TABLE 3.

Previously reported metabolite associations for identified HCHS/SOL metabolite associations with cognitive functions

Present study			Previously reported metabolite associations
Metabolite	APOE Ɛ4 stratum	Effect	Citation	Outcome	Effect	Study population	Note
MCI‐associated metabolites in SOL‐INCA
Glycodeoxycholatesulfate	Non‐carriers	Increased risk	Mahmoudian Dehkordi et al., 2019 36	AD	Increased risk	ADNI cohort, N = 1464	A serum metabolite, observed with increased levels in AD patients compared to cognitively normal elderlies and associated with worse cognitive function.
9,10‐DiHOME	Non‐carriers	Decreased risk	Kim, et al., 2019 37	Central Nervous System (CNS) Aβ	Decreased risk	Europeans with MCI, n = 236	A plasma metabolite associated with lower central nervous system Aβ in MCI patients.
Glycolithocholic acid 3‐sulfate	Non‐carriers	Increased risk	Mahmoudian Dehkordi et al., 2019 36	AD	Increased risk	ADNI cohort, N = 1464	A serum metabolite, observed with increased levels in AD patients compared to cognitively normal elderlies and associated with worse cognitive function.
3‐hydroxy‐3‐methylglutarate	carriers	Decreased risk	McFarlane et al., 2019 27	AD	Decreased risk	Review	Retrospective studied show lower AD prevalence among patients on 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitors, commonly known as statins. This metabolite inhibits the cholesterol biosynthesis activity of HMG‐CoA, thus acting as a statin.
1‐palmitoleoyl‐GPC (16:1)	Non‐carriers	Increased risk	Shi et al., 2019; 38 Dong et al., 2021 39	Processing speed test; CNS t‐tau	Increased risk	Bogalusa Heart Study, White and African Americans, n = 1177	A serum metabolite associated with processing speed, and a cerebrospinal fluid metabolite associated with t‐tau measured in CNS.
Isocitrate	Carriers	Increased risk	González‐Domínguez et al., 2015 29	AD	Increased risk	Europeans, N = 44	A serum metabolite associated with AD.
Global cognitive change‐associated metabolites in SOL‐INCA
Kynurenine	Combined	Decreased risk	Tanaka et al., 2020 40	AD, vascular cognitive dementia (VCD)	Increased risk	Review	Elevated levels of the metabolite have been observed in patients with AD and VCD, in serum, or brain tissue.
Methylguanine	Combined	Decreased risk	Shi et al., 2019 38	Digit coding test	Increased risk	Bogalusa Heart Study, Whites and Blacks, n = 1177	A serum metabolite negatively associated with digit coding test scores.
Quinolinate a	Combined	Decreased risk	Schwarcz et al., 2017 32	Neurodegenerative diseases	Increased risk	Review	Interacts with the immune system contributing to neuronal damage.
Creatinine	Non‐carriers	Decreased risk	Tsuruoka et al., 2013 41	Dementia	Increased risk	Japanese, n = 19	A serum metabolite increased in dementia patients compared to controls.
Gamma‐glutamylleucine	Non‐carriers	Decreased risk	Jeitner et al., 2013 42	Neurodegenerative diseases	Increased risk	Review	Gamma‐glutamylamines isoforms of this metabolite are found to have increased levels in major neurodegenerative disorders.
Gamma‐glutamylvaline	Non‐carriers	Decreased risk	Jeitner et al., 2013 42	Neurodegenerative diseases	Increased risk	Review	Gamma‐glutamylamines isoforms of this metabolite, are found to have increased levels in major neurodegenerative disorders.
N‐acetylcarnosine	Non‐carriers	Decreased risk	Berezhnoy et al., 2019 43	Neurodegenerative diseases	Decreased risk	Review	Carosine, an isoform of this metabolite, presents a therapeutic neuroprotective effect for neurodegenerative disorders.
Thymol sulfate	Non‐carriers	Decreased risk	Azizi et al., 2012 44	Cognitive impairment	Decreased risk	Rats	Thymol treatment is associated with enhanced cognitive activity in rat models of dementia.

Notes: In a case where an association was discovered in both the combined cohort and one of the strata (i.e., methylguanine, kynurenine, and quinolinate), we report the direction in the combined cohort.

^a Quinolinate was associated with both MCI and global cognitive change.

Abbreviations: Aβ, amyloid beta; AD, Alzheimer's disease; APOE, apolipoprotein E; CNS, central nervous system; HCHS/SOL, Hispanic Community Health Study/Study of Latinos; MCI, mild cognitive impairment; SOL‐INCA, Study of Latinos‐Investigation of Neurocognitive Aging; t‐tau, total tau.