Table 3.

Divergence of healthy and pathological aging in structural neuroimaging studies.

Population Type	Study Type	Sample Size/Age Range	Type of Measurement	Areas Affected	Evidence for Divergence	Reference
APOE 𝜀4 carriers vs. non-carriers (all w/1st- or 2nd-degree family history of dementia)	Cross-sectional	n= 24; ages 26–45	Gray matter atrophyGray matter increase	Bilateral dorsolateral and medial frontal, anterior cingulate, parietal, and lateral temporal corticesBilateral cerebellar, middle occipital, bilateral thalamic, bilateral fusiform, right lingual gyri, and some bilateral hippocampal regions	Patterns seen in carriers compared to non-carriers	Alexander et al., 2012∗
Healthy APOE 𝜀3 homozygous adults (VL/VL vs. S/S vs. S/VL TOMM40 poly-T lengths)	Cross-sectional	n = 117 (VL/VL = 35, S/S = 38, S/VL = 44); mean age = 55	Gray matter atrophy	Medial ventral precuneus, ventral posterior cingulate	Dose-dependent effects (greater atrophy per VL allele)	Johnson et al., 2011∗
Late middle-aged adults assessed for family history of parental AD (FH) and APOE 𝜀4 genotype	Cross-sectional	n = 343; ages 47–76	White matter damage	Genu of corpus callosum, superior longitudinal fasciculusUncinate fasciculus	Higher FA in FH+Lower axial diffusivity in FH+, APOE 𝜀4-; higher axial diffusivity in FH+, APOE 𝜀4+	Adluru et al., 2014∗
APOE 𝜀4/𝜀4 vs. 𝜀3/𝜀4 vs. 𝜀3/𝜀3	Cross-sectional	n= 60; ages 49–79	White matter damage	Posterior corpus callosum, occipito-frontal fasciculus, left hippocampus	Reduced FA in carriers compared to non-carriers (ages 49–64)	Persson et al., 2006∗
APOE 𝜀4 carriers vs. non-carriers	Cross-sectional	n = 203; ages 21.1–69.9 (mean = 47.6)	White matter damage	Basal temporal lobe, internal capsule, anterior parts of corpus callosum, forceps minor, superior longitudinal fasciculus, occipital and corticospinal pathways	Increased RD and MD in carriers compared to non-carriers	Westlye et al., 2012∗
Young adult vs. non-demented older adult vs. AD older adult	Cross-sectional	n = 75 (25 young, 25 non-demented older, 25 AD older); mean age young = 22, older = 77, AD older = 77)	White matter damage	Corpus callosum, lobar regions	Age affects in anterior white matter; AD-specific effects in posterior white matter	Head et al., 2004‡
Middle-aged adults assessed for parental family history (FH) of AD and APOE 𝜀4 genotype	Cross-sectional	n = 136; mean age FH+/𝜀4+ = 57.5, FH+/𝜀4- = 57.4, FH-/𝜀4+ = 55.4, FH-/𝜀4- = 58.4	White matter damage	Bilateral anterior corona radiata, left uncinate fasciculus/inferior fronto-occipital fasciculus, left superior corona radiata, left superior longitudinal fasciculus, left tapetum, bilateral posterior corona radiata, parts of the corpus callosum, right posterior cingulum, bilateral hippocampus	Reduced FA in FH+	Bendlin et al., 2010∗
Non-demented vs. AD late middle-aged adults	Cross-sectional	n = 37; mean age cognitively normal = 61.5, AD = 62.8	White matter damage	Left anterior cingulum, left posterior cingulum, bilateral descending cingulum, left uncinate tracts	Reduced FA in AD compared to cognitively normal	Zhang et al., 2009∗
Young adult vs. MCI vs. non-demented older adult vs. mild AD	Cross-sectional	n = 372; mean age young = 22.2, MCI = 61.4, non-demented older = 76.7, mild AD = 76.6	Network-related volume loss	Superior frontal cortices, putamen, caudateHippocampus; entorhinal, retrosplenial, posterior cingulate, precuneus cortices	Age-related changesAD-related changes	Fjell et al., 2010∗
Non-demented vs. AD older adults	Longitudinal	n = 26; mean age non-demented = 71.4, AD = 68.4	Volume loss	Right hippocampus Left hippocampus	–8.2% ± 2.6% per year in AD; -0.2 ± 1.2% per year in controls	Thompson et al., 2004‡
				Left hippocampus	–4.9% ± 1.8% per year in AD; -3.8 ± 1.6% per year in controls

APOE 𝜀4, Apolipoprotein E 𝜀4 allele; TOMM-40, Translocase of the outer mitochondrial membrane poly-T polymorphism; VL, Very long poly-T allele (associated with earlier onset of AD); S, Short poly-T allele; FH, Family history of parental AD, meaning one or both of the individual’s parents has a diagnosis of AD/dementia; FA, Fractional anisotropy; MD, Mean diffusivity; aMCI, Amnestic mild cognitive impairment; RD, Radial diffusivity; ^∗reports on preclinical dementia in midlife; ^‡ shows divergence of healthy and pathological aging, one area promising for midlife effects.