre MK, Bharadwaj PK, Lai MH, Wilcox RR, Alexander GE.
   Leisure-time sedentary behaviors are differentially associated with all-cause dementia regardless of engagement in physical activity.
   Proc Natl Acad Sci U S A. 2022 Aug 30;119(35):e2206931119. Epub 2022 Aug 22
   PubMed.
2. Bakrania K, Edwardson CL, Khunti K, Bandelow S, Davies MJ, Yates T.
   Associations Between Sedentary Behaviors and Cognitive Function: Cross-Sectional and Prospective Findings From the UK Biobank.
   Am J Epidemiol. 2018 Mar 1;187(3):441-454.
   PubMed.
3. Nguyen S, LaCroix AZ, Hayden KM, Di C, Palta P, Stefanick ML, Manson JE, Rapp SR, LaMonte MJ, Bellettiere J.
   Accelerometer-measured physical activity and sitting with incident mild cognitive impairment or probable dementia among older women.
   Alzheimers Dement. 2023 Jan 25;
   PubMed.
4. Walmsley R, Chan S, Smith-Byrne K, Ramakrishnan R, Woodward M, Rahimi K, Dwyer T, Bennett D, Doherty A.
   Reallocation of time between device-measured movement behaviours and risk of incident cardiovascular disease.
   Br J Sports Med. 2021 Sep 6;56(18):1008-17.
   PubMed.
5. Maesako M, Uemura K, Kubota M, Kuzuya A, Sasaki K, Hayashida N, Asada-Utsugi M, Watanabe K, Uemura M, Kihara T, Takahashi R, Shimohama S, Kinoshita A.
   Exercise Is More Effective than Diet Control in Preventing High Fat Diet-induced β-Amyloid Deposition and Memory Deficit in Amyloid Precursor Protein Transgenic Mice.
   J Biol Chem. 2012 Jun 29;287(27):23024-33.
   PubMed.
6. Moore KM, Girens RE, Larson SK, Jones MR, Restivo JL, Holtzman DM, Cirrito JR, Yuede CM, Zimmerman SD, Timson BF.
   A spectrum of exercise training reduces soluble Aβ in a dose-dependent manner in a mouse model of Alzheimer’s disease.
   Neurobiol Dis. 2016 Jan;85:218-24. Epub 2015 Nov 10
   PubMed.
7. Kim H, Wrann CD, Jedrychowski M, Vidoni S, Kitase Y, Nagano K, Zhou C, Chou J, Parkman VA, Novick SJ, Strutzenberg TS, Pascal BD, Le PT, Brooks DJ, Roche AM, Gerber KK, Mattheis L, Chen W, Tu H, Bouxsein ML, Griffin PR, Baron R, Rosen CJ, Bonewald LF, Spiegelman BM.
   Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors.
   Cell. 2018 Dec 13;175(7):1756-1768.e17.
   PubMed.

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