The Contribution of Vascular Pathology Toward Cognitive Impairment in Older Individuals with Intermediate Braak Stage Tau Pathology

Abstract

Background:

The pathological features of Alzheimer’s disease (AD) are well described but little is known as to how both neurodegeneration and vascular changes might interact in causing cognitive impairment.

Objective:

The present study aims to investigate relationships between vascular and AD pathology in cognitively healthy and cognitively impaired individuals with a particular emphasis on those at intermediate Braak tau stages.

Methods:

We investigated the interplay between Braak tau stage and measures of vascular pathology as described by the vascular cognitive impairment neuropathology guidelines (VCING) in 185 brains from the Brains for Dementia Research programme and The University of Manchester Longitudinal Study of Cognition in Healthy Old Age. VCING asserts that at least one large (>10 mm) infarct, moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, and moderate/severe arteriosclerosis in occipital white matter accurately predicts the contribution of cerebrovascular pathology to cognitive impairment.

Results:

We found that the extent of arteriosclerosis in the occipital white matter did not differ between cognitive groups at intermediate (III-IV) Braak stages whereas moderate/severe leptomeningeal occipital cerebral amyloid angiopathy was greater in cognitively impaired than normal individuals at Braak stage III-IV. This finding remained significant after controlling for effects of age, sex, CERAD score, Thal phase, presence/severity of primary age-related tauopathy, presence/severity of limbic-predominant age-related TDP43 encephalopathy and small vessel disease in basal ganglia.

Conclusion:

Interventions targeting cerebral amyloid angiopathy may contribute to delay the onset of cognitive impairment in individuals with intermediate Alzheimer’s type pathology.

Keywords

Alzheimer’s disease cerebral amyloid angiopathy cognition dementia neuropathology

INTRODUCTION

The relationships between cognitive trajectories and pathological features are ideally explored in longitudinal studies, which have brain donation and postmortem brain examination as an end point [1 –13]. In a recent study based on The University of Manchester Longitudinal Study of Cognition in Healthy Old Age (UMLCHA), no clear single pathological cause of cognitive impairment could be determined for 10% of cognitively impaired individuals [11]. In these cases, low loads of misfolded tau, amyloid-β (Aβ), alpha-synuclein, and pathological changes in brain vessels may have combined to cause cognitive impairment. Other longitudinal studies on aged individuals have had similar findings [2 , 15] indicating a need to explore the synergistic contribution of vascular co-morbidity.

Braak staging [16] measures the progression of misfolded tau accumulation where higher stages denote more advanced Alzheimer’s disease (AD) pathology. Previous studies [17] have suggested that Braak stage III is an important point of transition in the progression of AD. It is of note that some individuals at this Braak stage display cognitive impairment whereas others do not. Various factors have been examined to understand this discrepancy, including insulin resistance [18] and oxidative stress [19], but the full impact of vascular pathology on the cognitive status of individuals at intermediate Braak stages remains to be thoroughly investigated.

Attempts have previously been made to elucidate the relationships between Braak stage, cerebral amyloid angiopathy (CAA), and cognitive impairment. A recent study based on the Religious Orders Study cohort [20] observed that individuals with CAA were more likely to be at Braak stage III than those without CAA. These individuals were also more likely to score lower on test of global cognition and memory suggesting that CAA has an effect on cognition in individuals at Braak stage III.

A multicenter study [21], Vascular Cognitive Impairment Neuropathology Guidelines (VCING), aimed to elucidate which of the various vascular pathologies best predicted cognitive impairment. The authors found that at least one large (>10 mm) infarct, moderate/severe occipital leptomeningeal CAA, and moderate/severe arteriosclerosis in occipital white matter (WM) could accurately predict the contribution of cerebrovascular pathology to cognitive impairment. Thus, VCING measures can act as surrogate markers for extent of vascular cognitive impairment and also for the extent of CAA or SVD within the brain as a whole. VCING criteria established the main pathological changes in vessels that are responsible for cognitive impairment. However, the study did not take into account the impact of co-existent pathologies on the cognitive status.

In this study, we have investigated the interplay between tau-related pathology, as measured by Braak stage, and the changes in vascular pathology according to VCING criteria, in both cognitively normal and cognitively impaired individuals recruited in the Manchester arm of the Brains for Dementia Research (BDR) program and UMLCHA study. We focused principally on those individuals with AD pathology (without concomitant or secondary pathologies) and those with aging-related pathology only. We also focused on cases showing a mismatch between clinical phenotype and the extent of AD features at postmortem examination. We hypothesized that vascular changes as measured by VCING may drive dementia in those individuals where AD pathology alone would not explain their cognitive impairment. We found that concomitant occipital leptomeningeal CAA, rather than coincidental arteriosclerosis in the occipital WM, could explain why some individuals with intermediate levels of tau pathology were cognitively impaired while others with the same tau load were cognitively normal.

MATERIAL AND METHODS

The present study combines the UMLCHA and the Manchester arm of the BDR cohorts. Details concerning clinical characteristics and neuropathological features of these cohorts have been presented by the authors elsewhere [10 –12].

For the UMLCHA, cognitive status at death was assigned using a combination of last modified Telephone Instrument for Cognitive Status (TICSm) score (cut off point of 21), patient notes obtained via the participants’ general practitioner, cause of death as recorded on the death certificate and information gained from the Brain Bank Coordinator (SCG). Using cognitive status at death and neuropathological findings, diagnostic accuracy was approximately 74% within the ULMCHA. For the BDR, participants underwent cognitive assessments either via telephone interview (for those individuals without memory problems, participants without a significant hearing impairment, study partners for control participants, for follow up and retrospective interviews of control participants), or via a visit to the participant’s home (for the initial control visit, people with an existing diagnosis of dementia and controls with a significant hearing problem). Cognitive status was assigned using the Clinical Dementia Rating with a cut-off point of 0.5. Details of cognitive assessments have been previously described [12]. Using cognitive status at death and neuropathological findings, diagnostic accuracy was approximately 71% within the BDR cohort.

Neuropathological assessment

One hemi-brain was fixed in 10% neutral buffered formalin for 3–4 weeks; the other hemi-brain was frozen at –80°C. Standard blocks of frontal (mid frontal and superior frontal gyri), cingulate, temporal (including superior and middle temporal gyrus), inferior parietal and occipital cortex, entorhinal cortex and hippocampus, amygdala, corpus striatum (caudate nucleus, putamen, and globus pallidus), thalamus, midbrain (to include substantia nigra, III cranial nerve nucleus and red nucleus), brainstem (to include locus coeruleus and dorsal vagal nucleus), and cerebellum with the dentate nucleus were cut from the fixed tissue and processed into wax blocks. One section was stained with hematoxylin-eosin and further sections (6μm) were immunostained for Aβ (Cambridge Bioscience, monoclonal antibody 4G8, 1:3000), tau proteins phosphorylated at Ser202 and Thr205 (P-tau) (Innogenetics, monoclonal antibody AT8, 1:750), phosphorylated α-synuclein (rabbit polyclonal antibody #1175, 1:1000) (kind gift of Dr. Masato Hasegawa at Tokyo Metropolitan Institute of Medical Science, Japan) and phosphorylated and non-phosphorylated TDP-43 (polyclonal antibody, 10782-2-AP, Proteintech, Manchester, 1:1000). For antigen retrieval, sections were either immersed in 70% formic acid for 20 min (for Aβ) or (for the other antibodies) treated in microwave oven or pressure cooker (for 30 min, reaching 120°C and >15 kPa pressure) in 0.1 M citrate buffer, pH 6.0, prior to incubation with primary antibody.

Vascular pathologies were assessed following the VCING criteria [21] including the presence or absence of 1) one or more large (>10 mm) cerebral infarcts; 2) moderate or severe occipital leptomeningeal CAA (Fig. 1); and 3) moderate or severe occipital WM arteriosclerosis. As well as the binary scores for individual VCING measures, an overall VCING likelihood (Low, Moderate, or High) that cerebral vascular disease contributed to cognitive impairment was attributed to each case. In addition, small vessel disease (SVD) in basal ganglia (BG) was also semi-quantitatively assessed (0 –None; 1 –Mild; 2 –Moderate; 3 –Severe). Cohen’s κ was conducted on a random subset of cases (n = 40) to determine inter-rater reliability of semi-quantitative scores for SVD in BG. There was moderate agreement between the scores of the two neuropathologists (κ= 0.510, p < 0.001).

Fig. 1

Example of mild (A), moderate (B), and severe (C) occipital leptomeningeal CAA (Case numbers 17/32, 18/09 and 16/45, respectively).

By analyzing the immunostained sections, we were able use consensus criteria to establish the presence and staging of neurodegenerative diseases such as AD [22], dementia with Lewy bodies (DLB)/Parkinson’s disease [23 –25], frontotemporal lobar degeneration [26, 27], corticobasal degeneration (CBD) [28], progressive supranuclear palsy (PSP) [29], multiple system atrophy (MSA) [30], argyrophilic grain disease (AGD) [31], primary aging-related tauopathy (PART) [32], age related tau astrogliopathy [33], and limbic-predominant age-related TDP-43 encephalopathy (LATE) [34].

For the purpose of this study, we excluded all cases where the primary neuropathological diagnosis was not AD (DLB/PD = 42; AGD = 4; CBD = 4; PSP = 3; FLTD = 3; MSA = 1; No available diagnosis = 2) and also excluded AD cases where there was any concomitant or secondary pathology (other than CAA or SVD; n = 45). We included cases of PART and LATE due to the fact that they are common aging-related conditions. However, to avoid skewing results, we ensured that the presence and staging of PART and LATE pathologies was included in regression analyses. Although all brain regions were used in neuropathological diagnosis to enable the inclusion of relevant cases, brain regions relevant to Braak staging and VCING were the main focus of the present study.

The two ongoing cohorts currently comprise 289 subjects. After applying the above exclusion criteria, a total of 185 participants (87 BDR and 98 UMLCHA) were considered eligible for the present study (Supplementary Table 1).

Neuropathological diagnoses were assigned by experienced neuropathologists (DM & FR).

Genetic analysis

DNA was extracted from frozen brain tissue using REDExtract-N-Amp™ Tissue PCR Kit (Sigma) or from previously obtained blood samples (3 cases from UMLCHA). The APOE genotype was determined using routine polymerase chain reaction (PCR) methods [35]. APOE genotype could not be determined for 2 UMLCHA and 5 BDR participants due to lack of frozen brain tissue or blood samples.

Statistical analysis

Pearson’s Chi-squared test was used to compare demographic features and to analyze whether there were differences in vascular markers (as measure by VCING) between the various Braak stage groups. Fisher’s Exact test was used when the expected count was less than five.

Logistic regression was used to investigate whether adjustment for sex, age at death, presence of APOE ɛ4 allele(s), CERAD score [36], Thal phase [37], PART [32], LATE-NC [34], and SVD in BG made any difference to significant outcomes when analyzing VCING measures between cognitive status groups.

A p value of <0.05 was considered significant for all tests.

RESULTS

Demographics

The demographics of eligible participants, split by cohort, are shown in Table 1. Of the 185 eligible participants, 111 (60%) were female. 86 of the eligible participants (47%) had cognitive impairment/dementia whereas 99 (53%) remained cognitively unimpaired. Of the 182 participants who were genotyped for APOE, 66 (36%) carried one or more APOE ɛ4 allele(s). The mean age at death of eligible participants was 84.9±9.7 (BDR 80.5±11.2; UMLCHA 88.8±5.8).

Table 1

Demographics of the 185 eligible participants split by cohort (BDR, Brains for Dementia Research cohort; UMLCHA, The University of Manchester Longitudinal Study of Cognition in Healthy Old Age cohort)

	BDR		ULMCHA		P
	N	%	N	%
Sex
Male	45	51.7	29	29.6	0.002
Female	42	48.3	69	70.4
Cognitive status
Normal	30	34.5	69	70.4	<0.001
Impaired	57	65.5	29	29.6
Presence of
APOEɛ4 allele(s)
Absent	45	51.7	71	72.4	0.008
Present	39	44.8	27	27.6
Missing	3	3.4	0	0

In order to investigate the impact of VCING pathology in participants with cognitive impairment where tau-related pathology was insufficient to meet criteria for AD, scores for vascular pathology for both cognitively impaired and cognitively normal eligible participants in the BDR and the UMLCHA cohorts were compared according to Braak stage grouped into 0–II, III-IV and V-VI. To do this, we assessed the brain regions specified in Braak staging and in VCING criteria.

Braak tau stage and VCING

Braak tau stage and VCING of eligible participants, split by cohort and cognitive status, are shown in Table 2. Of the 185 eligible participants, 99 were considered cognitively unimpaired and 86 were considered cognitively impaired. Of those considered cognitively unimpaired, 82 were Braak stage 0–II and 17 were Braak stage III-IV. Of those considered cognitively impaired, 13 were Braak stage 0–II, 36 were Braak stage III-IV and 37 were Braak stage V-VI. The majority (77.9%) of cognitively impaired individuals were considered to have a low likelihood that cerebral vascular disease contributed to cognitive impairment according to the VCING criteria.

Table 2

Distribution of Braak tau staging and VCING of the 185 eligible participants split by cohort and cognitive status (BDR, Brains for Dementia Research cohort; UMLCHA, The University of Manchester Longitudinal Study of Cognition in Healthy Old Age cohort)

	BDR				ULMCHA				Combined cohorts
	Cognitively unimpaired		Cognitively impaired		Cognitively unimpaired		Cognitively impaired		Cognitively unimpaired		Cognitively impaired
	N	%	N	%	N	%	N	%	N	%	N	%
Braak tau stage
0 –II	27	90.0	7	12.3	55	79.7	6	20.7	82	82.8	13	15.1
III - IV	3	10.0	19	33.3	14	20.3	17	58.6	17	17.2	36	41.9
V - VI	0	0	31	54.4	0	0	6	20.7	0	0	37	43.0
VCING
Low	25	83.3	45	78.9	56	81.2	22	75.9	81	81.8	67	77.9
Moderate	3	10.0	9	15.8	9	13.0	3	10.3	12	12.1	12	14.0
High	2	6.7	3	5.3	4	5.8	4	13.8	6	6.1	7	8.1

Comparisons of vascular pathology between Braak stage groups

Initially, comparisons between Braak stage groups and VCING measures were made irrespective of the presence or absence of cognitive impairment. This analysis showed significant increases in the level of leptomeningeal CAA in the occipital lobe between Braak tau stages 0–II, and stages III-IV (p < 0.001) and also stages V-VI (p < 0.001), but not between stages III-IV and V-VI (p = 0.970) (Fig. 2A). Finally, there were significant differences found for total VCING scores between stages 0–II and stages III-IV (p = 0.024) (Fig. 2B). No differences between Braak stage groups were observed for presence of infarction or moderate/severe occipital WM arteriosclerosis.

Fig. 2

Comparisons of vascular measures (presence or absence of i) one or more large (>10 mm) cerebral infarcts; ii) moderate or severe occipital leptomeningeal CAA (Fig. 1); iii) moderate or severe occipital WM arteriosclerosis) between each Braak stage group, irrespective of presence/absence of cognitive impairment. A) Individual VCING measures. B) VCING score showing likelihood that cerebrovascular disease contributed to cognitive impairment.

Comparisons of vascular pathology between cognitively normal and cognitively impaired individuals at each Braak tau stage

The whole cohort of 185 participants was then stratified into cognitively impaired (n = 86) and cognitively normal (n = 99) subgroups. When comparing cognitively impaired and cognitively normal individuals at Braak stage 0–II, no significant differences were found for infarctions (p = 0.720) (Fig. 3A), moderate to severe occipital CAA (p = 0.149) (Fig. 3B), moderate to severe occipital WM arteriosclerosis (p = 0.062) (Fig. 3C), or total VCING scores (p = 0.896) (Fig. 3D). When comparing cognitively impaired and cognitively normal individuals at Braak stages III-IV, moderate to severe occipital CAA was significantly increased in the cognitively impaired subgroup when compared with the cognitively unimpaired subgroup (p = 0.049) (Fig. 3B). There were no such differences for infarcts (p = 0.642) (Fig. 3A), moderate to severe occipital WM arteriosclerosis (p = 0.447) (Fig. 3C) or total VCING scores (p = 0.933) (Fig. 3D). As there were no cognitively normal individuals at Braak stages V-VI, comparisons between the cognitive groups could not be made.

Fig. 3

Comparisons of vascular measures between cognitively unimpaired (white) and cognitively impaired (black) members of each Braak stage group. A) Presence of one or more large (>10 mm) cerebral infarcts. B) Presence of moderate or severe occipital leptomeningeal CAA. C) Presence of moderate or severe occipital WM arteriosclerosis. D) VCING score showing likelihood that cerebrovascular disease contributed to cognitive impairment. Note: The influence of sex, age at death, presence of APOE ɛ4 allele(s), Thal phase, CERAD score, presence/severity of PART pathology, presence/severity of LATE pathology, and SVD in BG did not alter the significant outcomes found for moderate or severe occipital leptomeningeal CAA at Braak stages III-IV between cognitively impaired and cognitively unimpaired individuals.

Comparisons between Braak stage III and Braak stage IV

There were no significant differences in age at death, sex, or cognitive impairment between individuals at Braak stage III and Braak stage IV. Likewise, there were no significant differences in any of the vascular measures assessed between individuals at Braak stage III and Braak stage IV.

Regression analyses

Regression analysis showed that sex, age at death, presence of APOE ɛ4 allele(s), CERAD score, Thal phase, PART, LATE-NC, and SVD in BG had no effect on the outcome of significant results found for moderate to severe occipital CAA at Braak stages III-IV between cognitively impaired and cognitively normal individuals (OR = 4.379; p = 0.049) (Table 3).

Table 3

Regression analysis model for Braak stages III-IV. The significant difference in moderate or severe occipital leptomeningeal CAA between cognitively normal and cognitively impaired individuals remains after controlling for sex, age at death, presence of APOE ɛ4 allele(s), CERAD score, Thal phase, PART, LATE-NC, and SVD in BG

	OR	95% C.I.	P
Moderate or severe occipital leptomeningeal CAA	4.379	1.008–19.021	0.049
Sex	0.429	0.092–1.996	0.281
Age at death	0.968	0.863–1.087	0.584
Presence of APOEɛ4 allele(s)	0.685	0.116–4.051	0.677
CERAD score	0.547	0.144–2.080	0.376
Thal phase	1.630	0.502–5.294	0.416
LATE-NC	1.766	0.386–8.081	0.463
PART	0.966	0.037–25.481	0.984
SVD in BG	0.508	0.215–1.199	0.122

DISCUSSION

A correlation with dementia can only be established in brains of those individuals with extensive accumulation of misfolded tau in the neocortex (higher than Braak stage IV). Conversely, intermediate Braak stages (III–IV) can be seen in either cognitively impaired or cognitively normal subjects. Consequently, we tested for associations between the extent of tau, measured by Braak stage, and vascular pathology, measured by VCING, to assess the impact of vascular changes in cognitively impaired individuals at Braak stages III-IV. Owing to the differences in cognitive testing between BDR and UMLCHA cohorts, it was not possible to use an individual test score to set a threshold for cognitive impairment. However, the final decision of whether an individual had been cognitively impaired in life came from clinicians heavily involved in each study. Thus, a high clinical/neuropathological diagnostic concordance was achieved in each of the cohorts.

In the present study, moderate/severe occipital leptomeningeal CAA in the occipital lobe was the most important finding with regard to potential associations between Braak tau stages and measures of vascular pathology in cognitively impaired and normal individuals. Occipital leptomeningeal CAA was more severe in the cognitively impaired than in cognitively healthy individuals who were at Braak tau stages III-IV, a finding which is supported by a recent work on participants in the Religious Orders Study [20]. Most importantly, this correlation remained valid after controlling for the effects of age at death, sex, presence of APOE ɛ4 allele(s), CERAD score, Thal phase, presence/severity of PART pathology, presence/severity of LATE pathology, and SVD in BG indicating that it is specifically CAA and not overall Aβ pathology (or PART/LATE pathology) that is contributing to cognitive status in individuals at Braak tau stages III-IV. It is worthy of note that there were no demographic or VCING differences between individuals at Braak stage III and Braak stage IV.

As expected, the degree of occipital leptomeningeal CAA was greater at Braak stages III-IV and Braak stages V-VI than in Braak stages 0–II. The extent of occipital leptomeningeal CAA in cognitively impaired individuals at Braak stages III-IV was significantly greater than that in cognitively normal individuals at that same Braak stage.

Why CAA found in the posterior part of the brain contributes to the largely frontal/temporal manifestations of cognitive impairment is unclear. It has been previously shown that CAA-induced tau phosphorylation can lead to tau-associated neurotoxicity [38]. Thus, there could be increased levels of tau-associated neurotoxicity in those individuals with CAA at Braak stages III-IV, which may render them more likely to be cognitively impaired. Also, in the present study, we analyzed only occipital leptomeningeal CAA as this was deemed to be the most clinically relevant. However, the accepted VCING model, which used the three criteria described in the present study, was the most accurate when analyzing the impact of vascular pathology on cognition. Therefore, moderate to severe occipital leptomeningeal CAA may act as a ‘surrogate’ marker for CAA in the brain as a whole.

The lack of significant contribution of moderate/severe occipital WM arteriosclerosis to the generation of cognitive impairment in those individuals with intermediate Braak tau stages may reflect the overall paucity of extensive occipital WM arteriosclerosis among the participants whether or not they were cognitively impaired. Indeed, only 28.6% of the participants exhibited moderate to severe occipital WM arteriosclerosis (26.3% of cognitively normal individuals and 31.4% of cognitively impaired individuals). It is worthy of note that most participants who suffered from hypertension within the BDR cohort had been treated with anti-hypertensive medication, thereby militating against the development of arteriosclerotic changes in cerebral blood vessels and resulting in the surprisingly low prevalence of moderate to severe occipital WM arteriosclerosis among the participants irrespective of cognitive status. The same details on anti-hypertensive therapy available for individuals within BDR cohort was not available for most individuals within UMLCHA cohort. However, we can infer that similar protective effects would have occurred in UMLCHA individuals as they would have been treated in a similar way. The evidence in the literature of fewer WM hyperintensities on MRI in individuals treated with anti-hypertensive drugs compared to those not treated [39, 40] supports this suggestion. Aging-related changes, including SVD, do not necessarily contribute to the progression or drive an intermediate, non-clinical Alzheimer-type pathology toward established AD with clinical dementia.

The underlying cause of CAA still remains uncertain. It has been suggested [41 –44] that the lack of pulsation in cerebral blood vessels affected by arteriosclerosis may facilitate the development of CAA by restricting the efflux of extracellular fluid containing Aβ peptides, especially Aβ₄₀, from the brain thereby promoting their aggregation and deposition within the wall of small arteries and arterioles. On face value, our study might argue against this hypothesis as although there were clear significant differences in CAA between Braak stages and between cognitively impaired and unimpaired individuals at Braak stages III-IV, there were no such significant findings regarding moderate/severe occipital WM arteriosclerosis between cognitively impaired and cognitively normal individuals at any Braak stage. Although moderate/severe occipital WM arteriosclerosis is only one measure of SVD and it does not provide an overall picture of severity of SVD, it was previously shown to associate with cognitive impairment [21]. In addition, the effect of SVD in BG did not alter the significant findings regarding CAA and cognition at intermediate Braak stages.

This study has some general limitations. As mentioned previously, clinical diagnosis was not entirely uniform due to the amalgamation of two separate studies into one cohort. However, the use of patient notes, cause of death, cognitive assessment, and clinical team records allowed the final cognitive diagnosis to be robust for both cohorts. There is always a chance that recruitment strategies can introduce bias. For example, it could be said that the geographical areas covered by BDR (North of England) and UMLCHA (Greater Manchester and Newcastle) may not reflect society as a whole. This could be addressed by future studies by adopting different strategies and, perhaps, recruiting individuals from a wider geographical area. During the conception stage, VCING criteria assessed the impact of many common vascular pathologies before concluding which were most relevant to cognition [21]. However, there is the possibility that vascular pathologies which fall outside the remit of VCING criteria (for example, small/lacunar infarctions or CAA in regions other than the occipital lobe) may interact with one another resulting in a change in cognition. Though this is outside the remit of the present study, any such interactions could be studied in future projects. However, it is important to note that VCING is the current consensus criteria and clearly outlines which vascular pathologies have the greatest effect on cognition. Finally, Braak staging is based on tau pathology as seen in AT8 immunostain. There is no clear proof that accumulations of amorphous, unaggregated tau in neurons renders them totally incapable of neurotransmission, though their functions may be limited. It is possible that cognitively normal individuals at Braak stage III-IV may actually have very few bona fide tangle-bearing cells. On the other hand, cognitively impaired people at Braak stage III-IV may have plenty of tangles which could help to explain the cognitive deficit. Future studies could address this by using a silver-based staining method, specific for neurofibrillary tangles, and comparing tangle load between cognitively normal and cognitively impaired individuals at Braak stage III-IV.

Strengths of the study include the use VCING as up-to-date consensus criteria to assess the contribution of cerebrovascular pathology to cognitive impairment. This surpasses previous similar studies which only looked at one measure of vascular pathology in isolation [20]. In addition, there was robust, uniform neuropathological assessment which allowed the two different cohorts to be merged into one larger study set for the present study.

In conclusion, the assessment of VCING criteria showed that moderate to severe occipital leptomeningeal CAA was an important determinant of cognitive status while the other VCING measures were less relevant. Thus, the presence and severity of occipital CAA might explain why some individuals with intermediate Alzheimer-type pathology are cognitively impaired and others remain cognitively normal. This effect appeared to be independent of moderate/severe occipital WM arteriosclerosis, which was equally common among cognitively impaired and cognitively normal individuals with intermediate Alzheimer-type pathology. It is difficult to comment on the mechanisms which link intermediate tau pathology and CAA-related pathology. Nonetheless we can speculate that age-related reduction in ‘cerebral reserve’ such as neuroinflammation and synaptic damage could combine to tip the balance toward cognitive impairment. Our study suggests that interventions to reduce CAA-related pathology may impact on cognitive impairment in those individuals with intermediate misfolded tau load.

Research ethics committee approval

The study was approved by Manchester Brain Bank Management Committee (REC reference 19/NE/0242). Under conditions agreed with the Research Ethics Committee, The Manchester Brain Bank can supply tissue or data to researchers, without requirement for researchers to apply individually to the REC for approval.

Footnotes

ACKNOWLEDGMENTS

Longitudinal Cognitive studies were funded by Medical Research Council, Economic and Social Research Council, The Wellcome Trust (grant reference number 003889) and Unilever PLC.

The work of Manchester Brain Bank is supported by Alzheimer’s Research UK and Alzheimer’s Society through the Brains for Dementia Research (BDR) Programme.

We also thank Daniel du Plessis and Piyali Pal for their help and assistance with neuropathology.

Authors’ disclosures available online ().

The supplementary material is available in the electronic version of this article: .

References

Matthews

, Brayne

, Lowe

, McKeith

, Wharton

, Ince

(2009) Epidemiological pathology of dementia: Attributable-risks at death in the Medical Research Council Cognitive Function and Ageing Study. PLoS Med 6, e1000180.

Neuropathology Group. Medical Research Council Cognitive Function and Aging Study (2001) Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Lancet 357, 169–175.

Snowden

, Nun Study (2003) Healthy aging and dementia: Findings from the Nun Study. Ann Intern Med 139, 450–454.

Bennett

, Schneider

, Arvanitakis

, Wilson

(2012) Overview and findings from the religious orders study. Curr Alzheimer Res 9, 628–645.

Cambridge City over 75 Cohort Study (2005) Cambridge City over 75 Cohort Study, http://www.cc75c.group.cam.ac.uk. Accessed January 19, 2018.

Gelber

, Launer

, White

(2012) The Honolulu-Asia Aging Study: Epidemiologic and neuropathologic research on cognitive impairment. Curr Alzheimer Res 9, 664–672.

Kukull

, Higdon

, Bowen

, McCormick

, Teri

, Schellenberg

, van Belle

, Jolley

, Larson

(2002) Dementia and Alzheimer disease incidence: A prospective cohort study. Arch Neurol 59, 1737–1746.

National Institute on Ageing (2013) Baltimore Longitudinal Study of Ageing, https://www.blsa.nih.gov. Accessed January 19, 2018.

Oxford Project to Investigate Memory and Ageing (2016) OPTIMA, http://www.ndcn.ox.ac.uk/research/centre-prevention-stroke-dementia/resources/optima-oxford-project-to-investigate-memory-and-ageing. Accessed January 19, 2018.

10.

Rabbitt

PMA

, McInnes

, Diggle

, Holland

, Bent

, Abson

, Pendleton

, Horan

(2004) The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, 1983 through 2003. Aging Neuropsychol Cogn 11, 245–279.

11.

Robinson

, Davidson

, Horan

, Pendleton

, Mann

DMA

(2018) Pathological correlates of cognitive impairment in The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age. J Alzheimers Dis 64, 483–496.

12.

Robinson

, Chew-Graham

, Davidson

, Horan

, Roncaroli

, Minshull

, du Plessis

, Pal

, Payton

, Pendleton

, Mann

DMA

(2020) A comparative study of pathological outcomes in The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age and Brains for Dementia Research Cohorts. J Alzheimers Dis 73, 619–632.

13.

University of Helsinki (2006) The Vantaa 85+study, http://www.hi.helsinki.fi/english/research/groups/pathology/vantaa85study.html. Accessed January 19, 2018.

14.

Sonnen

, Larson

, Crane

, Haneuse

, Li

, Schellenberg

, Craft

, Leverenz

, Montine

(2007) Pathological correlates of dementia in a longitudinal, population-based sample of aging. Ann Neurol 62, 406–413.

15.

Xuereb

, Brayne

, Dufouil

, Gertz

, Wischik

, Harrington

, Mukaetova-Ladinska

, McGee

, O’Sullivan

, O’Connor

, Paykel

, Huppert

(2000) Neuropathological findings in the very old. Results from the first 101 brains of a population-based longitudinal study of dementing disorders. Ann N Y Acad Sci 903, 490–496.

16.

Braak

, Braak

(1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82, 239–259.

17.

Carlson

, Gatz

, Pedersen

, Graff

, Nennesmo

, Lindstrom

, Gerritsen

(2015) Antemortem prediction of Braak stage. J Neuropathol Exp Neurol 74, 1061–1070.

18.

Kulstad

, Green

, Cook

, Watson

, Reger

, Baker

, Plymate

, Asthana

, Rhoads

, Mehta

, Craft

(2006) Differential modulation of plasma beta amyloid by insulin in patients with Alzheimer disease. Neurology 66, 1506–1510.

19.

Mufson

, Ikonomovic

, Counts

, Perez

, Malek-Ahmadi

, Scheff

, Ginsberg

(2016) Molecular and cellular pathophysiology of preclinical Alzheimer’s disease. Behav Brain Res 311, 54–69.

20.

Malek-Ahmadi

, Perez

, Chen

, Mufson

(2020) Braak stage, cerebral amyloid angiopathy, and cognitive decline in early Alzheimer’s disease. J Alzheimers Dis 74, 189–197.

21.

Skrobot

, Attems

, Esiri

, Hortobágyi

, Ironside

, Kalaria

, King

, Lammie

, Mann

, Neal

, Ben-Shlomo

, Kehoe

, Love

(2016) Vascular cognitive impairment neuropathology guidelines (VCING): The contribution of cerebrovascular pathology to cognitive impairment. Brain 139, 2957–2969.

22.

Montine

, Phelps

, Beach

, Bigio

, Cairns

, Dickson

, Duyckaerts

, Frosch

, Masliah

, Mirra

, Nelson

, Schneider

, Thal

, Trojanowski

, Vinters

, Hyman

; National Institute on Aging; Alzheimer’s Association (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: A practical approach. Acta Neuropathol 123, 1–11.

23.

McKeith

, Galasko

, Kosaka

, Perry

, Dickson

, Hansen

, Salmon

, Lowe

, Mirra

, Byrne

, Lennox

, Quinn

, Edwardson

, Ince

, Bergeron

, Burns

, Miller

, Lovestone

, Collerton

, Jansen

, Ballard

, de Vos

, Wilcock

, Jellinger

, Perry

(1996) Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the consortium on DLB international workshop. Neurology 47, 1113–1124.

24.

McKeith

, Dickson

, Lowe

, Emre

, O’Brien

, Feldman

, Cummings

, Duda

, Lippa

, Perry

, Aarsland

, Arai

, Ballard

, Boeve

, Burn

, Costa

, Del Ser

, Dubois

, Galasko

, Gauthier

, Goetz

, Gomez-Tortosa

, Halliday

, Hansen

, Hardy

, Iwatsubo

, Kalaria

, Kaufer

, Kenny

, Korczyn

, Kosaka

, Lee

, Lees

, Litvan

, Londos

, Lopez

, Minoshima

, Mizuno

, Molina

, Mukaetova-Ladinska

, Pasquier

, Perry

, Schulz

, Trojanowski

, Yamada

; Consortium on DLB (2005) Diagnosis and management of dementia with Lewy bodies: Third report of the DLB Consortium. Neurology 65, 1863–1872.

25.

McKeith

, Boeve

, Dickson

, Halliday

, Taylor

, Weintraub

, Aarsland

, Galvin

, Attems

, Ballard

, Bayston

, Beach

, Blanc

, Bohnen

, Bonanni

, Bras

, Brundin

, Burn

, Chen-Plotkin

, Duda

, El-Agnaf

, Feldman

, Ferman

, Ffytche

, Fujishiro

, Galasko

, Goldman

, Gomperts

, Graff-Radford

, Honig

, Iranzo

, Kantarci

, Kaufer

, Kukull

, Lee

VMY

, Leverenz

, Lewis

, Lippa

, Lunde

, Masellis

, Masliah

, McLean

, Mollenhauer

, Montine

, Moreno

, Mori

, Murray

, O’Brien

, Orimo

, Postuma

, Ramaswamy

, Ross

, Salmon

, Singleton

, Taylor

, Thomas

, Tiraboschi

, Toledo

, Trojanowski

, Tsuang

, Walker

, Yamada

, Kosaka

(2017) Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology 89, 88–100.

26.

Mackenzie

, Neumann

, Bigio

, Cairns

, Alafuzoff

, Kril

, Kovacs

, Ghetti

, Halliday

, Holm

, Ince

, Kamphorst

, Revesz

, Rozemuller

, Kumar-Singh

, Akiyama

, Baborie

, Spina

, Dickson

, Trojanowski

, Mann

(2009) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: Consensus recommendations. Acta Neuropathol 117, 15–18.

27.

Mackenzie

, Neumann

, Baborie

, Sampathu

, du Plessis

, Jaros

, Perry

, Trojanowski

, Mann

, Lee

(2011) A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 122, 111–113.

28.

Dickson

, Bergeron

, Chin

, Duyckaerts

, Horoupian

, Ikeda

, Jellinger

, Lantos

, Lippa

, Mirra

, Tabaton

, Vonsattel

, Wakabayashi

, Litvan

; Office of Rare Diseases of the National Institutes of Health (2002) Office of Rare Diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol 61, 935–946.

29.

Hauw

, Daniel

, Dickson

, Horoupian

, Jellinger

, Lantos

, McKee

, Tabaton

, Litvan

(1994) Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology 44, 2015–2019.

30.

Trojanowski

, Revesz

; Neuropathology Working Group on MSA (2007) Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy. Neuropathol Appl Neurobiol 33, 615–620.

31.

Braak

, Braak

(1998) Argyrophilic grain disease: Frequency of occurrence in different age categories and neuropathological diagnostic criteria. J Neural Transm 105, 801–819.

32.

Crary

, Trojanowski

, Schneider

, Abisambra

, Abner

, Alafuzoff

, Arnold

, Attems

, Beach

, Bigio

, Cairns

, Dickson

, Gearing

, Grinberg

, Hof

, Hyman

, Jellinger

, Jicha

, Kovacs

, Knopman

, Kofler

, Kukull

, Mackenzie

, Masliah

, McKee

, Montine

, Murray

, Neltner

, Santa-Maria

, Seeley

, Serrano-Pozo

, Shelanski

, Stein

, Takao

, Thal

, Toledo

, Troncoso

, Vonsattel

, White

3rd , Wisniewski

, Woltjer

, Yamada

, Nelson

(2014) Primary age-related tauopathy (PART): A common pathology associated with human aging. Acta Neuropathol 128, 755–766.

33.

Kovacs

, Ferrer

, Grinberg

, Alafuzoff

, Attems

, Budka

, Cairns

, Crary

, Duyckaerts

, Ghetti

, Halliday

, Ironside

, Love

, Mackenzie

, Munoz

, Murray

, Nelson

, Takahashi

, Trojanowski

, Ansorge

, Arzberger

, Baborie

, Beach

, Bieniek

, Bigio

, Bodi

, Dugger

, Feany

, Gelpi

, Gentleman

, Giaccone

, Hatanpaa

, Heale

, Hof

, Hofer

, Hortobágyi

, Jellinger

, Jicha

, Ince

, Kofler

, Kövari

, Kril

, Mann

, Matej

, McKee

, McLean

, Milenkovic

, Montine

, Murayama

, Lee

, Rahimi

, Rodriguez

, Rozemüller

, Schneider

, Schultz

, Seeley

, Seilhean

, Smith

, Tagliavini

, Takao

, Thal

, Toledo

, Tolnay

, Troncoso

, Vinters

, Weis

, Wharton

, White

3rd , Wisniewski

, Woulfe

, Yamada

, Dickson

(2016) Aging-related tau astrogliopathy (ARTAG): Harmonized evaluation strategy. Acta Neuropathol 131, 87–102.

34.

Nelson

, Dickson

, Trojanowski

, Jack

, Boyle

, Arfanakis

, Rademakers

, Alafuzoff

, Attems

, Brayne

, Coyle-Gilchrist

ITS

, Chui

, Fardo

, Flanagan

, Halliday

, Hokkanen

SRK

, Hunter

, Jicha

, Katsumata

, Kawas

, Keene

, Kovacs

, Kukull

, Levey

, Makkinejad

, Montine

, Murayama

, Murray

, Nag

, Rissman

, Seeley

, Sperling

, White Iii

, Yu

, Schneider

(2019) Limbic-predominant age-related TDP-43 encephalopathy (LATE): Consensus working group report. Brain 142, 1503–1527.

35.

Wenham

, Price

, Blandell

(1991) Apolipoprotein E genotyping by one-stage PCR. Lancet 337, 1158–1159.

36.

Mirra

, Heyman

, McKeel

, Sumi

, Crain

, Brownlee

, Vogel

, Hughes

, van Belle

, Berg

(1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41, 479–486.

37.

Thal

, Rüb

, Orantes

, Braak

(2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58, 1791–1800.

38.

You

, Perkins

, Cisternas

, Munoz

, Taylor

, You

, Garringer

, Oblak

, Atwood

, Vidal

, Lasagna-Reeves

(2019) Tau as a mediator of neurotoxicity associated to cerebral amyloid angiopathy. Acta Neuropathol Commun 7, 26.

39.

Dufouil

, Chalmers

, Coskun

, Besançon

, Bousser

, Guillon

, MacMahon

, Mazoyer

, Neal

, Woodward

, Tzourio-Mazoyer

, Tzourio

; PROGRESS MRI Substudy Investigators (2005) Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: The PROGRESS (Perindopril Protection Against Recurrent Stroke Study) magnetic resonance imaging substudy. Circulation 112, 1644–1650.

40.

Firbank

, Wiseman

, Burton

, Saxby

, O’Brien

, Ford

(2007) Brain atrophy and white matter hyperintensity change in older adults and relationship to blood pressure. Brain atrophy, WMH change and blood pressure. J Neurol 254, 713–721.

41.

Herzig

, Van Nostrand

, Jucker

(2006) Mechanism of cerebral beta-amyloid angiopathy: Murine and cellular models. Brain Pathol 16, 40–54.

42.

Nicoll

JAR

, Yamada

, Frackowiak

, Mazur Kolecka

, Weller

(2004) Cerebral amyloid angiopathy plays a direct role in the pathogenesis of Alzheimer’s disease. Pro-CAA position statement. Neurobiol Aging 25, 589–597.

43.

Weller

, Subash

, Preston

, Mazanti

, Carare

(2008) Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathol 18, 253–266.

44.

Weller

, Massey

, Newman

, Hutchings

, Kuo

, Roher

(1998) Cerebral amyloid angiopathy: Amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer’s disease. Am J Pathol 153, 725–733.