Table 1: Characteristics of selecting reviewed studies.

First author
(citation no.)
Experimental methodMeasure(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 ( )
Early-stage AD ( )
APOE ε4 carrier status VO2 peak
WMS III
WAIS
MMSE
Voxel-based morphometry
Diffusion tensor imaging
Older adults aged 73.4 (6.3) 117Higher 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 statusWalking, running, and jogging questionnaire
PIB
APOE ε4 carrier status
Healthy older adults aged 55–8856Physical 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 ( )
C57Bl6/SJL nontransgenic mice ( )
56IL-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 ( )
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 ( )
Morris water maze latency
Aβ mRNA expression CXCL1 and CXCL12 protein
Tg2576 transgenic mice
C57Bl6/SJL nontransgenic mice
24Transgenic 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 activityMinnesota leisure time activity questionnaire APOE ε4 carrier statusAdults aged >653,375Adults 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 ( ) carriers versus non-ε4 carriers ( )AX-Continuous Performance Task WAIS II
Color-Word Interference Task
CVLT-II
Healthy adults mean age 64.5186There 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)347Inactive 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 volumeAPOE 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 65–8568Effects 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 66.5142BDNF 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 ( )
Control group: IgG treated rats ( )
Morris water maze latency
Place navigation test
Spatial probe test
Male Sprague-Dawley rats13BDNF 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 accessBDNF mRNA levels in cortical regionsSprague-Dawley rats392, 4 and 7 days of exercise significantly increased BDNF mRNA levels in the hippocampus and caudate.
Stranahan et al. [33]Control 1: nontransgenic mice ( )
Control group 2: nontransgenic mice with access to running wheel ( )
Experimental group 1: leptin receptor mutant (db/db) transgenic mice ( )
Experimental group 2: leptin receptor mutant (db/db) transgenic mice with access to running wheel ( )
Open field activity
Hippocampal BDNF protein levels
Male db/db transgenic mice
Male C57Bl6/SJL nontransgenic mice
48Access 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 ; Val/Met ; Val/Val ) × 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)292At 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 ; Val ) participants
Experimental group: group running session 3x per week for 4 months (Met ; Val )
2-back working memory task
Stroop task
Dots-mixed task
Maximal field track fitness test
COMT genotype
Healthy adults aged 22.7 (5.7)75Val/Val individuals in running intervention showed increased cognitive performance compared to Met carriers.
Wishart et al. [35]Cross sectional: COMT genotype (Met/Met ; Val/Met ; Val/Val ) × cognitive performanceCOMT genotype
Trail making task
Healthy adults aged 18–8595COMT 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 rats24Both 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 performanceSerum omega-3 levels
WMS-III
WASI
Stroop task
Healthy middle aged adults aged 44.6 (6.7)280Higher 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)21Omega-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 70–89228Increased 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).