Potential Moderators of Physical Activity on Brain Health

Table 1

Characteristics of selecting reviewed studies.

First author; (citation no.)	Experimental method	Measure(s)	Population mean age; (standard deviation)	N	Significant finding(s)
APOE as variable of interest
Honea et al. [25]	Cross sectional: APOE ε4 carrier status, dementia status × global connectivity, GM volume, cognitive performance, and fitness; Nondemented (𝑛=56); Early-stage AD (𝑛=61)	APOE ε4 carrier status VO2 peak; WMS III; WAIS; MMSE; Voxel-based morphometry; Diffusion tensor imaging	Older adults aged 73.4 (6.3)	117	Higher aerobic fitness levels were related to greater brain volume in the medial temporal lobe in early AD patients.
Liang et al. [26]	Cross sectional: APOE ε4 carrier status × fitness, biomarker risk status	Walking, running, and jogging questionnaire; PIB; APOE ε4 carrier status	Healthy older adults aged 55–88	56	Physical activity was associated with reduced plaque deposition in APOE ε4 carriers.
Nichol et al. [27]	Control 1: nontransgenic mice; Control 2: Tg2576 mice; Experimental group 1: nontransgenic mice with 3 weeks access to running wheel; Experimental group 2: Tg2576 mice with 3 weeks access to running wheel	IL-1β; TNA-α; Aβ	Tg2576 transgenic mice (𝑛=29); C57Bl6/SJL nontransgenic mice (𝑛=27)	56	IL-β and Aβ fibrils are significantly lower in transgenic mice with access to running wheel than transgenic control mice.
Parachikova et al. [28]	Control 1: nontransgenic mice (𝑛=6); Control 2: Tg2576 mice (𝑛=6); Experimental group 1: nontransgenic mice with 3 weeks access to running wheel (𝑛=6); Experimental group 2: Tg2576 mice with 3 weeks access to running wheel (𝑛=6)	Morris water maze latency; Aβ mRNA expression CXCL1 and CXCL12 protein	Tg2576 transgenic mice; C57Bl6/SJL nontransgenic mice	24	Transgenic mice with voluntary exercise performed significantly better on Morris water maze than control transgenic mice showed no increase in inflammatory markers and increased mRNA production of CXCL1.
Podewils et al. [29]	Cross sectional: APOE ε4 carrier status × onset of dementia × physical activity	Minnesota leisure time activity questionnaire APOE ε4 carrier status	Adults aged >65	3,375	Adults who engaged in regular physical activity had significantly reduced risk of developing AD after a 5-year follow-up than those who were sedentary. ε4 carriers showed no significant changes in risk associated with increased participation in physical activity.
Reinvang et al. [30]	Cross sectional: APOE ε4 (𝑁=69) carriers versus non-ε4 carriers (𝑁=117)	AX-Continuous Performance Task WAIS II; Color-Word Interference Task; CVLT-II	Healthy adults mean age 64.5	186	There is a negative relationship between ε4 carrier status and performance on working memory tasks where ε4 carriers performed worse than noncarriers.
Schuit et al. [21]	Cross sectional: activity status × APOE ε4 carrier status, cognition; Inactive group: self-report less than 1 hr/day physical activity; Active group: more than 1 hr/day physical activity	MMSE; APOE ε4 allele carrier status	Healthy older adult males 74.6 (4.3)	347	Inactive group showed significant decrease in MMSE score over 3 years. APOE ε4 carriers showed significantly steeper decline than ε4 noncarriers.
Smith et al. [15]	Cross sectional: APOE ε4 carrier status × fitness, cognitive function, fMRI connectivity, and grey matter volume	APOE ε4 carrier status; Stanford Brief Activity Survey; MMSE; Mattis Dementia Rating Scale 2; Rey auditory verbal learning test; Geriatric depression scale; Whole-brain event-related fMRI; Voxel-based morphometry	Healthy older adults aged 65–85	68	Effects of PA on task-related activation were reliably more pronounced in APOE-ε4 carriers with no significant differences in grey matter volume.
BDNF as variable of interest
Erickson et al. [31]	Cross sectional: BDNF serum levels × grey matter volume, spatial memory performance	BDNF serum levels MRI first segmentation; Spatial memory task	Healthy older adults mean age 66.5	142	BDNF levels mediated the relationship between the significant decline in hippocampal volume as a function of age.
Mu et al. [32]	Experimental group: rats treated with BDNF antibody (𝑛=7); Control group: IgG treated rats (𝑛=6)	Morris water maze latency; Place navigation test; Spatial probe test	Male Sprague-Dawley rats	13	BDNF antibody treated rats had longer learning latencies and spatial memory performance.
Neeper et al. [22]	Cross sectional: 0, 2, 4, or 7 days of running wheel access	BDNF mRNA levels in cortical regions	Sprague-Dawley rats	39	2, 4 and 7 days of exercise significantly increased BDNF mRNA levels in the hippocampus and caudate.
Stranahan et al. [33]	Control 1: nontransgenic mice (𝑛=12); Control group 2: nontransgenic mice with access to running wheel (𝑛=12); Experimental group 1: leptin receptor mutant (db/db) transgenic mice (𝑛=12); Experimental group 2: leptin receptor mutant (db/db) transgenic mice with access to running wheel (𝑛=12)	Open field activity; Hippocampal BDNF protein levels	Male db/db transgenic mice; Male C57Bl6/SJL nontransgenic mice	48	Access to a running wheel increased hippocampal BDNF levels in both wild type and transgenic mice.
COMT as variable of interest
de Frias et al. [34]	Longitudinal: COMT genotype (Met/Met (𝑛=26); Val/Met (𝑛=46); Val/Val (𝑛=23)) × cognitive performance over 5-year period with 2 time points (0 and 5 years)	COMT genotype; Verbal fluency; Working memory task; Tower of Hanoi task; WAIS block design task	Healthy adult males aged 58.1 (12.86)	292	At baseline, COMT Met/Met group performed better than the Val/Val and Val/Met variants on executive function tasks and block design. Greater executive function decline after a 5-year follow-up in Val/Val individuals.
Stroth et al. [23]	Control: nonintervention (Met 𝑛=19; Val 𝑛=9) participants; Experimental group: group running session 3x per week for 4 months (Met 𝑛=33; Val 𝑛=14)	2-back working memory task; Stroop task; Dots-mixed task; Maximal field track fitness test; COMT genotype	Healthy adults aged 22.7 (5.7)	75	Val/Val individuals in running intervention showed increased cognitive performance compared to Met carriers.
Wishart et al. [35]	Cross sectional: COMT genotype (Met/Met (𝑛=26); Val/Met (𝑛=46); Val/Val (𝑛=23)) × cognitive performance	COMT genotype; Trail making task	Healthy adults aged 18–85	95	COMT Met/Met participants showed increased performance on trails B task than Val/Val or Val/Met genotypes.
Omega-3 fatty acid as variable of interest
Chytrova et al. [24]	Control: regular diet, no access to running wheel; Experimental group 1: regular diet, access to running wheel; Experimental group 2: DHA-enriched diet, no access to running wheel; Experimental group 3: DHA-enriched diet, access to running wheel	Morris water maze latency; Hippocampal levels of STX-3, STX-1, NR2B, and GAP-43	Male Sprague-Dawley rats	24	Both DHA and access to running wheel increased levels of NR2B, STX-3, and Morris water maze learning.
Muldoon et al. [36]	Cross sectional: serum omega-3 fatty acid levels × cognitive performance	Serum omega-3 levels; WMS-III; WASI; Stroop task	Healthy middle aged adults aged 44.6 (6.7)	280	Higher levels of DHA correlated to increased performance on several cognitive measures, specifically working memory.
Oksman et al. [37]	Control: standard diet; Experimental group 1: high omega-6 diet; Experimental group 2: high omega-3 diet	Morris water maze latency; Aβ42 levels and plaques	Female F3 or F4 generation Transgenic mice (APPswe/PS1dE9)	21	Omega-3 enriched diet decreased Aβ42 levels compared to the two control diets.
van Gelder et al. [38]	Longitudinal: omega-3 fatty acid levels × cognitive function over 5 year period with 2 time points (0 and 5 years)	Dietary questionnaire; MMSE	Healthy older Dutch males aged 70–89	228	Increased omega-3 fatty acid consumption was associated with smaller decline in cognitive function at 5-year followup.

Citation, experimental procedures, subject information, sample size, and main significant findings, are outlined for studies that have been highlighted as exemplary in text.
Weschler Memory Scale III (WMSIII), Weschler Abbreviated Scale of Intelligence (WASI), California Verbal Learning Test II (CVLTII), and Pittsburgh Compound B (PIB).