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. 2025 Jun;22(3):207–214. doi: 10.36131/cnfioritieditore20250304

Medical Comorbidities in Alzheimer’s Disease: An Autopsy Confirmed Study with a Focus on Sex-Differences?

Antonina Luca 1, Maria Luca 2, Raffaele Ferri 3, Marco Barbanti 1, Roberta Malaguarnera 1, Basilio Pecorino 1, Paolo Scollo 1, Alessandro Serretti 1,3
PMCID: PMC12302816  PMID: 40735383

Abstract

Objective

Systemic comorbidities are common in Alzheimer's disease (AD) and may influence disease progression, severity, and management. Aim of the study was to assess the prevalence of comorbid medical conditions in a large cohort of AD patients, focusing on sex differences.

Method

AD patients from the NIMH Alzheimer Disease Genetics Initiative were enrolled. Data on multimorbidity, demographics, disease characteristics, and clinical assessments were collected from interviews, medical records, and examinations. Univariate and multivariate logistic regression models were performed to identify possible associations between comorbidities and sex. Subgroup analysis was performed for patients with autopsy-confirmed AD.

Results

Four hundred and twenty-four AD patients (295 women; mean age: 78.4±8.3 years) were included. Men had a higher prevalence of heart disease, diabetes, chronic obstructive pulmonary disease and smoking, whereas thyroid disease, hypertension and depression were more common in women (all p<0.05). Except for hypertension, all associations found in the univariate analysis were confirmed in the multivariate analysis after adjustment for age. Subgroup analysis of autopsy-confirmed cases confirmed these findings.

Conclusions

Our findings support the importance of considering sex-specific comorbidities in AD for precision medicine and emphasize the need for comprehensive assessment of comorbidities to improve clinical outcomes, treatment strategies and health equity.nt.

Keywords: alzheimer, cardiovascular disorders, endocrinological disorders, lifestyle, depression

Introduction

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the primary cause of dementia (Scheltens et al., 2021).

The pathological hallmark of AD in the earlier (cellular) phase, is amyloid β accumulation inducing the spread of tau pathology and neurodegeneration (Scheltens et al., 2021). Furthermore, it has been reported that vascular dysfunction and chronic inflammation (Langworth-Green et al., 2023) act as either upstream or concomitant factors in the accumulation of amyloid β within this complex cellular disease landscape (Sighencea et al., 2024). Thus, several factors associated with circulatory system-related comorbidities and heart disease, including tobacco smoking, chronic hypertension (Sternberg et al., 2024; Wanleenuwat et al., 2019), type 2 diabetes (Wee et al., 2023), and hypercholesterolemia (Pappolla et al., 2024) may be relevant modulating factors in AD.

Notably, previous longitudinal studies reported the association between medical conditions and later occurrence of AD. In particular, atrial fibrillation, myocardial infarction and heart failure increased the risk of AD (Hendriks et al., 2024; Rusanen et al., 2014). Similarly, an association between AD and chronic hypoxia-causing comorbidities, such as obstructive sleep apnea syndrome and chronic obstructive pulmonary disease has been described (Zhang et al., 2019).

In this regard, in a recent study on data from the United States insurance companies (Schroeder et al., 2024), circulatory system-related comorbidities and mood disorders were frequent among patients with AD (Haussmann & Donix, 2023), thus emphasizing the importance of considering comorbidities in clinical practice and in trials in order to achieve a greater generalizability.

Moreover, as multimorbidity affects more than half of adults aged 65 years and older, with an age-related increase in prevalence (Marengoni et al., 2011), the assessment of medical comorbidity in patients with AD should be considered mandatory. Not less important is the consideration that medical comorbidities could significantly impact the progression of cognitive decline and influence the pharmacological management of both cognitive and behavioural symptoms (Howell et al., 2019; Kaushik et al., 2018; Serretti, 2024; Yohannes et al., 2022). Yet, to date, the presence of multimorbidity in AD patients remains to be fully explored, in particular considering possible male-female differences.

In the light of the above evidence, with a view to precision medicine, the aim of this study was to assess the prevalence of comorbid medical conditions in a large cohort of AD investigating possible sex-related differences.

Materials and methods

Patients with AD, diagnosed according to the NINCDS/ADRDA criteria (Blacker et al., 1994; McKhann et al., 1984) were collected within the NIMH Alzheimer Disease Genetics Initiative (Blacker et al., 1997; Blacker et al., 2003), from memory clinics, nursing homes and the local community. As detailed elsewhere, the AD Genetics Initiative is a research program designed to improve consistency, comparability, and reliability in genetic and biological research of AD. During the nearly 10-years of follow-up of the dataset, a percentage of deceased patients underwent autopsy for diagnostic confirmation of AD (“Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease,” 1997).

In the present study, we performed a secondary phenotypic analysis on the presence of multimorbidity (ie hypertension, diabetes, thyroid disorders, chronic obstructive pulmonary disorder, atrial fibrillation, traumatic brain injury…) collected from the family interview, the medical records and the patient interview and examination. Demographic data (e.g. age, sex), voluptuary habits (e.g. smoking, drinking), and clinical characteristics of dementia (e.g. disease duration) were also collected. Dementia severity was assessed with the administration of the Clinical Dementia Rating Scale (CDRS) and the Mini Mental State Examination (MMSE).

Statistical analysis

An extensive data cleaning process was carried out. Duplicate entries were removed, outliers were identified and treated, and missing data were addressed. Variables with more than 20% missing values were eliminated with the exception of the Mini-Mental State Examination (MMSE), having 31.3% missing values but retained in the analysis due to its clinical relevance. Univariate analyses and logistic regression were performed to assess possible sex differences. For categorical non-binary variables (ie Clinical Dementia Rating Scale, CDRS), ordinal logistic regression was performed. Then, a multivariate analysis, adjusting for age, considered a priori confounder, was performed. In our sample, we had a power of 0.8 to detect a medium effect size of d=0.30 with an alpha of 0.05 (one-tail). Odd ratios and 95% confidence intervals were reported. P-value<0.05 were considered significant. Given the exploratory nature of our approach and the potential for false negatives with a strict Bonferroni correction, as well as the strong intercorrelations between several clinical variables, we have reported uncorrected p-values (Amrhein et al., 2019).

To confirm findings obtained on the whole sample, a statistical analysis including only patients with autopsy confirmed AD was performed. Data were analyzed with STATA v.18.

Results

Four hundred twenty-four AD patients (295 women, mean age 78.4±8.3 years, mean education 11.7±3.5 years, disease duration 7.4±8.5 years) were included in the study. The MMSE mean score was 12.9±8.8. The CDRS mean score was 2.6±1.1. For more details about clinical characteristics of the sample, see table 1.

Table 1.

Demographic and clinical characteristics of the whole sample (n=424)

Clinical variables n, %
Systemic illnesses  
Hypertension (n=400) 147 (36.7)
Angina (n=400) 40 (10)
Cardiac arrhythmia (n=400) 66 (16.5)
Myocardial infarction (n=400) 23 (5.7)
Cardiac surgery (n=399) 16 (4.0)
Stroke (n=393) 19 (4.8)
Transient ischemic attack (n=394) 12 (3.0)
Seizures (n=397) 13 (3.3)
Traumatic brain injury (n=399) 12 (3.0)
Diabetes (n=400) 21 (5.2)
Thyroid disorders (n=400) 40 (10.0)
Vitamin B12 deficiency (n=391) 17 (4.3)
Dyslipidemia (n=424) 32 (7.5)
COPD (n=400) 22 (5.5)
Voluptuary habits  
Tobacco intake (n=400) 17 (4.5)
Previous tobacco intake (n=381) 139 (36.5)
Beer intake (n=396) 33 (8.3)
Wine intake (n=398) 63 (15.8)
Neuropsychiatric features  
Depression (n=382) 126 (32.9)
Anxiety (n=377) 86 (22.8)
Reduced motivation (n=386) 331 (85.7)
Wondering (n=386) 163 (42.2)
Verbal aggression (n=389) 150 (38.5)
Physical aggression (n=384) 110 (28.6)
Agitation or restlessness (n=390) 293 (75.1)
Frustration intolerance (n=365) 170 (46.6)
Sundowning (n=361) 185 (51.2)
Auditory dysperceptions (n=366) 133 (36.3)
Visual hallucinations (n=370) 142 (38.4)
Olfactory hallucinations (n=311) 11 (3.5)
Tactile hallucinations (n=311) 13 (4.2)
Paranoia (n=382) 227 (59.4)
Delusions (n=375) 137 (36.5)
Illusions (n=360) 87 (24.2)
Cognitive features  
Memory loss (n=404) 404 (100)
Language difficulties (n=406) 385 (94.8)
Spatial problems (n=405) 385 (95.1)
Conceptual problems (n=404) 399 (98.8)
Apathy (n=380) 176 (46.3)
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Legend: data are expressed as number and percentage. Abbreviations: COPD: chronic obstructive pulmonary disease; n=number of observations.

Women were older (mean age 79.2±7.7 years) than men (mean age 76.5±9.4 years, OR 0.9, 95% CI 0.93-0.98, p=0.003). No sex differences in disease duration between women (7.7±8.0 years) and men (7.2±9.6 years; OR 0.9; 95%CI 0.96-1.02; p=0.600) were found.

Concerning AD severity, women had a higher CDRS (2.6±1.2) than men (2.3±0.1; OR 0.8; 95%CI 0.63-0.93; p=0.008). No sex differences in MMSE score and in neuropsychiatric symptoms were recorded. Voluptuary habits were more common among men than women. Hypertension, depression and thyroid disorders were more frequent among women, while atrial fibrillation, myocardial infarction, previous cardiac surgery, diabetes and chronic obstructive pulmonary disease were more common in men (table 2).

Table 2.

Demographic and clinical characteristics: sex differences, univariate analysis

  Univariate analysis
  Women Men OR 95%CI p-value
(n=295) (n=123)
CDRS (n=407) 2.6±1.2 2.3±0.1 0.8 0.63-0.93 0.008
MMSE (n=269) 12.3±8.6 14.2±8.9 1.0 0.99-1.05 0.111
Systemic illnesses          
Hypertension (obs=400) 112 (39.9) 35 (29.4) 0.6 0.40-0.99 0.048
Angina (obs=400) 23 (8.2) 17 (14.3) 1.9 0.96-3.64 0.066
Atrial fibrillation (n=400) 36 (12.8) 30 (25.2) 2.3 1.33-3.94 0.003
Myocardial infarction (n=400) 8 (2.8) 15 (12.6) 4.9 2.02-11.9 <0.001
Cardiac surgery (n=399) 4 (1.4) 12 (10.2) 7.8 2.47-24.84 <0.001
Stroke (n=393) 14 (5.1) 5 (4.3) 0.8 0.29-2.41 0.754
Transient ischemic attack (n=394) 8 (2.9) 4 (3.4) 1.2 0.35-4.03 0.780
Seizures (n=397) 8 (2.9) 5 (4.2) 1.5 0.48-4.68 0.486
Traumatic brain injury (n=399) 6 (2.1) 6 (5.1) 2.4 0.77-7.77 0.127
Diabetes (n=400) 8 (2.8) 13 (10.9) 4.2 1.68-10.38 0.002
Thyroid disorders (n=400) 35 (12.5) 5 (4.2) 0.3 0.12-0.81 0.017
Vitamin B12 deficiency (n=391) 14 (5.1) 3 (2.6) 0.5 0.13-1.73 0.268
Dyslipidemia (n=424) 19 (6.4) 13 (10.6) 1.7 0.81-3.59 0.152
COPD (n=400) 10 (3.6) 12 (10.1) 3.0 1.27-7.24 0.012
Voluptuary habits          
Tobacco intake (n=400) 10 (3.6) 7 (5.9) 1.7 0.63-4.56 0.297
Previous tobacco intake (n=381) 75 (28.0) 64 (56.6) 3.4 2.13-5.31 <0.001
Beer intake (n=396) 11 (4.0) 22 (18.5) 5.5 2.56- 11.73 <0.001
Wine intake (n=398) 35 (12.5) 28 (23.7) 2.2 1.25-3.78 0.006
Neuropsychiatric features          
Depression (n=382) 99 (37.5) 27 (22.9) 0.5 0.30-0.81 0.005
Anxiety (n=377) 65 (24.9) 21 (18.1) 0.7 0.38-1.15 0.148
Reduced motivation (n=386) 230 (84.9) 101 (87.8) 1.3 0.67-2.46 0.448
Wondering (n=386) 115 (42.6) 48 (41.4) 0.9 0.61-1.48 0.825
Verbal aggression (n=389) 101 (37.3) 49 (41.5) 1.2 0.77-1.86 0.428
Physical aggression (n=384) 74 (27.7) 36 (30.8) 1.2 0.72-1.86 0.543
Agitation or restlessness (n=390) 205 (75.1) 88 (75.2) 1.0 0.61-1.66 0.980
Frustration intolerance (n=365) 111 (44.0) 59 (52.2) 1.4 0.89-2.17 0.149
Sundowing (n=361) 130 (52.0) 55 (49.5) 0.9 0.58-1.42 0.667
Auditory dysperceptions (n=366) 96 (37.5) 37 (33.6) 0.8 0.53-1.35 0.481
Visual hallucinations (n=370) 96 (37.1) 46 (41.4) 1.2 0.76-1.89 0.428
Olfactory hallucinations (n=311) 9 (4.1) 2 (2.1) 0.5 0.11-2.37 0.385
Tactile hallucinations (n=311) 7 (3.2) 6 (6.5) 2.1 0.69-6.47 0.190
Paranoia (n=382) 164 (60.7) 63 (56.2) 0.8 0.53-1.29 0.416
Delusions (n=375) 100 (38.0) 37 (33.0) 0.8 0.50-1.28 0.359
Illusions (n=360) 62 (24.6) 25 (23.1) 0.9 0.54-1.57 0.768
Cognitive features          
Memory loss (n=404) 286 (100) 121 (100) / / /
Language difficulties (n=406) 269 (94.1) 116 (96.7) 1.8 0.60-5.56 0.285
Spatial problems (n=405) 269 (94.7) 116 (95.9) 1.2 0.45-3.64 0.626
Conceptual problems (n=404) 280 (98.9) 119 (98.3) 0.6 0.10-3.86 0.624
Apathy (n=380) 122 (46.0) 54 (47.0) 1.0 0.69-1.61 0.869
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Legend: Abbreviations: CDRS: Clinical Dementia Rating Scale; MMSE: Mini Mental State Examination; OR: Odd Ratio; CI:

Confidence Intervals; CODP: Chronic obstructive pulmonary disease; n=number of observations.

At the multivariate analysis, adjusting for age, all the associations between comorbidities and sex recorded at the univariate analysis were confirmed, except for hypertension. However, the association between higher CDRS and female sex was not confirmed, after adjusting for age and disease duration (table 3).

Table 3.

Demographic and clinical characteristics: sex differences, multivariate analysis

  Multivariate analysis (adj for age)
  OR 95%CI p-value
CDRS (n=407) 0.8 0.68-1.06 0.154*
Systemic illnesses      
Hypertension (obs=400) 0.7 0.42-1.08 0.106
Atrial fibrillation (n=400) 2.6 1.51-4.63 0.001
Myocardial infarction (n=400) 5.6 2.26-13.73 <0.001
Cardiac surgery (n=399) 7.7 2.40-24.71 0.001
Diabetes (n=400) 3.9 1.56-9.93 0.004
Thyroid disorders (n=400) 0.3 0.11-0.78 0.015
COPD (n=400) 3.0 1.23-7.27 0.015
Voluptuary habits      
Previous tobacco intake (n=381) 3.2 2.02-5.09 <0.001
Beer intake (n=396) 4.7 2.18-10.26 <0.001
Wine intake (n=398) 2.0 1.16-3-58 0.013
Neuropsychiatric features      
Depression (n=382) 0.5 0.28-0.80 0.005
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Legend: CDRS: Clinical Dementia Rating Scale; COPD: Chronic Obstructive Pulmonary Disease; OR: Odd Ratio; CI: Confidence Intervals. *Adjusted for age and disease duration.

Eighty-six subjects (63 women, mean age at clinical assessment time 78.0±9.1 years, mean disease duration at clinical assessment time 7.6±4.8 years) selected in the present study underwent autopsy diagnostic confirmation. Due to the small sample size, only a descriptive statistical analysis was performed. However, a higher rate of hypertension, thyroid disorders and depression among women and atrial fibrillation, cardiac surgery, myocardial infarction, COPD and diabetes among men was confirmed (figure 1).

Figure 1.

Figure 1.

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Comorbidity in the autopsy confirmed Alzheimer’s disease: sex differences

Discussion

Differences in clinical presentation of AD pose significant challenges to understanding the complex relationship between health disparities, which is essential to advance precision medicine, facilitating personalized approaches to prevention, early detection, drug development and disease-modifying treatments. In our study, the prevalence of comorbidities in patients with AD were explored.

According to the US Department of Health and Human Services, several chronic conditions were reported to be common in the general population over the age of 65, including hypertension (59%), hypercholesterolemia (48%), arthritis (48%), cancer (26%), diabetes (20%), chronic lung disease (10%), and myocardial infarction (8%). In addition, more than 10% of adults aged 65 and over reported taking medication for depression or anxiety (Administration for Community Living, 2024). Interestingly, it should be noted that the prevalence of the above chronic conditions in our cohort was lower than that reported by the US Department of Health and Human Services. This finding may be related to a difference in survival between patients with and without AD. In our cohort there may indeed be an overrepresentation of ‘healthier’ individuals with a lower prevalence of comorbidities and mortality rate.

Notably, in our cohort, comorbidities had a specific sex-related prevalence. In particular, heart diseases s (ie atrial fibrillation, myocardial infarction, and previous cardiac surgery), COPD and diabetes were more common in men, whereas thyroid disorder and depression were more common in women, even after controlling for possible stratification factors.

prevalence of chronic diseases is increasing. Previous studies have reported that older men are healthier than older women, despite the fact that women tend to outlive men. This phenomenon is known as the 'male-female health-survival paradox' and is observed in the general population (Gordon & Hubbard, 2019) and in patients with AD (Merrick & Brayne, 2024).

These data are interesting given that studies evaluating sex differences in the prevalence of chronic medical disorders in older people are inconclusive. In particular, while depression and thyroid disorders are consistently reported to be more prevalent in women (Moore et al., 2012), the higher prevalence of and complications of heart diseases and diabetes in men are still debated (Kautzky-Willer et al., 2016; Woodward, 2019).

Considering the potential for a strong impact of comorbidities in AD occurrence, severity, and management, the identification of potentially modifiable or treatable associated medical conditions may improve clinical outcomes.

At the cellular and tissue level, several age-related biological mechanisms may be in fact responsible for a multi-system loss of reserve and function leading, in turn, to different brain and systemic illness (Fabbri et al., 2015). .

On this ground, previous studies have investigated not only the association between comorbidities and AD clinical presentation and severity, but also the role of comorbidities as risk factor for AD. However, only few studies focused on sex-differences, reporting inconclusive findings. Indeed, while some studies reported that hypertension was associated with greater risk of AD in women but not in men (Gabin et al., 2017; Gilsanz et al., 2017) other studies reported no sex-related differences (Alonso et al., 2009; Gottesman et al., 2017).

Similarly, data concerning heart disorders are far from conclusive. In our study, atrial fibrillation was more common among men than women. The Framingham Heart Study reported a different trend of association between atrial fibrillation and dementia depending on age and sex. In particular, in younger subjects, atrial fibrillation was associated with dementia only in men while, at older age, this association was recorded only in women (McGrath et al., 2022). Moreover, other studies reported not only a higher risk but also a faster cognitive decline progression in women with atrial fibrillation than men (Wood et al., 2023). Although the cross-sectional design of the present study did not allow us to infer a cause-effect relationship and makes comparison with longitudinal studies difficult, considering that men in our cohort were younger than women, our findings can be considered in line with literature data (McGrath et al., 2022).

In our study, we reported a higher prevalence of COPD in men than women, probably related to the higher percentage of tobacco smoking among the former. To date, no literature data concerning sex-differences in its prevalence in AD patients are available. However, a previous cross-sectional study reported worse performance in subjects with AD and COPD in comorbidity than in subjects without COPD, thus underlining the importance of a multidisciplinary monitoring in AD patients (Tondo et al., 2018).

Concerning diabetes, we observed a higher prevalence of diabetes among men than women. These data are interesting considering that the prevalence of T2DM and impaired glucose tolerance in the general population is 10% and 20% higher, respectively, in women than in men (Auryan & Itamar, 2008). Interestingly, some studies have reported that although rates of cognitive decline over time were similar for both sexes, diabetic women outperformed men in some cognitive domains, supporting some “cognitive advantage” for women with diabetes over men (Espeland et al., 2021). Therefore, diabetes comorbidity should prompt specific attention in men due to the negative prognostic effects (Biessels & Despa, 2018; Jash et al., 2020; Weiss et al., 2023).

In our cohort, a clinically relevant and lasting at least 2-week depression was more frequent among women, thus confirming that depression disproportionately affects women more than men, particularly during menopausal transition (Goldstein et al., 2014). To date, data concerning the association between AD and depression are inconsistent (Underwood et al., 2019). Indeed, while some studies reported that moderate depression (intended both as AD risk factor, prodromal symptoms or comorbid disorder) is more frequent among women than men (Nianogo et al., 2022), other studies reported that mild depressive disorder was associated with a higher risk of cognitive decline only in men (Forno, 2005; Nebel et al., 2018). Targeted and personalized treatment is therefore important (Haussmann & Donix, 2023; Matuskova & Vyhnalek, 2024; Serretti, 2024).

Finally, we found a higher prevalence of thyroid disorders in women. Previous studies have reported a higher prevalence of hypothyroidism among AD patients than controls, although conclusive data concerning sex-differences are not available (Salehipour et al., 2023). No conclusive literature data concerning the role of hyperthyroidism in dementia are available. However, considering that it is still uncertain whether thyroid dysfunction occurred before the onset of AD or represented an acknowledged consequence of medication such as quetiapine and lithium (Kakhki & Ahmadi-Soleimani, 2022; Khoodoruth et al., 2022), the dosage of thyroid hormones, especially in women, should be carried-out periodically. Several studies, in fact, reported the role of hypothyroidism in worsening cognitive performances (Chiovato et al., 2019).

We are aware that some limits should be considered when interpreting our findings. First, the cross-sectional nature of the study did not allow us to consider the role of comorbidities as risk factors for AD occurrence. Second, the presence of comorbidities was inferred by medical records and caregiver interview without performing laboratory and or instrumental evaluation (ie electrocardiogram, blood tests, blood pressure measurement, etc.). Finally, although a comprehensive neuropsychological assessment was assessed, due to the number of missing variables, it was not possible to investigate the possible sex specific association between comorbidities, impairment in specific cognitive domains and severity of cognitive decline.

However, to the best of our knowledge, this is the first study assessing the prevalence of several comorbidities in AD patients with a focus on sex and with an autopsy confirmed diagnosis.

Conclusions

Comorbidities are common in AD patients with a sex-related difference in prevalence. Considering that comorbidity may have consequences in terms of clinical outcomes, health equity, treatment choice, efficacy and risk of side effects, a comprehensive assessment of comorbidity in AD patients should be encouraged. Moreover, hormonal variations, lifestyle factors and potential disparities in access to health care may all play a role in shaping sex-differences in comorbidities.

Further longitudinal studies are needed to explore causal pathways and clarify the interplay between sex-related comorbidities and AD progression. Addressing these knowledge gaps could inform precision medicine approaches and promote appropriate healthcare strategies that better meet the different needs of men and women with AD.

Abbreviations

AD: Alzheimer’s disease

CDRS: Clinical Dementia Rating Scale

CI: Confidence Intervals

COPD: Chronic obstructive pulmonary disease

MMSE: Mini Mental State Examination

N: number of observations.

OR: Odd Ratio

Acknowledgments

Data for this publication were obtained from the NIMH Repository & Genomics Resource (supported by cooperative agreement U24 MH068457), a centralized national biorepository for genetic studies of psychiatric disorders. Data and biomaterials were collected in three projects that participated in the National Institute of Mental Health (NIMH) Alzheimer Disease Genetics Initiative. From 1991-98, the Principal Investigators and Co-Investigators were: Massachusetts General Hospital, Boston, MA, U01 MH46281, Marilyn S. Albert, Ph.D., and Deborah Blacker, M.D., Sc.D.; Johns Hopkins University, Baltimore, MD, U01 MH46290, Susan S. Bassett, Ph.D., Gary A. Chase, Ph.D., and Marshal F. Folstein, M.D.; University of Alabama, Birmingham, AL, U01 MH46373, Rodney C.P. Go, Ph.D., and Lindy E. Harrell, M.D.

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