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Alzheimer's Association International Conference 2026

July 12-15, 2026 | London, United Kingdom, and Online

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10518

Differences In Cognitive Performance Across Atrophy-defined Alzheimer’s Disease Subtypes

Poster Presenter

Shannon Risacher

Authors

Shannon Risacher

Affiliations

Wake Forest University School of Medicine

Part of Topic

Background:

Heterogeneous atrophy-defined subtypes of have been linked to differences in cognitive decline, APOE4 genotype, and other factors [1]. We sought to define differences in demographic and cross-sectional and longitudinal change in cognition by atrophy-defined subtype in patients diagnosed with dementia due to AD from three cohorts within the Alzheimer’s Disease Sequencing Project – Phenotype Harmonization Consortium (ADSP-PHC).

Methods:

• 1978 stable AD participants were included from three ADSP-PHC cohorts, including ADNI, NACC/SCAN, and HABS-HD. 762 of these individuals were confirmed to be Aβ-positive by PET or CSF.
 
• AD patients were divided into four groups based on atrophy patterns following a method modified from [1]. Briefly, AD patients with hippocampal and cortical volume >-0.5 SD relative to CNs were assigned to a minimal atrophy (Min. Atr.) sub-group. Hippocampal to cortex volume ratio was calculated and divided into quartiles. Those in the lowest quartile were assigned considered to be Limbic Predominant (LP), the highest quartile were defined as hippocampal sparing (HpSp). The remaining two quartiles were defined as typical AD (tAD).
 
• Memory, executive function, language, and visuospatial function composite scores were generated as previously described [2]. Additional cognitive and clinical tests that were common across the cohorts were included (MoCA, Digit Span, Trail Making, CDR).
 
• Demographics and clinical/cognitive performance at the first visit diagnosed with AD (baseline for prevalent, first visit with AD diagnosis for incident) were compared between groups using an ANCOVA or chi-square tests, covaried for age, sex, and education where appropriate. Changes in longitudinal cognitive performance (up to 7 years) were assessed using linear mixed effect models, adjusted for age, sex, and education. Analyses were performed in full sample (n=1978) and the Aβ-positive only subgroup (n=762)
 

Table 1. Sample Characteristics and Cognitive Performance – Full Sample

1Mean (SD); 2Count (%)

Min. Atr.

HpSp

tAD

LP

p

Pairs (p<0.05*)

N

655

329

662

332

  

*Bonferroni corrected

Age (yrs)1

71.4 (9.85)

69.7 (10.4)

74.9 (8.45)

76.4 (7.39)

<0.001

tAD, LP>Min>HpSp

Education (yrs)1

14.6 (3.86)

15.3 (3.36)

15 (3.39)

15.2 (3.21)

0.009

HpSp>Min

Sex (Female)2

321 (49.0%)

165 (50.2%)

321 (48.5%)

146 (44.0%)

0.381

n/a

Race (White, AA, Other)2

554 (84.6%)

67 (10.2%)

34 (5.2%)

302 (91.8%)

19 (5.8%)

7 (2.4%)

591 (89.3%)

48 (7.3%)

23 (3.5%)

305 (91.9%)

22 (6.6%)

5 (1.5%)

0.003

Min. vs. HpSp, LP

Ethnicity (Non-Hisp.)2

565 (86.7%)

301 (91.5%)

603 (91.4%)

309 (93.4%)

0.002

tAD, LP, HpSp > Min.

APOE4 Genotype2

326 (55.5%)

159 (53.0%)

410 (67.2%)

201(65.7%)

<0.001

tAD, LP>Min., HpSp

Memory1

-0.60 (0.57)

-0.86 (0.66)

-0.82 (0.51)

-0.99 (0.50)

<0.001

Min.>HpSp, tAD>LP

Executive1

-0.44 (0.82)

-0.98 (0.80)

-0.57 (0.72)

-0.37 (0.77)

<0.001

Min., LP>tAD>HpSp

Language1

-0.30 (0.67)

-0.6 (0.68)

-0.43 (0.64)

-0.39 (0.63)

<0.001

Min.>tAD, LP>HpSp

Visuospatial1

0.13 (0.65)

-0.33 (0.83)

-0.05 (0.68)

-0.02 (0.67)

<0.001

Min.>tAD>HpSp; LP>HpSp

MoCA Score1

17.7 (5.25)

14.6 (6.25)

16.6 (5.07)

16.4 (4.78)

<0.001

Min.>tAD, LP>HpSp

Digit Span Forward1

6.96 (2.20)

6.28 (2.42)

6.94 (2.09)

7.21 (2.09)

<0.001

Min., tAD, LP>HpSp

Digit Span Backward1

4.51 (2.37)

3.54 (2.03)

4.49 (2.08)

4.87 (2.15)

<0.001

Min., tAD, LP>HpSp

Trail Making A1

64.10 (38.5)

81.9 (39.9)

67.2 (37.7)

56.7 (34.0)

<0.001

HpSp>LP>tAD; HpSp>Min

Trail Making B1

180 (89.2)

240 (78.1)

213 (94.1)

181 (87.4)

<0.001

HpSp>tAD>LP, Min.

CDR-global1

0.82 (0.45)

0.97 (0.54)

0.88 (0.46)

0.96 (0.52)

<0.001

LP>tAD>Min.; HpSp>Min.

CDR-sum of boxes1

4.42 (2.45)

5.43 (3.09)

4.86 (2.46)

5.39 (2.68)

<0.001

tAD>HpSp, LP>Min.

Table 2. Sample Characteristics and Cognitive Performance – Aβ+ Sample

1Mean (SD); 2Count (%)

Min. Atr.

HpSp

tAD

LP

p

Pairs (p<0.05*)

N

239

123

261

139

  

*Bonferroni corrected

Age (yrs)1

73.6 (8.44)

69.3 (9.67)

74.7 (7.94)

76.3 (7.21)

<0.001

LP>Min>HpSp; tAD>HpSp

Education (yrs)1

15.7 (3.01)

15.8 (3.45)

15.4 (3.00)

15.4 (2.93)

0.467

n/a

Sex (Female)2

116 (48.5%)

65 (52.8%)

126 (48.3%)

53 (38.1%)

0.092

n/a

Race (White, AA, Other)2

226 (94.6%)

12 (5.0%)

1 (0.4%)

115 (93.5%)

8 (6.5%)

0 (0.0%)

247 (94.6%)

12 (5.0%)

1 (0.4%)

133 (95.7%)

6 (4.3%)

0 (0.0%)

0.697

n/a

Ethnicity (Non-Hisp.)2

226 (95.0%)

115 (93.5%)

247 (95.0%)

133 (95.7%)

0.942

n/a

APOE4 Genotype2

149 (67.7%)

63 (56.8%)

183 (76.3%)

90 (69.2%)

0.003

tAD>HpSp

Memory1

-0.61 (0.50)

-0.92 (0.55)

-0.81 (0.47)

-0.99 (0.48)

<0.001

Min.>tAD>LP; Min.>HpSp

Executive1

-0.30 (0.76)

-1.01 (0.83)

-0.52 (0.68)

-0.39 (0.71)

<0.001

Min.>tAD>HpSp; LP>HpSp

Language1

-0.11 (0.65)

-0.51 (0.65)

-0.33 (0.62)

-0.32 (0.60)

<0.001

Min.>tAD>HpSp, Min.>LP

Visuospatial1

0.12 (0.67)

-0.43 (0.84)

-0.06 (0.69)

-0.10 (0.69)

<0.001

Min., tAD, LP>HpSp

MoCA Score1

18.9 (4.72)

15.2 (6.01)

17.8 (4.52)

16.9 (4.73)

<0.001

Min., tAD>HpSp; Min.>LP

Digit Span Forward1

7.13 (2.07)

6.58 (2.77)

7.30 (2.06)

7.39 (2.03)

0.427

n/a

Digit Span Backward1

4.77 (2.34)

3.25 (2.01)

4.79 (1.87)

4.74 (2.07)

<0.001

Min., tAD, LP>HpSp

Trail Making A1

56.4 (32.5)

81 (42.2)

63.4 (35.1)

56.1 (31.5)

<0.001

HpSp>Min., tAD, LP

Trail Making B1

167 (84.5)

242 (76.2)

205 (88.8)

180 (83.8)

<0.001

HpSp>tAD>LP, Min.

CDR-global1

0.76 (0.39)

0.92 (0.47)

0.84 (0.42)

0.91 (0.51)

0.002

HpSp, LP>Min.

CDR-sum of boxes1

4.27 (2.03)

5.11 (2.59)

4.64 (2.01)

4.82 (2.08)

0.003

HpSp>Min.

 

 

 

Results/Discussion:

• AD patients with the hippocampal-sparing atrophy subtype showed poorer baseline cognition and faster longitudinal decline in general cognition (MoCA) and clinical dementia severity (CDR-SB), despite similar levels of dementia severity (CDR-global).

• Cognitive domain performance mapped onto atrophy subtypes, with the hippocampal-sparing atrophy subtype had the poorest performance at baseline in non-amnestic cognitive domains, while the limbic predominant had the poorest memory performance.
 
• APOE4 carrier status was less frequent in the hippocampal-sparing and minimal atrophy subtypes.
 
• AD patients with minimal hippocampal or cortical atrophy showed less clinical and cognitive impairment at baseline and slower clinical decline over time.
 
• Findings were similar in the full sample and in Aβ+ subset.
 
• These findings support our previous work, suggesting that cortical predominant (hippocampal-sparing) atrophy patterns are associated with faster clinical decline in AD patients AD. Future studies should explore differences in these subtypes on tau PET, as well as neuropathological changes at autopsy to understand the role of other potential pathologies beyond Aβ and tau pathology.
 

References: [1] Risacher et al. (2017), Neurology. PMID: 29070667; [2] Mukherjee et al. (2023), Neuropsychology, PMID: 3592573

Funding: U24 AG074855; P30 AG072947, P30 AG072976; R01 AG061788

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