Different Cognitive Profiles Are Associated with Progression Rate and Age at Death in Probable Alzheimer’s Disease

Abstract

Background:

Cognitive profiles characterized by primarily language or visuospatial deficits have been documented in individuals meeting diagnostic criteria for probable Alzheimer’s disease (AD), but their association with progression rate or overall survival is not well described.

Objective:

To compare time from diagnosis to severe disease stage and death in probable AD patients classified into three groups based on neuropsychological test performance: marked verbal impairment (Verb-PI) with relatively preserved visuospatial function, marked visuospatial impairment with preserved verbal function (Vis-PI), and balanced verbal and visuospatial impairments (Bal-PI).

Methods:

This prospective cohort study included 540 probable AD patients attending an academic memory clinic who were enrolled from 1995–2013 and followed annually. Eligible individuals had a Mini-Mental State Exam (MMSE) score ≥10 at baseline, and at least one annual follow up visit. We used Cox proportional hazards modeling to analyze the association of cognitive profiles with time to decline in MMSE and CDR Global Score.

Results:

Sixty-one (11.3%) individuals had a Verb-PI profile, 86 (16%) had a Vis-PI profile, and 393 (72.8%) a Bal-PI profile. MMSE decline to <10 was faster in Verb-PI than Vis-PI (HR 2.004, 95%CI, 1.062–3.780; p = 0.032). Progression to CDR-GS = 3 was faster in Verb-PI individuals compared to Bal-PI (HR 1.604, 95%CI, 1.022–2.515; p = 0.040) or Vis-PI (HR 2.388, 95%CI, 1.330–4.288; p = 0.004) individuals. Baseline cognitive profile did not affect mortality.

Conclusion:

A recognition of different AD profiles may help to personalize care by providing a better understanding of pathogenesis and expected progression.

Keywords

Alzheimer’s disease variants cognitive subtypes disease progression survival

INTRODUCTION

Atypical clinical presentations of Alzheimer’s disease (AD) that present with distinctive neuropsychological profiles have been described, including corticobasal syndrome [1, 2], logopenic variant primary progressive aphasia [3, 4], posterior cortical atrophy syndrome [5], and a dysexecutive syndrome that resembles behavioral variant frontotemporal dementia [4, 6]. Beyond these recognized atypical presentations, it has long been recognized that persons who meet the consensus criteria for a diagnosis of probable AD do not have uniform profiles of cognitive deficits. In the decades since the publication of the first consensus criteria for diagnosis of AD [7], a number of studies have been undertaken to identify the cognitive “subtypes” or “profiles,” that present in persons newly diagnosed with probable AD, and characterize their demographic, clinical, and pathological correlates. In a seminal study published in 1986, Martin et al. [8] studied 42 patients diagnosed with probable AD who underwent evaluation with a comprehensive neuropsychological test battery that included the Wechsler Adult Intelligence Scale (WAIS) [9], the Wechsler Memory Scale (WMS) [10], and measures of attention, visual, auditory and tactile recognition, visuospatial and constructional skill, language comprehension, fluency and naming ability, and learning and memory for verbal, nonverbal, and spatial information. The majority of patients had deficits of similar magnitude across all performance areas, but the investigators noticed that a group of patients that displayed markedly different deficits on tests of language function compared to tests of visuospatial abilities. The authors subjected three verbal ability tests (Boston Naming Test (BNT) [11], word fluency from the Multilingual Aphasia Examination [10], and the paired associates subtest from WAIS) and three tests of visuospatial function (WAIS Block Design, Rey-Osterrieth Figure Copy [12], and a third pattern discrimination test taken from a standardized college entrance exam) included in their neuropsychological battery to a factor analysis. This procedure yielded two factors that accounted for 70.5%of the score variance. A cluster analysis of the factor scores assigned patients to five groups. Three groups had comparable levels of impairment on each factor score but varied on degree of overall cognitive impairment. The remaining two groups had markedly different degrees of impairment on the two factors-a profound impairment on the language factor, but little impairment on the visuospatial factor and vice versa. This finding was interpreted as support for the hypothesis that distinct cognitive subtypes of AD exist, and a contradiction of the hypothesis that different cognitive profiles reflect different stages of disease. Becker et al. [13] undertook a study to confirm Martin’s findings as well as to identify clinical correlates and potential differences in progression rate. Becker et al. operationalized the “focal” presentation of AD as a difference of two standard deviations in a composite visual versus verbal impairment score. The existence of two groups defined by predominantly visual versus verbal impairments was confirmed, but there was insufficient longitudinal follow-up to permit an assessment of differences in progression rates. The only demographic variable distinguishing the three groups was a younger age of onset in the group with predominantly visual-spatial impairment. Other investigators attempted to replicate and extend the early work of Martin et al., and Becker et al., and, although they employed slightly different statistical methodology to reduce the data, they reliably identified the two phenotypes—one with an extreme deficit in language and naming ability with relatively spared visuospatial functions, and the other with the opposite profile [14 –17]. A common finding was a lower age of onset of AD in persons with the extreme visuospatial deficit profile. In addition, Finton et al. [18] found that APOE ɛ4 homozygotes were more likely to present with severe visuospatial impairment.

Following these early investigations of prevalence and characteristics of probable AD patients with an “asymmetrical” or “focal” presentation of cognitive deficits, additional studies have been carried out in larger samples, using a wide variety of cognitive test batteries, and relying on model based approaches to identify the number of cognitive profiles that emerged from the data [19 –22]. The aims of the majority of these studies included an effort to correlate cognitive profile membership with demographic and clinical variables, and one study [19] also examined the correlation between identified profiles and neuropathology findings at autopsy. The number and composition of the cognitive profiles that have been identified in the recent studies have varied considerably, although in most samples a predominant visuospatial impairment and predominant verbal impairment can be discerned. A major methodological difference between the studies that were modeled after the approach originated by Martin et al. [8], and other studies published after 2010 is the inclusion of memory tests in the principal components analysis or other data reduction techniques. The rationale for including or excluding memory tests has not been clearly addressed in any of the studies cited so far. Finton et al. [18] and Alverson et al. [23], who follow the methods introduced by Martin et al. [8], suggest that the calculation of the asymmetric visuospatial profile and verbal profiles should be independent of the memory deficits that are assumed to be present with a diagnosis of probable AD. When memory tests are included in the data reduction models, the results are typically dominated by a memory impairment factor. Other methodological differences across the studies cognitive subtypes of AD include differences in data reduction methods and calculation of cognitive profile scores, widely varying samples sizes and sample characteristics, and different neuropsychological test batteries. Because of this variation in methodology, no consensus has been established on the number and characteristics of distinct cognitive profiles that can present in patients with probable AD. Without this consensus, no consistent clinical or pathological correlates of different AD cognitive profiles have emerged.

Since 1989, The Alzheimer’s Disease and Memory Disorders Center (ADMDC) at Baylor College of Medicine has prospectively collected and stored the clinical, neuropsychological, laboratory data, and consensus diagnosis of patients seeking care for memory complaints in a research database [7, 24]. In one of the early studies of the visual predominant (Vis-PI) and verbal predominant (Verb-PI) profiles of cognitive impairment in probable AD, our group analyzed this clinical database using methodology similar to that of Martin [8] and Becker [13]. In this study, Strite et al. [25] showed that approximately 25%of the ADMDC population with probable AD had an asymmetric cognitive profile, and these profiles could be replicated across severity stages. In a later study [23] in our clinic sample, Alverson et al. examined predictors of the Vis-PI and Verb-PI subtypes, when a larger number of patients had accrued in our database. As in other samples, the Vis-PI group had a younger age of symptom onset. We also found a higher prevalence of APOE 4 homozygosity in the Vis-PI group that was consistent with that observed in the patient sample analyzed by Finton et al. [18]. In the present study, we aim to determine if the Vis-PI and Verb-PI profiles are associated with differences in AD progression and overall survival.

METHODS

Research participants

The patients were evaluated at an academic memory center according to a standard protocol. The consensus diagnosis of probable AD was assigned based on the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s disease and Related Disorders Association) criteria [7]. Baseline and annual follow-up clinical data were stored in a longitudinal database using methods described elsewhere [26]. The standard clinical workup included APOE genotyping, but other cerebrospinal fluid or imaging biomarkers were not available for the great majority of individuals. All members of this cohort signed informed consent for use of their data for research purposes. Individuals were eligible if their diagnosis at all visits was probable AD and there was at least one annual follow-up before the cut-off date for the survival analysis. Individuals were excluded if they met criteria for dementia with Lewy bodies [27], vascular dementia [28], fronto-temporal lobar degeneration [6], or depression [29], or atypical clinical variants of AD [2 –7].

Other exclusion criteria included a MMSE score < 10, age less than 50 years (to exclude familial AD) or greater than 89 years at the time of presentation (due lack of normative data on psychometric test battery beyond this age range), and left handedness or missing handedness information (due to potential confounding from right and mixed hemispheric dominance for language in the left-handed individuals). Handedness was determined using the Edinburgh Handedness inventory [30].

Measures

Participants’ baseline characteristics, including age, sex, ethnicity (Hispanic versus non-Hispanic), education, APOE genotype, cardiovascular disease risk factor and morbidity burden, expressed as the Cardiovascular Disease Equivalent (CVDE), symptom duration, and anti-dementia medication treatment at each visit were obtained.

Symptom duration was calculated to the nearest 0.5 year from the onset of first symptom related to dementia after a careful evaluation as further detai-led elsewhere [31]. CVDE is a summary indicator variable reflecting the burden of CVD. It was calculated as per the National Cholesterol Education Program–Adult Treatment Panel III [32] and considers the history of myocardial infarction, congestive heart failure, stent placement, diabetes mellitus, or high risk for congestive heart disease with any two of hypertension, hyperlipidemia, or current cigarette smoking.

Disease progression was assessed with two measures. The Mini-Mental State Exam (MMSE) [33] is a brief test of overall cognitive status test with scores that range from 0–30 points. Higher scores reflect better performance. It is used both to screen for cognitive impairment and to monitor disease progression. By convention, an MMSE score of <10 reflects a progression of cognitive decline from the mild stage (MMSE≥20) through moderate (MMSE = 10–19) to a severe stage of cognitive impairment. The Clinical Dementia Rating Scale is a measure of global impairment, incorporating both cognitive and functional aspects of disease [34]. The score is derived from a patient interview in conjunction with an interview of a collateral source. Impairment ratings of 0 (no impairment), 0.5, 1, 2 or 3 (severe impairment) are assigned to each of six functional domains, including memory, orientation, judgement/problem solving, social function, home and hobbies, and personal care. A summary global impairment rating (CDR-GS) is obtained from an algorithm available from Washington University (Saint Louis, MO, USA; https://www.alz.washington.edu/cdrnacc.html). The individual functional domain ratings can also be summed to obtain a “sum of boxes score” (CDR-SB), which ranges from 0–18, with higher scores reflecting greater impairment. The MMSE and the CDR were administered at each annual visit. Progression to severe disease stage was reached when the MMSE score at an annual visit was below 10 or a CDR-GS was 3.0.

Defining visual predominant and verbal predominant profiles

The participants were classified into one of three groups (Vis-PI, Verb-PI, or Bal-PI) based on the degree of discrepancy between their performance on tests of language function and visuospatial function included in the standard neuropsychological battery. Scores on the WAIS Similarities [35], semantic fluency [36], and BNT [11] were used to construct a Verb-PI composite score for each patient, and the WAIS block design [35], Rey-copy [37], and Beery Development Test of Visual-Motor Integration [38] comprised the Vis-PI composite. Following the methods described by Alverson et al. [23], patients’ scores were converted to z-scores using relevant norms. To avoid distortions in group means and standard deviations caused by extreme scores or constrained score ranges on some tests, two procedures were performed. First, individual scores across all tests were pooled, and then winsorized by assigning extreme z scores to the score representing the 97.5 percentile or the 2.5 percentile of the distribution as appropriate. The standard deviation for calculation of individual score deviations from the group mean (see below) was obtained by calculating the standard deviation of the pooled verbal test z-scores, and the same procedure was carried out to obtain a pooled visuo-spatial test z-score. These preliminary steps were carried out on a sample of 880 patients who met all inclusion criteria except that they did not have scores on at least two of the three tests comprising each cognitive domain. It was felt this approach would provide representative means and standard deviations for the analysis than restricting the preliminary distributional smoothing operations only to the final analytic sample of 540. The means and standard deviations from the larger sample were used to calculate the individual deviation scores for the analytic sample as follows, using the BNT as an example:

$\begin{matrix} DeviationScoreBNT \\ = \frac{Age normed z scoreBNT - Mean z scoreBNT over large sample}{S D_{tests within verbal composite over large sample}} \end{matrix}$

Each patient’s average deviation score (or composite score) among verbal tests minus the visuospatial composite score constituted the asymmetry index (AI). Patients with AIs ≥1.0 were classified as having a predominantly visuospatial cognitive deficit, and those with AIs ≤–1.0 were classified as having a predominantly verbal deficit. Patients with scores ranging between –1.0 and 1.0 were classified as balanced.

Statistical analysis

Baseline characteristics of the three groups were compared using analysis of variance and the Chi square test as appropriate. Time to decline to severe disease stage on each disease severity measure separately, and time to death were compared across groups using Cox Proportional hazards modeling. The Cox models were adjusted for age at baseline, sex, ethnicity (Hispanic versus non-Hispanic), APOE ɛ4 carrier status, years of education, CVDE, and duration of symptoms. The two disease severity models were also adjusted for the baseline score obtained on the relevant measure. In the case of the CDR Global score, the CDR-SB at baseline was used for adjustment. Additionally, baseline CDR-SB was included as a covariate in the mortality analysis. The duration of follow-up was limited to 10 visits because there were very few events of decline for asymmetric groups pass the 8th year. Anti-dementia drug treatment was expressed as a time-dependent dichotomous variable reflecting whether the subject was taking any anti-dementia treatment at each visit. We did not expect anti-dementia treatment to be associated with rate of progression [39], but it could have served as a confounder with severity, via the mechanism of indication bias. Prior to the approval of memantine for moderate to severe AD in the United States in October 2003, only cholinesterase inhibitors were available for treatment of AD. Since the earliest entry date in our cohort is 1995, we could not assess the effect of two drugs versus one in the entire cohort. However, we conducted a sensitivity analysis in persons who entered the cohort after 2003 to determine if accounting for the use of memantine in addition to a cholinesterase inhibitor altered the association be-tween cognitive profile and the two defined study outcomes. For each outcome, an initial model was tested that included all covariates. Backward elimination was used to arrive at a model adjusted only for significant covariates.

Kaplan-Meier curves were used to examine the survival curves. We tested whether the proportional hazards assumption was violated by evaluating a model that included a product term of asymmetry and log (time) and examining Schoenfeld residuals versus log (time). We concluded that the proportional hazard assumption was satisfied. All analyses were performed using SAS Version 9.4.

RESULTS

Figure 1 shows the participant selection process. Of the 1,470 participants with probable AD, 515 did not have a follow-up visit before the censoring date. After application of the remaining inclusion criteria, 540 participants entered the study.

Fig. 1

Flow diagram of study design.

Characteristics of the study population

Table 1 shows the baseline characteristics of the three cohorts. 61 (11%) of participants were classified as Verb-PI and 86 (16%) as Vis-PI. The symptom duration of the three groups prior to diagnosis was comparable. At the time of presentation, Vis-PI pat-ients were 5.2 years younger than the balanced AD group and 6.5 years younger than the Verb-PI group (p < 0.001). There were no significant differences in education, baseline MMSE, CDR-SB (baseline), CDR GS (baseline), ethnicity, sex, CVDE, or percentage that died among the three groups. Use of anti-dementia drugs was not different across groups either at the baseline visit or the final visit. As expected, Immediate logical memory (LM-1) was more impaired in Verb-PI participants, and Immediate visual reproduction (VR-1) was more impaired in the Vis-PI groups, but no significant group differences were noted in delayed Logical memory (LM2) (p = 0.07) or delayed visual reproduction (VR2) (p = 0.321) among the three groups. AI for balanced AD was 0.02; 1.493 for Vis-PI and –1.423 for Verb-PI groups (p < 0.001).

Table 1

Baseline characteristics among Balanced Impaired (Bal-PI), Visuospatial Impaired (Vis-PI), and Verbal Impaired group (Verb-PI)

Total 540 (%)	Bal-PI 393 (72.8)	Vis-PI 86 (15.9)	Verb-PI 61 (11.3)	P
Age at baseline, mean (SD), y	75.03 (7.49)	69.82 (8.47)	76.30 (7.13)	<0.001^*
Age at death, mean (SD), y	82.30 (7.16)	77.75 (8.51)	82.68 (7.16)	0.003^*
Education, mean (SD), y	14.4 (3.3)	14.4 (3.1)	14.5 (3.0)	0.979
Length of follow-up, mean (SD), y	3.89 (2.46)	3.91 (2.47)	3.62 (2.23)	0.709
Symptom duration, mean (SD), y	3.51 (1.98)	3.53 (1.92)	3.57 (1.99)	0.972
Time to death, mean (SD), y	6.19 (3.30)	5.96 (3.15)	5.92 (3.46)	0.73
Time to decline in MMSE <10, mean (SD), y	3.27 (2.09)	3.28 (1.99)	2.98 (1.84)	0.576
Time to decline in CDR-GS = 3, mean (SD), y	3.26 (2.06)	3.44 (2.13)	2.94 (1.79)	0.341
Hispanic ethnicity, No. (%)	19 (4.87)	3 (3.53)	3 (5.00)	0.861
Female sex, No. (%)	266 (67.7)	51 (59.3)	36 (59.0)	0.181
CVD equivalent, No. (%)	247 (63.8)	48 (56.5)	38 (62.3)	0.447
Anti-dementia medication initial visit, No. (%)	197 (50.1)	48 (55.8)	30 (49.2)	0.608
Anti-dementia medication last visit, No. (%)	376 (95.7)	82 (95.4)	60 (98.4)	0.588
APOE ɛ4 carrier status,	383 (97.5)	81 (94.2)	59 (96.7)
No.(%) with data
ɛ4 alleles,0, No. (%)	133 (34.7)	26 (32.1)	35 (59.3)	<0.001^*
ɛ4 alleles, 1, No. (%)	196 (51.2)	34 (42.0)	18 (30.5)	<0.001^*
ɛ4 alleles, 2, No. (%)	54 (14.1)	21 (25.9)	6 (10.2)	<0.001^*
ɛ4 positive, No. (%)	250 (65.3)	55 (67.9)	24 (40.7)	<0.001^*
Cognitive scores
MMSE (Baseline), mean (SD)	22.96 (4.14)	22.85(3.67)	21.66 (4.35)	0.07
CDR-SB (Baseline), mean (SD)	4.81 (2.73)	4.84 (2.17)	5.69 (2.53)	0.051
CDR-GS (Baseline), mean (SD)	0.86 (0.42)	0.84 (0.36)	0.98 (0.43)	0.104
Memory scores
Logical memory I (z), mean (SD)	–1.633 (0.684)	–1.624 (0.670)	–1.980 (0.540)	<0.001
Visual reproduction I (z), mean (SD)	–1.210 (1.075)	–1.642 (0.816)	–1.048 (1.107)	<0.001
Logical memory II (z), mean (SD)	–2.061 (0.580)	–1.976 (0.620)	–2.207 (0.501)	0.07
Visual reproduction II (z), mean (SD)	–2.019 (0.659)	–2.124 (0.649)	–1.961 (0.774)	0.321
Cognitive asymmetry
Verbal composite, mean (SD)	0.237 (0.676)	0.423 (0.456)	–0.645 (0.506)	<0.001
Visuospatial composite, mean (SD)	0.217 (0.739)	–1.070 (0.670)	0.777 (0.499)	<0.001
Asymmetry index, mean (SD)	0.02 (0.508)	1.493 (0.360)	–1.423 (0.366)	<0.001

CVD Equivalent, Cardiovascular Disease Equivalent; CDR-SB, Clinical Dementia Rating Sum of Boxes; CDR-GS, Clinical Dementia Rating Global Score.

The Verb-PI group had a lower prevalence of an APOE ɛ4 allele (40.7%) compared to the Vis-PI (68%) and balanced groups (65.3%) (p < 0.001). The Vis-PI group was much more likely to be homozygous for the APOE ɛ4 allele than the other two groups (25.9%versus 14.10%and 10.2%respectively, p < 0.001).

Disease progression

The results of the modeling of time to progression are in Table 2. Time to MMSE decline to below 10 in the full model was not significantly different for the Verb-PI group compared to the balanced AD cohort (HR 1.554, 95%CI, 0.899–2.690; p = 0.119) or the Vis-PI group compared to Bal-PI (HR = 0.839, 95%CI, 0.511–1.379; p = 0.49) However, decline was significantly faster in the Verb-PI compared to the Vis-PI group (HR 1.852, 95%CI, 0.951–3.605; p = 0.028). Age (HR 0.927, 95%CI, 0.955–1.071; p < 0.001), baseline MMSE (HR 0.781, 95%CI, 0.738–0.826; p < 0.001), and Hispanic ethnicity (HR 2.324, 95%CI, 1.248–4.327; p = 0.008) were also significant predictors for time to decline in MMSE below 10 points; However, sex, education, duration of symptoms, and APOE ɛ4 carrier status were not significant predic-tors. Removal of the education, sex, APOE ɛ4 carrier status, and duration of symptoms from the full model made CVDE a significant protective factor for progr-ession (HR 1.471, 95%CI, 1.039–2.192; p = 0.045).

Table 2

Hazard Ratios (HR)of time to decline to severe stage as measured by MMSE <10 points and CDR = 3.

	Full model^a				Reduced model^b
	Decline in MMSE <10		Time to CDR global = 3		Decline in MMSE <10		Time to CDR global = 3
Factor	HR (95%CI)	p	HR (95%CI)	p	HR (95%CI)	p		p
Verbal predominant AD versus balanced AD	1.554 (0.899, 2.690)	0.119	1.561 (0.963, 2.532)	0.071	1.646 (0.992, 2.731)	0.054	1.604 (1.022, 2.515)	0.04
Visuospatial predominant AD versus balanced AD	0.839 (0.511, 1.379)	0.49	0.662(0.4051.081)	0.099	0.821 (0.507, 1.332)	0.424	0.672 (0.418, 1.078)	0.099
Verbal predominant AD versus visuospatial predominant AD	1.852 (0.951, 3.605)	0.028	2.358 (1.268, 4.384)	0.007	2.004 (1.062, 3.780)	0.032	2.388 (1.330, 4.288)	0.004
Age	0.927 (0.955, 1.071)	<0.001	0.947 (0.923, 0.972)	<0.001	0.927 (0.903, 0.950)	<0.001	0.952 (0.929, 0.974)	<0.001
Education	1.011 (0.955, 1.071)	0.698	1.002 (0.950, 1.058)	0.932
Female sex	1.044 (0.677, 1.609)	0.846	1.258 (0.833, 1.892)	0.273
Hispanic ethnicity	2.324 (1.248, 4.327)	0.008	2.472 (1.304, 4.685)	0.005	2.230 (1.235, 4.132)	0.009	2.387 (1.278, 4.459)	0.006
Number of ɛ4(1)	0.990 (0.644, 1.522)	0.964	0.982 (0.673, 1.458)	0.926
Number of ɛ4(2)	0.894 (0.495, 1.616)	0.711	0.880 (0.517, 1.529)	0.645
Baseline MMSE	0.781 (0.738, 0.826)	<0.001			0.775 (0.736, 0.817)	<0.001
Baseline CDR-SB			1.363 (1.277, 1.455)	<0.001			1.380 (1.300, 1.466)	<0.001
CVD equivalent (Not present)	1.443 (0.97982.130)	0.065	1.034 (0.715, 1.487)	0.857	1.471 (1.039, 2.192)	0.045
Symptom duration, y	1.032 (0.935, 1.139)	0.536	1.085 (0.996, 1.186)	0.066
Anti-dementia medication	0.994 (0.301, 3.288)	0.992	1.284 (0.447, 3.688)	0.643

^aThe full model includes all covariates. ^bThe reduced model includes significant factors after the removal of non-significant factors (p < 0.05) in a backward elimination process. Hazard ratios computed using Chi-squares.

Table 2 presents the models predicting time to increase in CDR-GS of 3 from the baseline. Progression to CDR-GS of 3 in the full model approached clinical significance in Verb-PI group compared to the Bal-PI group (alpha <0.1) (HR 1.561, 95%CI, 0.963–2.532; p = 0.071), and was highly significant in the Verb-PI versus Vis-PI group (HR 2.358, 95%CI, 1.268–4.384; p = 0.007). There was no significant difference in CDR-GS progression to severe stage for Vis-PI AD versus balanced AD. In the reduced model, the HR for progression in the Verb-PI versus Bal-PI comparison reached statistical significance (HR 1.604, 95%CI, 1.022–2.515; p = 0.04), and there was little change in the HR for Verb-PI versus Vis-PI (HR 2.388, 95%CI, 1.330–4.288; p = 0.004). Only age (HR 0.952, 95%CI, 0.929–0.974; p < 0.001), baseline CDR-SB (HR 1.380, 95%CI, 1.300–1.466; p < 0.001), and Hispanic ethnicity (HR 2.387, 95%CI, 1.278–4.459; p = 0.006) were significant predictors of progression on the CDR-GS.

Figures 2 3 contain the Kaplan Meier survival curves for the progression experience in each group. for the Schoenfeld residuals, Supremum Test for proportional Hazard Assumption as well as addition of the product term of group and log(time) in the model indicated that the proportional hazards assumption was not violated for any of the outcomes.

Fig. 2

Kaplan-Meier survival curve for time to decline to MMSE <10.

Fig. 3

Kaplan-Meier survival curve for time to decline to CDR global of 3.

Any anti-dementia treatment was not associated with either outcome, and in sensitivity analyses, the results when the use of both memantine and a cholinesterase inhibitor were modeled did not alter the effect sizes associated with cognitive profile in any way (data available on request).

Mortality

The full and reduced proportional hazards models for time to death after diagnosis, in Table 3, indicate that there were no significant differences across cognitive subtypes in overall survival after diagnosis. Higher age (HR 1.045, 95%CI, 1.024–1.066; p < 0.001) was associated with higher mortality. Female sex (HR 0.654, 95%CI, 0.493–0.869; p = 0.003) and Hispanic ethnicity were associated with lower mortality hazard (HR 0.322, 95%CI, 0.140–0.744; p = 0.008). Higher baseline MMSE (HR 0.924, 95%CI, 0.893–0.957; p < 0.001) showed significant effect on lower mortality. Baseline CDR-SB, Education, CVDE, duration of symptoms, and APOE ɛ4 carrier status showed no effects on mortality.

Table 3

Hazard ratio for time to death

	Full model^a		Reduced model^b
Factor	HR (95%CI)	p	HR (95%CI)	p
Verbal predominant AD versus balanced AD	1.055(0.700, 1.590)	0.798	1.066 (0.715, 1.588)	0.755
Visuospatial predominant AD versus balanced AD	1.016 (0.674, 1.531)	0.941	1.104 (0.743, 1.640)	0.624
Verbal predominant AD versus visuospatial predominant AD	1.039(0.561, 1.653)	0.974	0.965 (0.571, 1.632)	0.728
Age, y	1.048 (1.025, 1.068)	<0.001	1.045 (1.024, 1.066)	<0.001
Education, y	0.984 (0.947, 1.026)	0.443
Female sex	0.617 (0.457, 0.837)	0.002	0.654 (0.493, 0.869)	0.003
Hispanic ethnicity	0.385 (0.155,0.938)	0.038	0.322 (0.140, 0.744)	0.008
Number of ɛ4(1)	1.092 (0.791, 1.471)	0.580
Number of ɛ4(2)	1.311 (0.841, 1.919)	0.201
Baseline CDR-SB	1.035 (0.966, 1.101)	0.303
Baseline MMSE	0.938 (0.893, 0.973)	0.005	0.924 (0.893, 0.957)	<0.001
CVD equivalent (Not present)	1.023 (0.735, 1.296)	0.880
Symptom duration	0.990 (0.927, 1.065)	0.792
Anti-dementia medication	0.569 (0.334, 0.969)	0.038

DISCUSSION

This is the first study to provide long-term follow-up information on differences in the clinical course associated with the two cognitive phenotypes first identified by Martin et al. [8], and subsequently examined by a number of investigators who provided additional cross-sectional data on demographic and clinical correlates of the Vis-PI and Verb-PI phenotypes [13 –23]. Our study confirmed the findings of Becker et al. [13], Rasumusson and Brandt [40], Finton et al. [18], and Alverson et al. [23] that patients classified as Vis-PI have a younger age of symptom onset than those classified as Verb-PI. In addition, we confirmed Finton et al.’s finding that individuals with the Vis-PI profile are more likely to be APOE ɛ4 homozygous than those with either the Verb-PI profile or a balanced profile. The principal finding of our study was that individuals with the Verb-PI cognitive phenotype are likely to progress to a severe stage of dementia more rapidly than those classified as Vis-PI. The risk of rapid decline is particularly marked when assessed with the CDR. Although survival time after diagnosis was not different across groups, the Vis-PI group had a younger age at death on average, consistent with the younger age of onset. Except for age of symptom onset and prevalence of an APOE ɛ4 allele, demographic and clinical characteristics were remarkably similar across the three cognitive subtypes. All three subtypes presented after an average 3–4 years of symptoms, and at a similar severity level. Individuals in all the three cohorts lived on average 6 years after diagnosis.

Younger age at disease presentation and Hispanic ethnicity predicted a faster progression to severe stage, regardless of asymmetry group. The Hispanic population was relatively small in our study population; therefore, results should not be generalized. Baseline MMSE (full and adjusted model), and a negative history of CVDE, reflecting absence of cardiovascular risk factors (in adjusted model) were also significant predictors of time to decline to a severe level on MMSE (less than 10), whereas baseline CDR-SB and symptom duration were significant predictors of time to increase in CDR-GS to a severe level (score of 3). It is noteworthy that, although the APOE genotype was associated on a cross-sectional basis with prevalence of the cognitive profiles, it was not related to progression of disease. Not surprisingly, age, sex, ethnicity, and baseline MMSE significantly predicted mortality during the average of 4 years patients were followed.

The younger age of symptom onset associated with the Vis-PI cognitive profile has been found in other studies of cognitive subtypes within probable AD, as well as in comparisons of early versus late onset AD [41, 42]. In addition, our study confirmed the findings of Finton et al. [18] that APOE ɛ4 homozygosity increases susceptibility to a Vis-PI profile. Many neuroanatomical and imaging studies have been carried out to determine the pathological correlates of atypical clinical presentations of AD with involvement of specific brain region in different presentation [43 –53]. From these studies, it appears that derangements in dominant parieto-temporal region lead to language related presentation, involvement of right sided and posterior parietal regions align with visual variant, and frontal brain region involvement is linked to dysexecutive presentation. However, atypical patterns of deposition of various iso-forms of tau, alpha-synuclein, amyloid, and other misfolded proteins may lead to atypical clinical presentations distinct from pathological classification of these neurodegenerative diseases. It is quite possible that the cognitive phenotypes of extreme visual spatial deficits with preserved verbal function, or vice versa, share similar co-morbid pathologies or patterns of neurodegeneration with logopenic variant primary progressive aphasia and posterior cortical atrophy, but without the sparing of memory functions that helps to establish the diagnosis of these atypical AD presentations.

Although there have been numerous studies that address the anatomical and functional correlations of atypical AD variants, few studies have focused on the pathogenetic or neuroanatomical correlates of different cognitive phenotypes observed in probable AD. Of the investigations of cognitive profile heterogeneity within the diagnosis of probable AD, only Scheltens et al. [20, 21] and Qui et al. [19] attempted a correlation between different cognitive profiles and AD biomarkers or neuropathology findings. Scheltens et al. [21] found a complex set of associations between eight different cognitive profiles identified through latent class analysis and white matter hyperintensities (WMH) global and regional atrophy assessed on structural MRI. In a study using a different sample, Scheltens et al. [20] found a higher degree of posterior cortical atrophy on structural MRI in a cognitive subtype of AD with less memory impairment, Qui et al. [19] reported a lower Braak stage on autopsy in persons who were classified as having an “atypical” cognitive profile. None of these studies used the same approach to identify cognitive subtypes as ours, nor were the cognitive subtypes identified across these studies comparable to one another. Thus, generalization to samples or methods outside of the individual studies is not possible. Since there are clear age and genetic risk factors for the Vis-PI and Verb-PI phenotypes, additional investigations of neuroimaging and neuropathological correlates of these phenotypes using the same neuropsychological classification criteria will help advance our understanding of the mechanisms underlying these phenotypic differences and implications for appropriate management with disease modifying therapies. Studies of regional variations in tau and amyloid distributions using PET imaging [49] hold the greatest promise for elucidating early neuroanatomical correlates of the different cognitive profiles defined in our study. Novel blood biomarkers, including specific phospho-tau isoforms [55 –57] may also be useful in expanding our understanding of the pathogenetic basis for the variability in cognitive test performance that is predictive of subsequent progression rate.

As described in detail in the methods section, allocation of our participants to these three cognitive subtypes was based upon psychometric features rather than a syndromic definition of the clinicians. All the patients satisfied the NINCDS-ADRDA criteria for AD and had involvement of episodic memory as a core criterion for the diagnosis. The revised National Institute on Aging (NIA-AA) diagnostic criteria published in 2011 [24] recognized a “non-amnestic” phenotype of AD, which could pre-sent as a primarily visuospatial impairment, language impairment, or dysexecutive syndrome. Similarly the International Working Group-2 (IWG-2) criteria also recognizes [58] atypical AD with “relative” preservation of memory. Both of these recent criteria call for biomarkers to confirm AD pathology but do not give any guidance for defining these syndromes based on neuropsychological test performance nor do they address the specific phenotype that is described by our classification methodology—i.e., a patient who has a severe deficit in visuospatial function but relatively preserved verbal function, and vice versa, along with an episodic memory deficit.

We have not explored the possibility of identifying an extreme executive dysfunction profile with preserved visual and verbal functions in the population of patients meeting criteria for probable AD. Finton et al. noted the possibility that the Vis-PI phenotype may contain elements of executive dysfunction because of the inclusion of timed tests in the classification of visuospatial deficits. Scheltens et al. [21], using latent class analysis, extracted a profile characterized by relatively spared memory and a primarily dysexecutive pattern of deficits. However, the deficits were mild, and did not vary by more than 0.5 standard deviations from tests in other domains.

Our findings are strengthened by the fact that the faster progression rate in the Verb-PI group especially when compared to the Vis-PI group, was observed both on the MMSE, a heavily language-based assessment tool, and on the CDR-GS, a measurement with a built-in functional decline assessment that depends on the patient and an informant or expert clinician evaluation. While a faster decline on a language-based instrument in persons with a strong verbal deficit on presentation would be expected, the similarity in the results on a function measure support the hypothesis that there are underlying differences in disease progression across the groups.

The strengths of this study include the large sample size of cognitive subtypes of AD, with longitudinal follow-up and complete information on mortality. A relative weakness of the study is lack of imaging data to further characterize the subgroups. Further studies with serial brain MRI scan with cortical thickness in different AD subtypes and functional studies with serial amyloid, tau, and FDG PET will further help correlate the clinical disease progression with these biological markers.

In conclusion, we found that Vis-PI AD individuals are likely to be younger and more likely to be APOE ɛ4 positive, but that they do not progress more rapidly than those with a more balanced profile of deficits. Disease progression to a severe stage was faster in the Verb-PI phenotype, not only on a measure that is highly confounded by language, but also on a global measure that is not. Despite the differences in rate of progression to a severe stage of dementia, asymmetry did not affect survival time after diagno-sis. If these findings are replicated, they suggest that Verb-PI AD patients may require greater assistance sooner after their diagnosis of AD, whereas Vis-PI AD patients may have earlier mortality due to their younger age of onset. Identification of these two phenotypes at baseline provides clinically significant information about the expected trajectory of their illness and differences in risk factors (age and APOE ɛ4 carrier status) point to potentially important biological differences that, if understood, could shed light on AD etiology in general and be important in selecting appropriate disease modifying therapies. Correlation of these two phenotypes with biomarkers of neurodegeneration and neuropathological findings could lead to more personalized approaches to disease management.

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/20-1124r2).

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